YIJOM-2324; No of Pages 7

Int. J. Oral Maxillofac. Surg. 2012; xxx: xxx–xxx

doi:10.1016/j.ijom.2012.01.017, available online at http://www.sciencedirect.com

Research Paper
Oral Pathology

Glucocorticoid and calcitonin R. L. M. Nogueira1,2, M. H. G. Faria3,

R. L. V. Osterne4, R. B. Cavalcante5,
R. A. Ribeiro6, S. H. B. Rabenhorst7

receptor expression in central

1
Department of Dental Clinic, Discipline of
Oral and Maxillofacial Surgery and
Stomatology, Federal University of Ceara
School of Dentistry, Fortaleza, Brazil;

giant cell lesions: implications 2

Department of Oral and Maxillofacial
Surgery, Memorial Batista Hospital, Fortaleza,
Brazil; 3Molecular Genetics Laboratory,

for therapy
LABGEM, Department of Pathology and
Forensic Medicine, School of Medicine,
Federal University of Ceará, Brazil;
4
Department of Pathology, Fortaleza
University School of Medicine, Fortaleza,
Brazil; 5Department of Oral and Maxillofacial
R. L. M. Nogueira, M. H. G. Faria, R. L. V. Osterne, R. B. Cavalcante, R. A. Pathology, Fortaleza University School of
Ribeiro, S. H. B. Rabenhorst: Glucocorticoid and calcitonin receptor expression in Dentistry, Fortaleza, Brazil; 6Department of
central giant cell lesions: implications for therapy. Int. J. Oral Maxillofac. Surg. Physiology and Pharmacology, Federal
2012; xxx: xxx–xxx. # 2012 International Association of Oral and Maxillofacial University of Ceara School of Medicine,
Surgeons. Published by Elsevier Ltd. All rights reserved. Fortaleza, Brazil; 7Department of Pathology
and Forensic Medicine, Molecular Genetics
Laboratory – LABGEM, Federal University of
Ceara, School of Medicine, Fortaleza, Brazil

Abstract. Central giant cell lesion is an uncommon benign jaw lesion, with uncertain
aetiology, and variable clinical behaviour. Studies of molecular markers may help
to understand the nature and behaviour of this lesion, and eventually may represent a
target for pharmacological approaches to treatment. The aim of this study was to
analyse the expression of glucocorticoid and calcitonin receptors in central giant
cell lesions before and after treatment with intralesional steroid. Paraffin-embedded
blocks from patients who underwent treatment with intralesional triamcinolone
hexacetonide injections were stained immunohistochemically. Biological material
from patients who underwent a surgical procedure after treatment were tested
immunohistochemically. 18 cases (9 aggressive and 9 non-aggressive) were
included. The difference in calcitonin receptor expression was not statistically
significant between the aggressive and non-aggressive lesions and between the
patients with a good response and those with a moderate/negative response to
treatment. Glucocorticoid receptor expression in the multinucleated giant cells was
Key words: central giant cell lesion; glucocorti-
higher in patients with a good response. It can be postulated that coid receptor; calcitonin receptor; immunohis-
immunohistochemical staining for glucocorticoid receptors may provide a tool for tochemistry.
selecting the therapeutic strategy. An H-score greater than 48 for glucocorticoid
receptors in multinucleated giant cells predicted a good response in this study. Accepted for publication 20 January 2012

Central giant cell lesion (CGCL) is an
uncommon benign intraosseous lesion
found in the maxillofacial region that
has variable clinical behaviour.1–4 CGCLs
have been classified as non-aggressive and
aggressive lesions.5 Most cases present as
asymptomatic, slow growing lesions with-
out cortical perforation. Aggressive
CGCLs are characterized by rapid growth,
pain, bony expansion, root resorption and
dental mobility. In aggressive lesions,
recurrence is common. The nature of
CGCLs is controversial; lesions found
after bone trauma, such as dental extrac-
tion,6 point to the reactive nature of

0901-5027/000001+07 $36.00/0 # 2012 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Nogueira RLM, et al. Glucocorticoid and calcitonin receptor expression in central giant cell lesions:
implications for therapy, Int J Oral Maxillofac Surg (2012), doi:10.1016/j.ijom.2012.01.017
YIJOM-2324; No of Pages 7
2 Nogueira et al.
CGCLs. Aggressive CGCLs with rapid
growth and high recurrence rates are
thought to be neoplastic in nature.
Histologically, CGCL is characterized
by the presence of multinucleated giant
cells (MGCs) in a cellular background
composed of mononucleated stromal cells
(MSCs) with ovoid or spindle-shaped
nuclei.3,4 In aggressive lesions, MGCs
are usually more numerous, larger and
uniformly scattered throughout the
lesion.4 The cellular lineage from which
MGCs are derived is controversial. Posi-
tive immunohistochemical expression of
receptor activator of nuclear factor-kB
(RANK),7 tartrate-resistant acid phospha-
tase (TRAP), vitronectin receptor (VNR)2
and calcitonin receptor8 have suggested an
osteoclastic phenotype for MGCs. The
presence of CD68 glycoprotein9 and
alpha-1-antichymotrypsin10 has suggested
that MGCs have a macrophage/histiocyte
origin.
CGCL is an uncommon lesion that
occurs more frequently in females.1,4,11,12
Although it can be found in all age groups,
most cases appear before the age of 30
years.1,4,11 The mandible is more often
involved than the maxilla1 with a mandib-
ular/maxillary ratio of 2:1.12 In the max-
illa, the anterior region is usually affected,
whilst in the mandible, the anterior and
posterior regions are equally affected.1
Traditionally, surgery is the treatment
of choice for CGCLs, and the extent of
surgery ranges from curettage with or
without adjuvant therapy, such as cryosur-
gery, peripheral ostectomy and carnoy
solution, to aggressive en bloc resec-
tion,12,13 resulting in varying degrees of
deformity.11 Non-surgical methods have
been proposed to treat CGCLs, including
radiotherapy,14 systemic calcitonin,15–17
intralesional injection with corticoster-
oids1–21 and systemic a interferon.22,23
In an earlier report,24 the authors pre-
sented excellent results with intralesional
triamcinolone with a good response in 15/
21 patients, a moderate response in 4/21
patients and a negative response in 2/21
patients.
The actions of glucocorticoids and cal-
citonin are mediated, at least in part, via
specific glucocorticoids receptors (GR)
and calcitonin receptors (CTR).7 GR and
CTR are expressed in CGCLs, which has
been previously described8,25; but no dis-
tinction was made in staining character-
istics between MSCs and MGCs prior to
and after treatment with glucocorticoids.
The purpose of this study was to analyse
the expression of GR in CGCLs immuno-
histochemically before and after treatment
with intralesional triamcinolone. Also, as
Please cite this article in press as: Nogueira RLM, et al. Glucocorticoid and calcitonin receptor expression in central giant cell lesions:
implications for therapy, Int J Oral Maxillofac Surg (2012), doi:10.1016/j.ijom.2012.01.017
Vered et al.25 demonstrated that the use of
calcitonin may influence the expression of
GR and CTR, the expression of CTR was
also evaluated to determine whether CTR
expression could be influenced by intrale-
sional corticosteroid treatment.
Materials and methods
Formalin-fixed paraffin-embedded blocks
from 21 consecutive cases of primary
CGCLs from patients who underwent
treatment with intralesional triamcinolone
hexacetonide injections24 (20 mg/ml
diluted in an anaesthetic solution of 2%
lidocaine/epinephrine 1:200.000 in a ratio
of 1:1; 1.0 ml of the solution infiltrated
every 1 cm3 of radiolucide area of the
lesion totalling 6 biweekly applications)
were retrieved. 11 were male and 10
female, with ages ranging from 5 to 25
years (median 15.5 years). The mandible
was the most frequent localization (13
cases) followed by the maxilla (8 lesions).
According to the criteria established by
Chuong et al.,5 the lesions from 10 patients
were classified as aggressive, and 11 were
classified as non-aggressive.
The treatment response was determined
using previously determined scores24 in
which four criteria were considered: sta-
bilization or regression of lesion size
evaluated clinically and in follow-up
radiographs; the absence of symptoms;
increased radio-opacity in radiographs,
representing peripheral and/or central cal-
cification of the lesion; increased difficulty
in solution infiltrating the lesion during the
sequence of applications. When a case met
all four criteria, the response was deter-
mined to be good; meeting two or three
criteria was determined to be moderate;
and meeting one criterion or no criteria
implied a negative response to treatment.
On the basis of these criteria, 15 patients
had a good response, 4 had a moderate
response, and 2 had a negative response.
Although these criteria present some sub-
jective topics, such as ‘increased difficulty
of the injection’, the treatment is usually
performed by the same surgeon so increas-
ing the difficulty of the injection can be
measured. This finding is reported by sev-
eral authors,18–20,24 and it reflects the ossi-
fication of the lesion. It is recommended
that the surgeon takes notes about the
resistance of the injections.
Immunostaining was performed accord-
ing to a previously described protocol.26
For antigen retrieval, deparaffinized sec-
tions were pretreated by heating in a
microwave oven in 10 mM citrate buffer
pH 6.0 for 15 min. After cooling, the
sections were immersed in phosphate
buffered saline (PBS) containing 3%
hydrogen peroxide for 10 min to block
endogenous peroxidase activity. The sec-
tions were then incubated in a humid
chamber overnight at 4 8C with the fol-
lowing primary antibodies: anti-glucocor-
ticoid receptor (NCL-GCR; dilution 1:50;
Vision-Biosystems1, UK) or anti-calcito-
nin receptor (anti-calcitonin receptor pre-
cursor antibody; dilution 1:50; Novus
Biologicals1, USA). After rinsing with
PBS, the slides were incubated with sec-
ondary antibody followed by streptavidin–
peroxidase complex both for 30 min at
room temperature with a PBS wash
between each step (LSAB+ system; Dako-
Cytomation1, USA). The slides were
developed with diaminobenzidine–H2O2
(DAB+ system; DakoCytomation1,
USA), counterstained with Harry’s hae-
matoxylin and mounted. Thyroid tissue
for CTR and tonsil tissue for GR were
used as positive controls. Controls of pri-
mary antibody specificity included the
omission or substitution of primary anti-
serum with normal bovine serum.
The immunohistochemical staining was
assessed using a direct light microscope,
accordingly to the site of stain of each
antibody (GR, nuclei; CTR, nuclei and
cytoplasm). A differential count was per-
formed for MSCs and MGCs. Staining
was quantified through manual counting
of at least 1000 MSCs in 10 different fields
at a magnification of 400. In the same 10
high-power fields, all MGCs were counted
to a maximum of 1000 cells. The labelling
index (LI) was expressed as the percentage
of positive cells with nuclear staining for
CTR in each section.27 The H-score (H)
takes into account the intensity of the
cytoplasmic CTR staining and nuclear
GR staining expressed in values ranging
from 0 to 3+ (0, no stain; 1+, weak; 2+,
moderate; 3+, strong) in accordance with
the methods described by McCarty et al.28
Statistical analysis
The data were analysed using the SPSS
13.0 (SPSS Inc., Chicago, IL, USA) sta-
tistical package. The results were
expressed as the mean. To compare the
marker H-score with respect to clinical
presentation and treatment result groups,
the nonparametric Mann–Whitney U-test
was used. Significance was established at
a p value 0.05.
Results
From the 21 previously selected paraffin-
embedded blocks of CGCLs, 18 had
enough pretreatment biological material
YIJOM-2324; No of Pages 7

Glucocorticoid and calcitonin receptor in central giant cell lesion 3

Table 1. Gender, age, aggressiveness and response to treatment of CGCL.

Response to Case number in
Gender Age Behaviour treatment Jaw Site previous report24
Male 20 Aggressive Good Maxilla Anterior 1
Male 7 Non-aggressive Good Mandible Posterior 2
Female 23 Aggressive Good Mandible Anterior 3
Female 19 Non-aggressive Good Mandible Anterior 5
Male 9 Aggressive Good Mandible Posterior 6
Male 5 Aggressive Moderate Maxilla Anterior 7
Female 15 Aggressive Moderate Mandible Posterior 8
Male 12 Non-aggressive Good Mandible Posterior 9
Female 24 Non-aggressive Good Maxilla Anterior 10
Female 20 Aggressive Negative Mandible Anterior 12
Male 7 Non-aggressive Moderate Mandible Posterior 13
Female 9 Non-aggressive Good Maxilla Anterior 14
Male 25 Non-aggressive Good Mandible Posterior 15
Female 10 Non-aggressive Good Mandible Anterior 16
Female 18 Aggressive Moderate Mandible Anterior 17
Male 6 Aggressive Good Maxilla Anterior 19
Male 13 Aggressive Good Maxilla Anterior 20
Female 17 Non-aggressive Good Mandible Posterior 21

to perform all the immunohistochemical
reactions for GR and CTR. Amongst them,
9 lesions were classified as aggressive and
9 as non-aggressive. Regarding the treat-
ment result groups, 13 had a good
response, 4 had a moderate response and
1 had a negative response to treatment
(Table 1). Amongst the 21 patients, 13
underwent surgical procedures after treat-
ment with intralesional triamcinolone, 8
with a moderate-to-good response under-
went osteoplasty to reestablish facial
aesthetics, 3 with a moderate-to-good
response showed small radiolucide areas
and underwent curettage, and 2 patients
with a negative response underwent sur-
gical resection, but only 12 had enough
biological material to perform immuno-
histochemical reactions (7 with good
response, 4 with moderate response and
1 with negative response).
GR analysis
Examples of immunostaining for GR are
illustrated in Fig. 1. The rate of GR-positive
staining for CGCLs was 77.7% before and
100.0% after treatment. Immunohisto-
chemical reactivity for GR was detected
in the nuclei of MSCs and MGCs. Con-
sidering the clinical forms of CGCLs, no
significant difference was observed in the
median GR H-score of MSCs and MGCs
between aggressive and non-aggressive
CGCLs either before or after treatment.
The data have shown that the median GR
H-score of MSCs and MGCs were reduced
after treatment (Table 2). Considering the
response before treatment, a significantly

Fig. 1. Immunohistochemical staining for GR in formalin-fixed paraffin-embedded CGCLs (400). (A) Non-aggressive CGCL with a good
response to treatment and moderate/intense nuclear staining in MSCs (red arrow) and MGCs (yellow arrow) before treatment. (B) Aggressive
CGCL with a negative response to treatment and diffuse nuclear staining in MSCs (red arrow) and MGCs (yellow arrow) before treatment. (C)
Aggressive CGCL with a moderate response to treatment and moderate nuclear staining in MSCs (red arrow) and MGCs (yellow arrow) after
treatment. (D) Non-aggressive CGCL with a good response to treatment and moderate/intense nuclear staining in MSCs (red arrow) and MGCs
(yellow arrow) after treatment.

Please cite this article in press as: Nogueira RLM, et al. Glucocorticoid and calcitonin receptor expression in central giant cell lesions:
implications for therapy, Int J Oral Maxillofac Surg (2012), doi:10.1016/j.ijom.2012.01.017
YIJOM-2324; No of Pages 7

4 Nogueira et al.

Table 2. Parameters used for the calculation of Mann–Whitney U-test for the evaluation of the expression of GR in MSC and MGC according to
aggressiveness of CGCL.
Cell type Aggressiveness n Median Q25–Q75 Mean of ranks Sum of ranks U p
Before treatment
MSC Aggressive 9 102 58.5–152.5 9.72 87.50 38.50 0.860
Non-aggressive 9 89 56.5–156 9.28 83.50
MGC Aggressive 9 29 23–55.5 8.50 76.50 31.50 0.427
Non-aggressive 9 48 23.5–83 10.50 94.50
After treatment
MSC Aggressive 6 9 0–130.25 5.33 32.00 11.00 0.259
Non-aggressive 6 82 51–136.75 7.67 46.00
MGC Aggressive 6 1 0–19.25 6.25 37.50 16.50 0.797
Non-aggressive 6 5.5 0–12.50 6.75 40.50
MSC, monunoclear stromal cells; MGC, multinucleated giant cells.

Table 3. Parameters used for the calculation of Mann–Whitney U-test for the evaluation of the expression of GR in MSC and MGC according to
the results of treatment with intralesional triancinolone in CGCL.
Cell type Treatment result n Median Q25–Q75 Mean of ranks Sum of ranks U p
Before treatment
MSC Good 13 142 86–156 10.92 142.00 14.00 0.068
Moderate/negative 5 59 30.5–120.5 5.80 29.00
MGC Good 13 48 31.5–83 11.73 152.50 3.50 0.004
Moderate/negative 5 22 10.5–22.5 3.70 18.50
After treatment
MSC Good 7 67 0–91 5.43 38.00 10.00 0.220
Moderate/negative 5 127 9–169.5 8.00 40.00
MGC Good 7 0 0–11 6.07 42.50 14.50 0.602
Moderate/negative 5 2 0–29 7.10 35.50
MSC, mononucleated stromal cells; MGC, multinucleated giant cells.

higher median H-score (median H-score

48) for GR was found for MGCs in
the good response group compared with
the moderate/negative response group
(p = 0.004). A higher median H-score
was found in MSCs in CGCLs with a good
response to treatment (p = 0.068). After
treatment, the median H-score in MSCs
and MGCs in CGCLs with a good response
to treatment decrease, whilst in CGCLs
with a moderate/negative response there
was a reduction in the median H-score in
MGC and a increase in MSCs (Table 3).

CTR analysis
Examples of immunostaining for CTR are
illustrated in Fig. 2. CTR positivity (nuclear
and/or cytoplasmic) in the studied CGCLs
was 100.0% before and 61.5% after treat-
ment. Immunohistochemical reactivity for
CTR was detected in the nuclei and cyto-
plasm of MSCs and MGCs. No significant
difference between the clinical forms of
CGCLs (Table 4) was observed for LI
(nuclear expression) and H-score (cyto- Fig. 2. Immunohistochemical staining for CTR in formalin-fixed paraffin-embedded CGCLs
(400). (A) Aggressive CGCL with a good response to treatment and intense nuclear staining in
plasmic expression) CTR expression in
MSCs (red arrow) before treatment. (B) Aggressive CGCL with a good response to treatment
MSCs and MGCs. Before treatment, the (same case as A) and intense cytoplasmic staining in MGCs (red arrow) before treatment. (C)
good response to treatment group had a Aggressive CGCL with a negative response to treatment and diffuse cytoplasmic staining in
higher LI and H-score median compared MGCs (red arrow) and MSCs (yellow arrow) after treatment. (D) Aggressive CGCL with a
with the moderate/negative response group negative response to treatment (same case as C) and intense nuclear staining in MGCs (red
for MSCs, although no statistical difference arrow) after treatment. (For interpretation of the references to colour in this figure legend, the
was found (Table 5). Table 5 shows that reader is referred to the web version of the article.)

Please cite this article in press as: Nogueira RLM, et al. Glucocorticoid and calcitonin receptor expression in central giant cell lesions:
implications for therapy, Int J Oral Maxillofac Surg (2012), doi:10.1016/j.ijom.2012.01.017
YIJOM-2324; No of Pages 7

Glucocorticoid and calcitonin receptor in central giant cell lesion 5

Table 4. Parameters used for the calculation of Mann–Whitney U-test for the evaluation of the expression of CTR in MSC and MGC according to
aggressiveness of CGCL.
Cell type Aggressiveness n Median Q25–Q75 Mean of ranks Sum of ranks U p
LI before treatment
MSC Aggressive 9 18 12–29 8.61 77.50 32.50 0.479
Non-aggressive 9 27 13–46.5 10.39 93.50
MGC Aggressive 9 12 6–24.5 8.11 73.00 28.00 0.269
Non-aggressive 9 27 8.5–43 10.89 98.00
H-Score before treatment
MSC Aggressive 9 40 30–82.5 9.89 89.00 37.00 0.757
Non-aggressive 9 36 28.5–87 9.11 82.00
MGC Aggressive 9 42 23.5–93 7.89 71.00 26.00 0.200
Non-aggressive 9 87 53.5–121.5 11.11 100.00
LI after treatment
MSC Aggressive 6 9 2.25–24.5 5.67 34.00 13.00 0.423
Non-aggressive 6 15 9.5–40.75 7.33 44.00
MGC Aggressive 6 19.5 1.5–36.5 6.00 36.00 15.00 0.631
Non-aggressive 6 19.5 17.75–45.25 7.00 42.00
H-Score after treatment
MSC Aggressive 6 61 35.25–93.5 5.92 35.50 14.50 0.575
Non-aggressive 6 73.5 44.75–153.75 7.08 42.50
MGC Aggressive 6 75 42.75–131.50 5.33 32.00 11.00 0.262
Non-aggressive 6 137.5 55.25–160.0 7.67 46.00
MSC, monunoclear stromal cells; MGC, multinucleated giant cells; LI, nuclear expression; H-score, cytoplasmic expression.

Table 5. Parameters used for the calculation of Mann–Whitney U-test for the evaluation of the expression of calcitonin in MSC and MGC
according to the results of treatment with intralesional triancinolone in CGCL.
Cell type Treatment result n Median Q25–Q75 Mean of ranks Sum of ranks U p
LI before treatment
MSC Good 13 19 16–43 10.38 135.00 21.00 0.256
Moderate/negative 5 10 0–43 7.20 36.00
MGC Good 13 12 9–33.5 9.92 129.00 27.00 0.587
Moderate/negative 5 21 2–31.5 8.40 42.00
H-Score before treatment
MSC Good 13 40 32–83.5 10.04 130.50 25.50 0.490
Moderate/negative 5 35 14.5–86 8.10 40.50
MGC Good 13 81 45.5–92 10.12 131.50 24.50 0.430
Moderate/negative 5 34 18–124.5 7.90 39.50
LI after treatment
MSC Good 7 13 4–24 6.57 46.00 17.00 0.935
Moderate/negative 5 14 5.5–21.5 6.40 32.00
MGC Good 7 18 9–38 6.43 45.00 17.00 0.935
Moderate/negative 5 20 9.5–33 6.60 33.00
H-Score after treatment
MSC Good 7 63 47–89 6.64 46.50 16.50 0.871
Moderate/negative 5 62 23.5–106 6.30 31.50
MGC Good 7 134 57–175 7.14 50.00 13.00 0.465
Moderate/negative 5 91 32.5–129 5.60 28.00
MSC, monunoclear stromal cells; MGC, multinucleated giant cells; LI, nuclear expression; H-score, cytoplasmic expression.

the median H-score of both MGCs and
MSCs increased after the treatment with
intralesional corticosteroid.
Discussion
The functional and aesthetic alterations as
well as the psychological consequences
caused by the surgical treatment of CGCL
have encouraged researchers to look for
effective alternative therapeutic strategies.8
Amongst these strategies is the use of sys-
temic calcitonin15–17,25 and intralesional
injections with corticosteroids.18–21,24 Both
of these strategies are increasingly being
used and have shown promising results.
The actions of such medications are
mediated via GR and CTR.7 Thus, Vered
et al.8 proposed that the immunohistochem-
ical analyses of CGCLs for GR and CTR
may help the clinician decide on the most
appropriate therapeutic strategy.
Some reports18,19,29 related to CGCL
treatment with calcitonin and glucocorti-
coid did not evaluate CTR and GR expres-
sion in the lesion before the therapeutic
treatment. The first report of intralesional
steroid injections in CGCLs was based on
the similarity of MGCs in CGCLs to giant
cells from sarcoidosis, which were thought
to be of macrophage origin. The use of
calcitonin was based on the histological
similarity of CGCLs and the brown
tumours of hyperparathyroidism.30
Positive expression of GR was found in
all cellular components of CGCLs, but in
this study, no difference was found between
aggressive and non-aggressive lesions. The
median H-score of GR expression in MSCs
was higher in CGCLs with a good response
to treatment compared with lesions with a
moderate/negative response to treatment

Please cite this article in press as: Nogueira RLM, et al. Glucocorticoid and calcitonin receptor expression in central giant cell lesions:
implications for therapy, Int J Oral Maxillofac Surg (2012), doi:10.1016/j.ijom.2012.01.017
YIJOM-2324; No of Pages 7
6 Nogueira et al.
(p = 0.068), which is consistent with stu-
dies from O’Malley et al.31 and Liu et al.32
in which they postulated that the fibro-
blast-like component of MSCs are the
proliferative cells in CGCLs. In MGCs,
a statistically significant difference in GR
expression was found between the lesions
with a good or moderate/negative response
to treatment (p = 0.004). In this study, an
H-score > 48 in MGCs (median H-score
before treatment in MGCs with good
response) was predictive of a good response
to intralesional triamcinolone hexaceto-
nide. As postulated by Vered et al.,8 immu-
nohistochemical staining for GR in CGCLs
can be a predictive marker for therapeutical
response to intralesional glucocorticoid
therapy. The diffuse GR expression in
CGCLs could be the reason why this lesion
has a good response to intralesional gluco-
corticoid therapy.24
Although aggressive CGCLs had higher
CTR expression,7 no significant difference
in CTR expression in different clinical
forms of CGCLs was found in this study.
Although, there was not a clear modifica-
tion in the median LI of CTR expression
before and after treatment with intrale-
sional triamcinolone in MSCs or MGCs,
the median H-score of CTR in MGCs and
MSCs was higher after the treatment with
intralesional triancinolone hexacetonide.
Experimental findings have shown that
steroids may modulate the regulation of
CTR gene expression6 and increase the
expression of CTR.33
The osteoclast-like characteristics of
MGCs, such as positive immunohisto-
chemical expression of RANK,7 TRAP,
VNR2 and CTR8 together with the expres-
sion of VNR, TRAP,2 and CTR in MSCs,
support the use of systemic calcitonin to
treat CGCLs. Calcitonin has been admi-
nistered in a nosespray and as subcuta-
neous daily injections.16,25 This hormone
increases the influx of calcium into the
bones, functions as an antagonist to para-
thyroid hormone, and inhibits osteaclastic
bone resorption.16 The present data could
suggest the first nonsurgical therapeutical
approach by using glucocorticoid injec-
tions with triamcinolone hexacetonide. In
case of negative response, other treatment
modalities can be used. Recently, a CGCL
has been treated with a combination of
glucocorticoid injections and calcitonin.34
Nogueira et al.24 postulated that the intra-
lesional steroid treatment of CGCLs may
inhibit the extracellular production of pro-
teases, transcription factors for intracellu-
lar proliferation or the apoptotic action on
osteoclast-like cells.
The positive GR and CTR expression
found in this study and other studies in the
Please cite this article in press as: Nogueira RLM, et al. Glucocorticoid and calcitonin receptor expression in central giant cell lesions:
implications for therapy, Int J Oral Maxillofac Surg (2012), doi:10.1016/j.ijom.2012.01.017
literature2,7–10 indicate that MGCs may be
similar to osteoclasts and macrophages/
histiocytes and that CGCL can be
prompted to respond to calcitonin or intra-
lesional glucocorticoid as shown in the
literature.24,25 A good strategy would be
to follow these changes with regular biop-
sies of the lesion during treatment because
MSCs and MGCs may undergo a dynamic
process of transdifferentiation and thus
affect the therapeutical approach.25 The
histological analysis could detect transdif-
ferentiation and help adjust therapy.8
Although CGCL is more frequently
diagnosed in female patients,4,7,34 data
from the 18 cases studied found an equal
frequency; also, the average age in males
patients was lower than in female patients.
Similar to other reports,4,7,23,34 CGCL
occurred more often in the mandible.
Although aggressive lesions usually affect
younger patients compared with non-
aggressive lesions, an almost equal aver-
age age was found in this study. The
authors know that this small sample does
not show statistical significance, and may
not represent the true prevalence of CGCL
in the population.
In summary, MSCs and MGCs in
CGCLs express CTR and GR, and cal-
citonin and intralesional steroids injec-
tions can be used to treat CGCLs. GR
immunohistochemical staining may pro-
vide a tool for selecting the therapeutic
strategy because MGCs in lesions with a
good response to intralesional steroids
injections had a significantly higher H-
score for GR. A H-score > 48 (median
H-score in MGCs with good response to
treatment) predicted a good response in
this study. The transdifferentiation phe-
notype with modified GR and CTR
expression during treatment with intrale-
sional steroids should be investigated
further.
Competing interests
None declared.
Funding
None.
Ethical approval
Approved by Ethical Committee from the
Ceara Federal University-Fortaleza-Ceará-
Brazil.
References
1. de Lange J, van den Akker HP. Clinical
and radiological features of central giant-
cell lesions of the jaw. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod
2005;99:464–70.
2. Itonaga I, Hussein I, Kudo O, Sabokbar A,
Watt-Smith S, Ferguson D, et al. Cellular
mechanisms of osteoclast formation and
lacunar resorption in giant cell granuloma
of the jaw. J Oral Pathol Med 2003;32:
224–31.
3. Jundt G. Central giant cell lesion. In: Barnes
L, Eveson JW, Reichart P, Sidransky D,
editors. World Health Organization classifi-
cation of tumours. Pathology and genetics of
head and neck tumours. Lyon: IARC Pub-
lishing Group; 2005. p. 324.
4. Kruse-Lösler B, Diallo R, Gaertner C, Mis-
chke KL, Joos U, Kleinheinz J. Central giant
cell granuloma of the jaws: a clinical, radi-
ologic, and histopathologic study of 26
cases. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2006;101:346–54.
5. Chuong R, Kaban LB, Kozakewich H,
Perez-Atayde A. Central giant cell lesions
of the jaws: a clinicopathologic study. J Oral
Maxillofac Surg 1986;44:708–13.
6. Unal M, Karabacak T, Vayisoğlu Y, Bağiş
HE, Pata YS, Akbaş Y. Central giant cell
reparative granuloma of the mandible caused
by a molar tooth extraction: special reference
to the manuever of drilling the surgical field.
Int J Pediatr Otorhinolaryngol 2006;70:
745–8.
7. Tobón-Arroyave SI, Franco-González LM,
Isaza-Guzmán DM, Floréz-Moreno GA,
Bravo-Vásquez T, Castaneda-Peláez DA,
et al. Immunohistochemical expression of
RANK, GRa and CTR in central giant cell
granuloma of the jaws. Oral Oncol
2005;41:480–8.
8. Vered M, Buchner A, Dayan D. Immunohis-
tochemical expression of glucocorticoid and
calcitonin receptors as a tool for selecting
therapeutic approach in central giant cell
granuloma of the jawbones. Int J Oral Max-
illofac Surg 2006;35:756–60.
9. Flórez-Moreno GA, Henao-Ruiz M, Santa-
Sáenz DM, Castañeda-Peláez DA, Tobón-
Arroyave SI. Cytomorphometric and immu-
nohistochemical comparison between cen-
tral and peripheral giant cell lesions of the
jaws. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2008;105:625–32.
10. Tiffee JC, Aufdemorte TB. Markers for
macrophage and osteoclast lineages in giant
cell lesions of the oral cavity. J Oral Max-
illofac Surg 1997;55:1108–12.
11. Rawashdeh MA, Bataineh AB, Al-Khateeb
T. Long-term clinical and radiological out-
comes of surgical management of central
giant cell granuloma of the maxilla. Int J
Oral Maxillofac Surg 2006;35:60–6.
12. Tosco P, Tanteri G, Iaquinta C, Fasolis M,
Roccia F, Sid Berrone Garzino-Demo P.
Surgical treatment and reconstruction for
central giant cell granuloma of the jaws: a
review of 18 cases. J Craniomaxillofac Surg
2009;37:380–7.
YIJOM-2324; No of Pages 7
13. Bataineh AB, Al-Khateeb T, Rawashdeh
MA. The surgical treatment of central giant
cell granuloma of the mandible. J Oral
Maxillofac Surg 2002;60:756–61.
14. Eisenbud L, Stern M, Rothberg M, Sachs
SA. Central giant cell granuloma of the jaws:
experiences in the management of thirty-
seven cases. J Oral Maxillofac Surg
1988;46:376–84.
15. Borges HO, Machado RA, Vidor MM, Bel-
trão RG, Heitz C, Filho MS. Calcitonin: a
non-invasive giant cells therapy. Int J Pediatr
Otorhinolaryngol 2008;72:959–63.
16. de Lange J, Rosenberg AJ, van den Akker
HP, Koole R, Wirds JJ, van den Berg H.
Treatment of central giant cell granuloma of
the jaw with calcitonin. Int J Oral Maxillofac
Surg 1999;28:372–6.
17. Sadiq Z, Goodger NM. Calcitonin-induced
osteoplastic reaction in the mandible. Br J
Oral Maxillofac Surg 2011;49:578–9.
18. Abdo EN, Alves LC, Rodrigues AS, Mes-
quita RA, Gomez RS. Treatment of a central
giant cell granuloma with intralesional cor-
ticosteroid. Br J Oral Maxillofac Surg
2005;43:74–6.
19. Adornato MC, Paticoff K. Intralesional cor-
ticosteroid injection for treatment of central
giant-cell granuloma. J Am Dent Assoc
2001;132:186–90.
20. Carlos R, Sedano HO. Intralesional corticos-
teroids as an alternative treatment for central
giant cell granuloma. Oral Surg Oral Med Oral
Pathol Oral Radiol Endodont 2002;93:161–6.
21. Comert E, Turanli M, Ulu S. Oral and intra-
lesional steroid therapy in giant cell granu-
loma. Acta Otolaryngol 2006;126:664–6.
22. Baker SB, Parikh PM, Rhodes DN, Abu-
Ghosh A, Shad AT. Aggressive central giant
Please cite this article in press as: Nogueira RLM, et al. Glucocorticoid and calcitonin receptor expression in central giant cell lesions:
implications for therapy, Int J Oral Maxillofac Surg (2012), doi:10.1016/j.ijom.2012.01.017
Glucocorticoid and calcitonin receptor in central giant cell lesion
cell lesion of the maxilla: surgical manage-
ment and the use of adjuvant interferon Alfa-
2a. Plast Reconstr Surg 2008;122:77e–9e.
23. de Lange J, van Rijn RR, van den Berg H,
van den Akker HP. Regression of central
giant cell granuloma by a combination of
imatinib and interferon: a case report. Br J
Oral and Maxillofac Surg 2009;47:
59–61.
24. Nogueira RL, Teixeira RC, Cavalcante RB,
Ribeiro RA, Rabenhosrt SH. Intralesional
injection of triamcinolone hexacetonide as
an alternative treatment for central giant-cell
granuloma in 21cases. Int J Oral Maxillofac
Surg 2010;39:1204–10.
25. Vered M, Shohat I, Buchner A, Dayan D,
Taicher S. Calcitonin nasal spray for treat-
ment of central giant cell granuloma: clin-
ical, radiological, and histological findings
and immunohistochemical expression of cal-
citonin and glucocorticoid receptors. Oral
Surg Oral Med Oral Pathol Oral Radiol
Endod 2007;104:226–39.
26. Faria MH, Patrocı́nio RM, Moraes Filho
MO, Rabenhorst SH. Immunoexpression of
tumor suppressir genes P53, P21WAF1/CIP1
AND P27KIP1 in human astrocytic tumors.
Arq Neuropsiquiatr 2007;65:1114–22.
27. Landber G, Roos G. Proliferating cell
nuclear antigen and Ki-67 antigen expres-
sion in human haematopoietic cells during
growth stimulation and differentiation. Cell
Prolif 1986;26:427–37.
28. McCarty Jr KS, Miller LS, Cox EB, Konrath
J, McCarty Sr KS. Estrogen receptor ana-
lyses. Correlation of biochemical and immu-
nohistochemical methods using monoclonal
antireceptor antibodies. Arch Pathol Lab
Med 1985;109:716–21.
7
29. Jacoway JR, Howell FV, Terry BC. Central
giant cell granuloma: an alternative to sur-
gical therapy. Oral Surg Oral Med Oral
Pathol 1988;66:572.
30. Harris M. Central giant cell granulomas of
the jaws regress with calcitonin therapy. Br J
Oral Maxillofac Surg 1993;31:89–94.
31. O’Malley M, Pogrel MA, Stewart JC, Silva
RG, Regezi JA. Central giant cell granulo-
mas of the jaws: phenotype and prolifera-
tion-associated markers. J Oral Pathol Med
1997;26:159–63.
32. Liu B, Yu S-F, Li TJ. Multinucleated giant
cells in various forms of giant cell contain-
ing lesions of the jaws express features of
osteoclasts. J Oral Pathol Med 2003;32:
367–75.
33. Kurokawa M, Michelangeli VP, Findlay
DM. Induction of calcitonin expression by
glucocorticoids in T47D human breast can-
cer cells. J Endocrinol 1991;130:321–6.
34. Rachmiel A, Emodi O, Sabo E, Aizenbud D,
Peled M. Combined treatment of aggressive
central giant cell granuloma in the lower jaw.
J Craniomaxillofac Surg; in press.
Address:
Rafael Lima Verde Osterne
Department of Pathology
Fortaleza University School of Medicine
Av. Washington Soares
1321
Edson Queiroz
PO Box 1258
60811-905 Fortaleza
Ceará
Brazil
Tel.: +55 85 99281718
E-mail: rlimaverde@unifor.br