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Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology

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Case report

Fibrous dysplasia of mandibleReport of a case presenting with a rare clinical course

Tadataka Tsuji a, , Susumu Tanaka a,b , Mitsunobu Kishino c , Mikihiko Kogo a
1st Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan Department of Dentistry, Oral and Maxillofacial Surgery, Osaka Police Hospital, Osaka 543-0035, Japan c Department of Oral Pathology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan
b a

a r t i c l e

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a b s t r a c t
Gnathic brous dysplasia (FD) and chronic diffuse osteomyelitis (CDO) are independent disease states which have overlapping clinical and radiographic characteristics. Diagnosis is crucial because of the different treatments needed for these clinical conditions. We report here a case of FD of the left mandible which followed a rare clinical course and the initial clinical symptoms and radiographic examination were misinterpreted as indicating CDO. A 28-year-old Japanese male was referred to our hospital due to a dull intermittent pain of the left mandibular molars in April 2002. From the clinical and radiographic examination results, we suspected CDO. Antibiotic treatment produced a remission of these symptoms and periodical follow-up was performed in another hospital. In March 2007 the patient returned with rm swelling in the left cheek region. Panoramic radiographic and CT examination revealed remarkable bony expansion with a thickened cortex and diffuse smoky mottled lucent-radiopaque appearance in the left molar region of the mandible. We suspected bro-osseous lesions of the mandible and surgical reduction was performed in January 2008. Histological examination revealed brous and bone tissue proliferation along with the chronic inammatory lesions and an absence of cortical bone. Mutational analysis demonstrated guanine nucleotide binding protein, alpha atimulating activity polypeptide (GNAS) mutations, resulting in a nal diagnosis of FD. Chronic inammation may complicate the diagnosis of FD of the jaw. The detection of GNAS mutations may provide a useful adjunct to conventional histopathological diagnosis in difcult cases. 2013 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.

Article history: Received 25 October 2012 Received in revised form 12 April 2013 Accepted 17 April 2013 Keywords: Fibrous dysplasia Chronic diffuse osteomyelitis GNAS mutation

1. Introduction Gnathic brous dysplasia (FD) and chronic diffuse osteomyelitis (CDO) are distinct disease states which have overlapping clinical and radiographic characteristics. Diagnosis is crucial because different treatments are indicated for these clinical conditions. Typical cases of maxillofacial FD are distinguished by radiological ndings and histological appearance. FD is a benign bone lesion characterized by the replacement of bone with bro-osseous connective tissue, histologically exhibiting varying degrees of osseous metaplasia that results from mosaicism due to a mutation in the

GNAS (guanine nucleotide binding protein, alpha stimulating activity polypeptide) 1 gene [1]. However, this lesion often presents a diagnostic dilemma because of uncertainties concerning the diagnostic signicance of specic radiological and histological features, so an accurate diagnosis of these lesions can be difcult [25]. Toyosawa et al. analyzed the expression of osteogenic markers and GNAS mutations in cases of gnathic brous dysplasia and ossifying broma and demonstrated that PCR analysis of the peptide nucleic acids in the GNAS mutations at the Arg201 codon is a useful method for diagnosing brous dysplasia [6]. This case report describes FD with a rare course in which the initial clinical symptoms and radiographic examination presented as CDO, and we discuss the possibility that GNAS mutations may be a useful adjunct to conventional histopathological diagnosis. 2. Case report A 28-year-old Japanese male was referred to our hospital due to an intermittently oppressive pain with diffuse swelling of the marginal gingiva near the left mandibular rst and second molars

Abbreviations: FD, brous dysplasia; CDO, chronic diffuse osteomyelitis; GNAS, guanine nucleotide binding protein alpha atimulating activity polypeptide. AsianAOMS: 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 6 6879 2936; fax: +81 6 6876 5298. E-mail address: g2787b@dent.osaka-u.ac.jp (T. Tsuji).

2212-5558/$ see front matter 2013 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ajoms.2013.04.007

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Fig. 1. Comparison of the panoramic radiographs taken at different stages. (A) April 2002; (B) August 2002; (C) June 2003 and (D) December 2003.

in April 2002. Panoramic radiograph revealed a radiolucent lesion in the root apex of the left mandibular rst and second molars, sclerogenic change around them (Fig. 1A). Computed tomography (CT) images revealed a mixed radiolucent and radiopaque lesion of the left mandible without any remarkable bone expansion (Fig. 2B and C). Antibiotic treatment was transiently effective for the symptoms, we clinically diagnosed CDO and periodically checked. From the rst medical examination to a time point of 4 months, no inammatory changes were seen in the clinical presentation or on medical imaging (Fig. 1B). When the patient came to our hospital complaining mainly of a dull pain in the same area almost 1 year 2 months and 1 year 8 months after the rst visit, radiographic ndings showed a trend toward an increase in the radiolucent lesion

and bone sclerosis (Fig. 1C and D), consistent with gingival swelling and tenderness at the same site. In each case, antibiotic treatment resulted in improvement of the symptoms. To diagnose this lesion more precisely, we suggested excisional biopsy. He chose a waitand-see strategy and so was periodically followed up in another hospital, with the result of frequent episodes of remission and exacerbation. The patient noticed left cheek swelling in February 2007 and was admitted to our hospital with a complaint of increased swelling in March 2007. He had an asymmetry of the face with diffuse swelling from the left cheek to the submandibular region (Fig. 4A). A hard, bone-like bulge extending from the body of the left mandible to the left ramus and tenderness of the left mandibular molars were

Fig. 2. Comparison between the panoramic radiographs (A and D), an axial section of a CT image (B and E) and 3-dimensional CT image (C and F) taken in April 2002 (AC) and in December 2007 (DF). (A, B, D and E) A remarkable bone expansion with a thickened cortex and a diffuse, smoky mottled lucent-radiopaque appearance in the left molar region of the mandible were observed in December 2007; (C and F) 3-dimensional CT image of the general bony changes, with expansion to the mandible, which is consistent with FD, in December 2007. CT images were reformatted with OsiriX imaging software (OsiriX Foundation).

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Fig. 3. Comparison of a coronal section of the CT images taken in different stages. (A) A schema of an axial section of the CT image with four section lines; (B) representative coronal section of a CT image taken in April 2002 (a) and December 2007 (b).

detected on palpation (Fig. 4B). A panoramic radiograph showed a signicant buccolingual bulge around the left mandibular molars and mixed radiolucent/radiopaque lesions from the left body to the left ramus of the mandible in comparison with April 2004 (Fig. 2A and D). In December 2007, CT images revealed a marked buccolingual bony expansion of the left mandible, thickened cortical bone and a disappearance of bone trabeculae in the left mandible with the so-called smoky mottled appearance (Fig. 2E and F). From the left mandibular premolars to the left ramus, extreme vertical expansion was noted as well as less marked horizontal expansion, relative to that in April 2004 (Fig. 3B). The relevant laboratory values were as follows: white blood cells count 6 109 /l, ALP 415 U/l, CRP 1.7 mg/dl. We suspected brous-osseous lesions and surgical reduction was planned. The procedure was performed in January 2008 under general anesthesia. The excised tissues exhibited markedly bloated buccolingual bones, the surface of which was spongious, and softened by degeneration (Fig. 5A). The tissues taken by curettage from the area in which there was a radiolucent lesion in the root apex of the left mandibular molars had been seen at the rst visit were not soft tissues, but degenerating bone tissues, suggesting that FD had occurred in the radiolucent area. Histologically, the most enlarged bone tissues in the left mandibular molars exhibited a mixture of the two different features without evident involvement of the cortical bones (Fig. 5B). Most part of the lesion was composed of irregular-shaped woven bone and brous tissue of variety cellularity (Fig. 5C and D). The woven bone spicules exhibited a variety of shapes with or

without rimming of osteoblasts (Fig. 5D(a)). On the other hand, foci of inammatory inltration were occasionally seen (Fig. 5C(a)). These ndings were consistent with CDO, but brous-osseous lesions were not ruled out because of the prominence of the mandibular bulge and absence of obvious cortical bone. Then, the presence of GNAS mutations at the Arg201 codon was examined as an auxiliary diagnosis, and it was observed that this pattern was similar to FD and unlike ossifying broma (Fig. 6). FD was diagnosed based on a consideration of the total ndings. 3. Discussion It is often difcult to diagnose FD from clinical and/or radiographic images [7,8]. In this case, the diagnosis of FD was difcult at the initial stage. One reason was the fact that there were no typical ndings of FD in the clinical presentation or radiographic images in the period from rst visit to 1 year 8 months. Another reason for the delayed diagnosis was the response to antibiotic treatment, to which FD does not normally respond, but in this case, the inammatory symptoms and signs improved. Finally, there was no biopsy sample, as the patient had chosen monitoring as his preferred approach. It can be said that FD of the mandible typically exhibits one of two clinical courses. One course has an osseous lesion that gradually increases without evident pain and swelling, leading to facial asymmetry. The other course presents with inammatory signs and symptoms accompanied by increased bone turnover. This case

Fig. 4. A pre-operative photograph shows the facial form from the front and also the intraoral nding in March 2007. (A) An asymmetry of the face is evident, with diffuse swelling from the left cheek to the submandibular region and (B) a bone-like hard bulge on the left mandible.

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Fig. 5. A photograph of a surgical specimen and photomicrographs of H&E-stained specimen. (A) Excised bone tissues were characterized by markedly bloated buccolingual bones which had a surface that was spongious and softened by degeneration. (a) A view from the basal aspect; (b) a view from buccal side. (B) The photomicrographs show that the focus of marked inammatory inltration is mainly composed of neutrophils (Ca) with peripheral new bone formation (Cb), and irregular-shaped woven bone with brous stroma (Da) is observed extensively. Original magnications: (B) 1; (C and D) 40 and (inset a, b, and c) 400.

probably falls into the latter type. We speculate that FD of the mandible had occurred at the time of the rst visit, and an inammatory response similar to that in CDO was observed because of the destructive changes to the mandible caused by inammation of the periodontal tissues. Histopathologically, 24 patients in our department were diagnosed as having FD during the 26 year period from 1983 to 2008. The patient age ranged from 9 years to 74 years. The mean age was 26.6 years, close to the 24 years reported in a systematic review by MacDonald-Jankowski [9]. The sex ratio was 12 males to 12 females. The physical location was broken down to 16 in the maxilla and 8 in the mandible. None of them had been considered, from the histological images, as indicating osteomyelitis. FD accompanying osteomyelitis and presenting with a mandible lesion is an extremely rare entity [10]. The limited reports indicate that it is difcult to diagnose osteomyelitis in the presence of FD, such as in cases in which the osteomyelitis occurred secondary to an infection or severe trauma [1113]. In our case, the initial symptoms and radiographic appearance of the lesion in this patient in his 20 s

was not consistent with the common descriptions of FD, but rather, with CDO. When the patient was in his middle 30 s, typical clinical symptoms of FD occurred without the trigger of an infection and severe trauma manifested during the course of the disease. We consider this case to have followed a particularly unusual course. Chang et al. reported that when the clinical signs include pain, swelling, increased serum alkaline phosphate level, rapid growth of the lesion and invasion into the cortical bone, we should keep in mind that there is the possibility of malignant change [11]. According to the review of Santiago et al., FD is one of the several bone diseases known to undergo malignant transformation along with Pagets disease and both solitary and multiple osteochondromas [14]. Typically, the malignancy is a sarcomatous lesion, most commonly an osteosarcoma, but brosarcoma, chondrosarcoma and malignant brohistiocytoma have also been reported [1520]. In some cases, the FD diagnosed in childhood can undergo malignant transformation as much as 4 decades later. Thus the risk of recurrence and malignancy of this lesion requires that careful, long term monitoring be carried out.

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T. Tsuji et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2013) xxxxxx 5 [2] Waldron CA. Fibro-osseous lesions of the jaws. J Oral Maxillofac Surg Am Assoc Oral Maxillofac Surg 1993;51:82835. [3] Brannon RB, Fowler CB. Benign bro-osseous lesions: a review of current concepts. Adv Anatomic Pathol 2001;8:12643. [4] Alawi F. Benign bro-osseous diseases of the maxillofacial bones. A review and differential diagnosis. Am J Clin Pathol 2002;118(Suppl.):S5070. [5] Weerasuriya T, Nashi S, Morgan A, Ebizie A. A dilemma of brous dysplasia versus chronic osteomyelitis of the clavicle. BMJ Case Rep 2012, http://dx.doi.org/10.1136/bcr.12.2011.5319. [6] Toyosawa S, Yuki M, Kishino M, Ogawa Y, Ueda T, Murakami S, et al. Ossifying broma vs brous dysplasia of the jaw: molecular and immunological characterization. Modern Physiol 2007;20:38996. [7] Khairallah E, Antonyshyn O, Farb R, Ehrlich L, Morava-Protzner I, OBrien J. Progressive unilateral mandibular swelling in adolescence: a diagnostic dilemma. J Craniofac Surg 1997;8:327. [8] Jacobsson S, Hallen O, Hollender L, Hansson CG, Lindstrom J. Fibro-osseous lesion of the mandible mimicking chronic osteomyelitis. Oral Surg Oral Med Oral Pathol 1975;40:43344. [9] MacDonald-Jankowski D. Fibrous dysplasia: a systematic review. Dent Maxillofac Radiol 2009;38:196215. [10] Lee JS, FitzGibbon EJ, Chen YR, Kim HJ, Lustig LR, Akintoye SO, et al. Clinical guidelines for the management of craniofacial brous dysplasia. Orphanet J Rare Dis 2012;7(Suppl. 1):S2. [11] Chang CY, Wu KG, Tiu CM, Hwang B. Fibrous dysplasia of mandible with chronic osteomyelitis in a child: report of one case. Acta Paediatr Taiwan 2002;43:3547. [12] Kozlowski K, Barrett I. Polyostotic brous dysplasia and chronic osteomyelitis in a 12-year-old boy. Diagnostic difculties in double bone pathology. Radiol Med 1987;73:1513. [13] Williams GT, Anderson W, Bryce DP. Osteomyelitis complicating brous dysplasia of the skull. Arch Otolaryngol 1972;96:27881. [14] Santiago Chinchilla A, Ramos Font C, Tello Moreno M, Rebollo Aguirre AC, Navarro-Pelayo Lainez M, Gallego Peinado M, et al. Fibrous dysplasia of the bone. Contribution of nuclear medicine in the diagnosis of suspicion of sarcomatous degeneration. Rev Esp Med Nucl 2010;29: 1726. [15] Sadeghi SM, Hosseini SN. Spontaneous conversion of brous dysplasia into osteosarcoma. J Craniofac Surg 2011;22:95961. [16] Ruggieri P, Sim FH, Bond JR, Unni KK. Malignancies in brous dysplasia. Cancer 1994;73:141124. [17] Doganavsargil B, Argin M, Kececi B, Sezak M, Sanli UA, Oztop F. Secondary osteosarcoma arising in brous dysplasia, case report. Arch Orthop Trauma Surg 2009;129:43944. [18] Ebata K, Usami T, Tohnai I, Kaneda T. Chondrosarcoma and osteosarcoma arising in polyostotic brous dysplasia. J Oral Maxillofac Surg 1992;50: 7614. [19] Kaushik S, Smoker WR, Frable WJ. Malignant transformation of brous dysplasia into chondroblastic osteosarcoma. Skeletal Radiol 2002;31: 1036. [20] Kim GT, Lee JK, Choi BJ, Kim J, Han SH, Kwon YD. Malignant transformation of monostotic brous dysplasia in the mandible. J Craniofac Surg 2010;21: 6013. [21] Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCuneAlbright syndrome. N Engl J Med 1991;325:168895. [22] Malchoff CD, Reardon G, MacGillivray DC, Yamase H, Rogol AD, Malchoff DM. An unusual presentation of McCuneAlbright syndrome conrmed by an activating mutation of the Gs alpha-subunit from a bone lesion. J Clin Endocrinol Metab 1994;78:8036. [23] Alman BA, Greel DA, Wolfe HJ. Activating mutations of Gs protein in monostotic brous lesions of bone. J Orthop Res 1996;14:3115. [24] Bianco P, Riminucci M, Majolagbe A, Kuznetsov SA, Collins MT, Mankani MH, et al. Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCuneAlbright brous dysplasia of bone. J Bone Miner Res 2000;15:1208.

Fig. 6. Analysis of mutations in the GNAS gene at the Arg201 codon using PCR-RFLP. PCR-RFLP analysis of the Arg201 codon of the GNAS gene in gnathic brous dysplasia served as the positive control (lane 1), along with this present specimen (lanes 2 and 3) and ossifying broma as a negative control (lane 4) in the presence of PNA. After EagI digestion, gnathic brous dysplasia and this present specimen exhibited persistent undigested 88-bp fragments (lanes 13). In contrast, ossifying bromas exhibited digested 74-bp fragments (lane 4). A 10-bp ladder was used as a size marker.

In 1991, Weinstein et al. demonstrated that mutations in the GNAS1 genes at the Arg201 codon which code for the alpha subunit of the stimulatory G protein gene were present in the lesional tissues of patients with McCuneAlbright syndrome [21]. Additionally, GNAS mutations were subsequently observed in extragnathic FD without McCuneAlbright syndrome, identifying them as a marker of FD [2224]. Toyosawa et al. analyzed the expression of osteogenic markers and GNAS mutations in gnathic FD compared with extragnathic FD and ossifying broma with typical clinical, radiological and histological features. They demonstrated that PCR analysis with PNA for GNAS mutations at the Arg201 codon was useful for distinguishing between FD and ossifying broma [6]. As in the present case, they analyzed the GNAS mutations and observed that this pattern was similar to FD and unlike ossifying broma. According to our ndings, we diagnosed the case as FD with CDO. On the basis of these results, when a patient returns with frequent remissions and exacerbations, priority should be given to the performance of a biopsy, even if the common FD features in terms of the radiograph and clinical course are not present. Furthermore, in the event there is a histopathologically mixed picture of FD and CDO, as in the case described above, the total ndings are required, including an analysis to identify any GNAS mutations. References
[1] Feller L, Wood NH, Khammissa RA, Lemmer J, Raubenheimer EJ. The nature of brous dysplasia. Head Face Med 2009;5:22.