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Journal of Oral and Maxillofacial Surgery, Medicine, and
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Contents lists available at SciVerse ScienceDirect
Journal ofOral and Maxillofacial Surgery,Medicine, and
Pathology
journal homepage: www.elsevier .com/ locate / jomsmp
Case report
Fibrous dysplasia ofmandibleReport ofa case presenting with a
rare clinical
course
Tadataka Tsujia,, Susumu Tanakaa,b, Mitsunobu Kishinoc, Mikihiko
Kogoa
a 1stDepartment of Oral andMaxillofacial Surgery, Graduate
School of Dentistry, Osaka University, 1-8Yamadaoka, Suita, Osaka
565-0871, Japanb Department of Dentistry, Oral andMaxillofacial
Surgery, OsakaPolice Hospital, Osaka543-0035, Japanc Department of
Oral Pathology, Graduate School of Dentistry,OsakaUniversity, Osaka
565-0871, Japan
a r t i c l e i n f o
Article history:Received25 October 2012
Received in revised form 12 April 2013
Accepted17 April 2013
Keywords:
Fibrous dysplasia
Chronic diffuse osteomyelitis
GNAS mutation
a b s t r a c t
Gnathic fibrous dysplasia (FD) and chronic diffuse osteomyelitis
(CDO) are independent disease states
which have overlapping clinical and radiographic
characteristics. Diagnosis is crucial because ofthe dif-
ferent treatments needed for these clinical conditions. We
report here a case ofFDofthe left mandible
which followed a rare clinical course and the initial clinical
symptoms and radiographic examination
were misinterpreted as indicating CDO. A 28-year-oldJapanesemale
was referred to our hospital due to
a dull intermittent pain ofthe left mandibular molars in April
2002. From the clinical and radiographic
examination results, we suspected CDO. Antibiotic treatment
produced a remission ofthese symptoms
andperiodical follow-upwasperformed inanotherhospital.
InMarch2007thepatientreturnedwithfirm
swelling in the left cheek region. Panoramic radiographic and CT
examination revealed remarkablebony
expansionwith a thickenedcortex and diffuse smoky mottled
lucent-radiopaqueappearancein the left
molar region ofthe mandible.We suspected fibro-osseous
lesionsofthe mandibleand surgical reduction
was performed in January 2008. Histological examination revealed
fibrous and bone tissue prolifera-
tion along with the chronic inflammatory lesions and an absence
of cortical bone. Mutational analysis
demonstrated guanine nucleotide binding protein, alpha
atimulating activity polypeptide (GNAS) muta-
tions, resulting in a final diagnosisofFD. Chronic
inflammationmay complicate the diagnosisofFDofthe
jaw. The detection ofGNAS mutations may provide a useful adjunct
to conventional histopathologicaldiagnosis in difficult cases.
2013 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published
by Elsevier Ltd. All rights reserved.
1. Introduction
Gnathic fibrous dysplasia (FD)andchronic diffuse
osteomyelitis
(CDO) are distinct disease states which have overlapping
clini-
cal and radiographic characteristics. Diagnosis is crucial
because
different treatments are indicated for these clinical
conditions.
Typical cases of maxillofacial FD are distinguished by
radiological
findings and histological appearance. FD is a benign bone
lesion
characterized by the replacement of bone with fibro-osseous
con-nective tissue, histologically exhibiting varying degrees of
osseous
metaplasia that results from mosaicism due to a mutation in
the
Abbreviations: FD, fibrous dysplasia; CDO,chronic diffuse
osteomyelitis;GNAS,
guanine nucleotidebinding protein alpha atimulating activity
polypeptide. AsianAOMS:AsianAssociationof Oral andMaxillofacial
Surgeons; ASOMP:Asian
Society of Oral and Maxillofacial Pathology; JSOP: Japanese
Society of Oral Pathol-
ogy; JSOMS: Japanese Society of Oral and Maxillofacial Surgeons;
JSOM: Japanese
Society of Oral Medicine; JAMI: JapaneseAcademy of Maxillofacial
Implants. Corresponding author. Tel.: +816 6879 2936;fax: +81 6
6876 5298.
E-mail address: [email protected] (T. Tsuji).
GNAS(guaninenucleotidebindingprotein,alpha stimulatingactiv-
ity polypeptide) 1 gene [1]. However, this lesion often presents
a
diagnostic dilemma because of uncertainties concerning the
diag-
nostic significanceof specific radiological and histological
features,
so an accurate diagnosis of these lesions can be difficult
[25].
Toyosawa et al. analyzed theexpression of osteogenic markers
and
GNAS mutations in cases of gnathic fibrous dysplasia and
ossify-
ing fibroma and demonstrated that PCR analysis of the
peptide
nucleic acids in the GNAS mutations at the Arg201
codon is a use-ful method for diagnosing fibrous dysplasia [6].
This case report
describes FD with a rare course in which the initial clinical
symp-
toms and radiographic examination presented as CDO, and we
discuss thepossibilitythatGNASmutationsmaybe a usefuladjunct
to conventional histopathological diagnosis.
2. Casereport
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 first and second
molars
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
JOMSMP-157; No. of Pages 5
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Fig. 1. Comparison of thepanoramic radiographs taken at
differentstages. (A)April2002; (B)August 2002; (C) June 2003 and(D)
December 2003.
in April 2002. Panoramic radiograph revealed a radiolucent
lesion
in theroot apex of theleft mandibularfirst andsecond molars,
scle-
rogenic changearound 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).Antibiotictreatmentwastransiently effective
forthesymptoms,
we clinically diagnosed CDO and periodically checked.
From the first medical examination to a timepoint of 4
months,
no inflammatory changes were seen in the clinical presentation
or
onmedical imaging (Fig.1B).When thepatientcameto ourhospital
complaining mainly of a dull pain in the same area almost 1 year
2
months and 1 year 8 months after the first visit, radiographic
find-ings showed a trend toward an increase in the radiolucent
lesion
andbone sclerosis (Fig.1C andD), 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
wait-
and-see strategy and so was periodically followed up in
another
hospital,withthe resultof frequentepisodesof
remissionandexac-
erbation.
ThepatientnoticedleftcheekswellinginFebruary2007andwas
admitted to our hospital with a complaint of increased swelling
in
March2007.Hehadan asymmetry of theface 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
tothe left ramus and tenderness of the left mandibular molars
were
Fig. 2. Comparison between thepanoramic radiographs (A andD), an
axial section of a CT image (B andE) and3-dimensional CT image (C
and F) taken in April 2002 (AC)
and in December2007 (DF).(A, B, D and E) A remarkable bone
expansion with a thickenedcortexand a diffuse,
smokymottledlucent-radiopaque appearance in theleft
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 withFD, in December 2007. CT images werereformatted
with OsiriX imaging software (OsiriX Foundation).
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Fig. 3. Comparison of a coronal section of theCT images taken in
differentstages. (A)A schemaof an axial section of theCT 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
significant buccolingual bulge around the left mandibular
molarsandmixedradiolucent/radiopaque lesions from theleft 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
buccolin-
gual 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 val-
ues were as follows: white blood cells count 6109/l, ALP 415
U/l,
CRP 1.7mg/dl.
We suspected fibrous-osseous lesions and surgical reduction
wasplanned. Theprocedurewasperformedin January 2008 under
general anesthesia.Theexcised tissues
exhibitedmarkedlybloatedbuccolingual bones, the surface of which
was spongious, and soft-
ened bydegeneration(Fig. 5A). Thetissues taken
bycurettagefrom
the area in which there was a radiolucentlesion in the root apex
of
the left mandibular molars had been seen at the first visit
werenot
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
fea-
tures without evident involvement of the cortical bones (Fig.
5B).
Most part of the lesion was composed of irregular-shaped
woven
bone and fibrous 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,
fociof inflammatory infiltrationwereoccasionally
seen(Fig.5C(a)).These findings were consistent with CDO, but
fibrous-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 exam-
ined as an auxiliary diagnosis, and it was observed that
this
pattern was similar to FD and unlike ossifying fibroma (Fig.
6).
FD was diagnosed based on a consideration of the total find-
ings.
3. Discussion
It is often difficult to diagnose FD from clinical and/or
radio-
graphic images [7,8]. In this case, the diagnosis of FD was
difficult
at the initial stage. One reason was the fact that there were
notypical findings of FD in the clinical presentation or
radiographic
images in the period from first visit to 1 year 8 months.
Another
reason for the delayed diagnosis was the response to
antibiotic
treatment, towhich FD does notnormally respond, butin this
case,
theinflammatory symptomsand signsimproved.Finally, therewas
no biopsy sample, as the patient had chosen monitoring ashis
pre-
ferred approach.
It can be said that FD of the mandible typically exhibits one
of
two clinical courses. One course has an osseous lesion that
gradu-
ally increases without evident pain and swelling, leading to
facial
asymmetry. The other course presents with inflammatory signs
andsymptoms accompanied by increasedbone turnover. This case
Fig. 4. A pre-operative photograph shows the facial form from
the front and also the intraoralfinding in March 2007. (A) An
asymmetry of the face is evident, with diffuse
swellingfrom theleft cheek to thesubmandibularregion and(B) a
bone-like hard bulge on theleft mandible.
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Fig. 5. A photograph of a surgical specimenandphotomicrographs
of H&E-stainedspecimen. (A) Excised
bonetissueswerecharacterized by markedly bloated buccolingual
bones which had a surface that was spongiousand softenedby
degeneration. (a)A view from thebasal aspect; (b) a view from
buccal side. (B)The photomicrographs show
that the focus of marked inflammatory infiltration is mainly
composed of neutrophils (Ca)withperipheral new boneformation (Cb),
and irregular-shapedwoven bonewith
fibrous stroma (Da) is observedextensively.
Originalmagnifications: (B) 1; (Cand 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 first visit, and an
inflam-
matory response similar to that in CDO was observed because
of
the destructive changes to the mandible caused by
inflammation
of the periodontal tissues.Histopathologically, 24 patients in
our department were diag-
nosed 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
max-
illa and 8 in the mandible. Noneof themhad beenconsidered,
from
the histological images, as indicating osteomyelitis. FD
accompa-
nying osteomyelitis and presenting with a mandible lesion is
an
extremely rare entity [10]. The limited reports indicate that it
is
difficult to diagnose osteomyelitis in the presence of FD, such
as in
cases in which the osteomyelitis occurred secondary to an
infec-
tion or severe trauma [1113]. In our case, the initial
symptoms
and radiographic appearanceof the lesion in thispatient inhis
20s
wasnotconsistent with thecommon descriptionsof FD,but
rather,
with CDO. When the patient was in his middle 30s, typical
clini-
cal symptoms of FD occurred without the trigger of an
infection
andseveretraumamanifested duringthecourseof thedisease. 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, weshouldkeep
in
mind that there is thepossibility of malignantchange [11].
Accord-
ing 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
com-
monly an osteosarcoma, but fibrosarcoma, chondrosarcoma and
malignant fibrohistiocytoma have also been reported [1520].
In
some cases, theFD diagnosed in childhoodcan undergo
malignant
transformation as much as 4 decades later. Thus the risk of
recur-
rence andmalignancy of this lesionrequires that careful, long
term
monitoring be carried out.
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Fig. 6. Analysis of mutations in theGNASgene at theArg201
codonusing PCR-RFLP.
PCR-RFLP analysisof theArg201 codonof theGNAS gene in gnathic
fibrousdysplasia
served as the positive control (lane 1), along with this present
specimen (lanes 2
and 3) and ossifying fibroma as a negative control (lane 4) in
the presence of PNA.
After EagI digestion, gnathic fibrous dysplasia and this present
specimen exhibited
persistent undigested 88-bp fragments (lanes 13). In contrast,
ossifying fibromas
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
sub-
unit of the stimulatory G protein gene were present in the
lesional
tissuesof patientswithMcCuneAlbrightsyndrome[21]. Addition-
ally, 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 fibroma with typical
clinical,
radiological and histological features. They demonstrated that
PCR
analysiswith PNAforGNAS mutationsat theArg201 codonwasuse-
ful for distinguishing between FD and ossifying fibroma [6]. As
in
the present case, they analyzed the GNAS mutations and
observed
that this pattern was similar to FD and unlike ossifying
fibroma.
According to our findings, we diagnosed the case as FD with
CDO.
On the basis of these results, when a patient returns with
fre-
quent remissions andexacerbations,priorityshould begivento
the
performance of a biopsy, even if the common FD features in
terms
of the radiograph andclinical course arenot present.
Furthermore,
in the event there is a histopathologically mixed picture of FD
and
CDO, as in thecase describedabove, the total findings
arerequired,
including an analysis to identify any GNAS mutations.
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