Journal of
Oral Pathology & Medicine
doi: 10.1111/j.1600-0714.2009.00870.x
Mast cells in periapical lesions: potential role in their
pathogenesis
Radojica Dražić1, Jelena Sopta2, Arsa J. Minić3
1
Clinic of Oral Surgery, Faculty of Stomatology; 2Institute of Pathology, Faculty of Medicine, University of Belgrade, Belgrade;
3
Department of Pathology, Medical Academy, University of European Studies, Belgrade, Serbia
OBJECTIVE: The aim of this study was to qualitatively
and semi-quantitatively analyze mast cells in periapical
lesions.
MATERIALS AND METHODS: Biopsy specimens of 96
periapical lesions were stained with hematoxylin–eosin,
histochemical Giemsa and immunohistochemical CD 117
(C kit) antibody. Mast cell count below 100 mast cells on
1000 fields of high power magnification was noted as
negative’, 101–400 as mild’, 401–800 cells as moderate’,
and over 800 cells as severe’.
RESULTS: Mast cells are found in 68 (70.8%) lesions. The
presence of mast cells was greater in cysts than in gran-
ulomas (P < 0.0028). There was no difference in semi-
quantitative expression of CD 117 in granulomas and
cysts (P > 0.05). Mast cells were placed in both: inflam-
matory infiltrate and in fibroblastic areas of periapical
lesions, and their presence was most frequently mild to
moderate.
CONCLUSIONS: The findings of present study could
suggest a role of mast cells in regulation of cellular
immune mechanisms in periapical lesions, balancing
between alterative and reparatory processes in inflamed
periapical tissue.
J Oral Pathol Med (2010) 39: 257–262
Keywords: CD 117; mast cells; periapical lesions
Introduction
A bacterial, chemical, or mechanical irritation from
tooth root canals usually causes inflammation of peri-
apical tissue and formation of periapical lesions (1, 2).
As the inflammation in periapical lesions could be of
acute or chronic form, periapical lesions could be
manifested differently, either clinically or microscop-
ically (3, 4). Depending on the stage of development,
histopathologic examination of periapical lesions reveals
a numerous inflammatory cells such as polymorpho-
Correspondence: Dražić Radojica, Clinic of Oral Surgery dr Subotica
4 11000 Belgrade, Serbia. Tel: + 38163288535, Fax: + 381112685824,
E-mail: raddraz@sbb.rs
Accepted for publication November 13, 2009
J Oral Pathol Med (2010) 39: 257–262
ª 2010 John Wiley & Sons A/S Æ All rights reserved
interscience.wiley.com/journal/jop
nuclear leukocytes, macrophages, lymphocytes, plasma
cells, mast cells, basophils, and eosinophils (2, 5, 6).
During the acute phase they are infiltrated mostly
by polymorphonuclear leukocytes, whereas in chronic
phase they are mostly infiltrated by plasmocytes, lym-
phocytes, macrophages (7, 8). The presence of these cells
indicates the existence of local immune reactions in
periapical lesions (2, 6, 7).
Mast cells (MC) are rarely present in periapical
granulomas and cysts (6). The role of mast cells as the
key effector cells of allergic inflammation is well known.
Apart from their role in anaphylactic inflammatory
reactions, mast cells are involved in either IgE-depen-
dent or IgE-independent immune response through
expression of numerous mediators (9). Histamine and
leukotriene C4 (LTC4) increases vascular permeability
of small blood vessels, LTB4 targets neutrophils and
mast-cell progenitors, while prostaglandin D2 (PGD2)
may act as a pro-inflammatory mediator (10, 11).
Cytokines released by mast cells such as IL-3 induce
basophil recruitment and activation, IL-5 eosinophil
recruitment and activation and IL-13 induction of IgE
synthesis by B cells (12, 13). Mast cells are able to
produce a wide spectrum of mediators, creating
reciprocal functional interaction between mast cell
activation and subsequent T-lymphocyte stimulation.
Moreover it has been shown recently that mast cells
have a possible protective role in host defense against
viral infection (14).
It has also been shown that mast cells may enhance
bone resorption by heparin production (15). Another
possible pathway that stimulates osteoclast activity may
be production of tumor necrosis factor alpha (TNF-a)
in periapical lesions (16). Contrary to this mast cells may
be implicated in tissue repair and collagen synthesis (6,
17, 18). Mast cells tryptase may activate fibroblasts to
produce collagen (19), thus contributing wound healing
and fibrosis (9).
Among some other cells surface of mast cells express
KIT (CD 117) which is a transmembrane tyrosine kinase
receptor protein encoded by the proto-oncogene c-kit
that maps to chromosome 4 (4q11-12). KIT is expressed
at high levels in several normal tissues, including
hematopoietic stem cells, mast cells, melanocytes, germ
 Mast cells in periapical lesions
Dražić et al.

258
cells as well as in gastrointestinal stromal tumors (20). and then mounted in Canada balsam (Molar Chemical,
Binding of stem cell factor to CD 117 forms a dimer that Budapest, Hungary).
activates signaling through second messengers (21). Each paraffin block was cute in 10 slides, and each
Such signaling through CD117 plays a role in cell slide was analyzed in 100 different fields of high power
survival, proliferation, and differentiation (22). Point magnification (HPM · 400), totally 1000 fields.
mutations of proto-oncogene c-kit have been associated Slides stained with CD 117 were semi-quantitatively
with mastocytosis (23, 24). analyzed for the presence of mast cells. Mast cell count
There is a paucity of data about the possible role of below 100 mast cells on 1000 fields of high power
MC in periapical lesions (25, 26). The aim of this study magnification was noted as negative’, 101–400 as mild’,
was to analyze the presence of mast cell qualitatively 401–800 cells as moderate’, and over 800 cells as
and semi-quantitatively in periapical lesions based on severe’.
immunohistochemical expression of CD 117, with The comparison between the expression of CD 117
regard to their possible role in pathogenesis of periapical in granulomas and cysts was performed with Pearson
lesions. Chi-squared tests, and one-way ANOVA tests. A
P value <0.05 or less was designated as statistically
significant.
Materials and methods
Ninety-six periapical lesions in 86 patients from The
Results
Register of Institute of Pathology from 2001 to 2003
were analyzed. All specimens were obtained after According to pathological characteristics 63 specimens
periapical surgery or tooth extraction in the cases of were diagnosed as granulomas’, and 33 as cysts’.
previously failed endodontic treatment. Mast cells were found in 68 (71%) periapical lesions,
while in 28 (29%) periapical lesions they were absent.
Staining for mast cells The presence of mast cells was categorized as mild’ in 45
Biopsy specimens were fixed in 10% neutral buffered (47%), and as moderate’ in 15 (16%) cases. Just in eight
formalin and processed for either HE histology, Giemsa (8%) of all periapical lesions we found >800 mast cells
stain or immunohistochemistry. Specimens obtained by on 1000 HPM (Table 1).
HE staining served for differentiation of cysts from Mast cells were found in both areas: of inflammatory
granulomas. Cysts were diagnosed according to the infiltrate and fibroblastic areas, with slight predomina-
following histological criteria: lesions that were com- tion in the inflammatory zone (Fig. 1). Mast cells were
posed of a cavity that was partially or totally lined with
epithelium, were diagnosed as cysts. Lesions composed
of chronically inflamed fibrous tissue without cavity
Table 1 Presence of mast cells in periapical lesions stained with
within the lesion were diagnosed as granulomas. Using CD 117
Giemsa methods, mast cells were colored metachromat-
ically violet. Giemsa staining was used for diagnostic
Intensity n %
purposes.
For the immunostain with CD 117, paraffin-embed- Absent 28 29
ded specimens were cut with a microtome at 4-lm Mild 45 47
moderate 15 16
thickness and, after a thorough dewaxing, tissue Severe 8 8
sections were incubated with 0.5% hydrogen peroxide Total 96 100.0
in methanol at 22C for 10 min, and then washed in
running tap water for 15 min. Sections were treated
with 0.1% trypsin (Sigma, Pool, UK) mixed in 0.1%
calcium chloride (pH 7.8) for 10 min at 37C. Non-
specific binding of protein was blocked by incubation
in normal rabbit serum diluted 1:5 in Tris-buffered
saline (TBS; pH 7.6) for 15 min. The slides were then
incubated for 18 h at 4C with the polyclonal rabbit
anti-human antibody CD 117 (anti-c kit antibody)
DAKO (A) 4502, Dako, Cambridge, UK), washed in
TBS for 7 min and then incubated for 30 min with
biotinylated rabbit anti-mouse IgG (Amersham, Amer-
sham, UK). After the slides had been washed in TBS
for 7 min, they were incubated with streptavidin-biotin
complex conjugated with horseradish peroxidase
(DAKO k0377; Dako) for 30 min. The slides were
developed in diaminobenzidine-hydrogen peroxide
substrate (Sigma) for 10 min, rinsed in TBS and Figure 1 Numerous mast cells are surrounded by chronic and acute
washed in tap water for 5 min. Sections were then inflammatory cells. Cytoplasm of mast cells is granulated, and nucleus
counterstained with hematoxylin, dehydrated, cleared, is located eccentrically (H&E, 400·).

J Oral Pathol Med

 Mast cells in periapical lesions
Dražić et al.

259
A B

Figure 2 (A) Degranulated mast cells are colored metachromatically violet. (B) Lesions background consists of fibroblast (Giemsa stain, 400·).

active, and showed signs of degranulation on Giemsa The versatile role of mast cells in allergy, in innate
stain (Fig. 2a,b). The other inflammatory cells (lympho- immune responses is well recognized. Their participation
cytes, plasma cells, neutrophilic granulocytes) and in the pathogenesis of periapical lesions is not fully
macrophages were presented in the tissue. Mast cells cleared, and has often been connected with allergic
were not associated with eosinophils in any of the hypersensitivity reactions (6, 27, 29). The membrane of
specimens. MC contains IgE antibodies, and their cytoplasm
Mast cells were found in 39 of 63 granulomas (62%), contains histamine, serotonin, heparin, and proteases.
and 29 of 33 cysts (88%). The presence of mast cells was These mediators released after degranulation of mast
greater in cysts than in granulomas (P < 0.0028) cells play an important role in inflammatory and allergic
(Graph 1). In both lesions – 27(69%) granulomas, and
in 18 (62%) cysts, expression of CD 117 was most
frequently found to be mild’. Infiltration with 401–800
cells classified as moderate’ was more frequently found
in cysts eight (28%), than in granulomas seven (18%)
(Fig. 3). Severe’ mast cells infiltration was found in five
(13%) granulomas and three (10%) cysts (Fig. 4).
Although there are a difference in semi-quantitative
expression of CD 117 between cysts and granulomas,
these differences are not statistically significant
(P > 0.05) (Graph 2).

Discussion
Inflammatory infiltrate of periapical lesions is composed
mostly of plasmocytes, lymphocytes, and macrophages
(3, 6, 27). Among other inflammatory cells, MC
represent minority of the inflammatory infiltrate of Figure 3 CD 117 (c-kit) expression semi-quantitative categorized as
periapical lesions (28). moderate’ (400·).

100%
90%
80%
Present
70% 61.90%
60% Present
87.88%
50%
40%
30%
Absent
20% 38.10%
10% Absent
12.12%
0%
Granulomas Cysts
Absent Present

Graph 1 Presence of mast cells in granulomas and cysts stained with Figure 4 CD 117 (c-kit) expression semi-quantitative categorized as
CD 117. severe’ (400·).

J Oral Pathol Med

 Mast cells in periapical lesions
Dražić et al.
260
100%
Severe Severe
90% 13.00% 10.00%
80% Moderate Moderate
70%
18.00% 28.00%
60%
50%
40% Mild
69.00% Mild
30% 62.00%
20%
10%
0%
Granulomas Cysts
Mild Moderate Severe
Graph 2 Semi-quantitative infiltration of CD 117 in granulomas and
cysts.
reactions (6, 27). Mast cells in periapical lesions could
release histamine which increases vascular permeability
of small blood vessels (6). The existence of allergic
reactions could be evidenced by the presence of IgE
positive plasma cells and mast cells at the same locations
(27).
A close relationship between immunocompetent cells
and MC exists. It has been shown that secretion
products of T lymphocytes intensify the growth of MC
in vitro’, and that the migration of basophils is modified
by interleukins (8). On the other hand, reciprocal
interaction between T lymphocytes and basophils ⁄ mast
cells indicates a possibility that histamine (released from
MC) inhibits the activity of T lymphocytes by suppres-
sion of production of interferons and interleukins.
Histamine, released from MC, could block immune
responses reactions by reduction of production and
absorption interleukins and interferons produced by
T lymphocytes. It seems that MC are part of a negative
feedback mechanism in blockage of immune responses
(7, 8).
One of the first studies of MC by Matheisen (30)
demonstrated presence of mast cells in granulomas and
cysts, but without description of its localization.
Another study restricted only to periapical granulomas
quantified number of MC, based on staining with
toluidine blue, found them to be more numerous in
granulomas with proliferating epithelium and lower in
chronic apical abscesses (26). Staining MC with tolui-
dine blue seems to be dependent on a intact number of
mast cell granules, whereas the more sensitive immuno-
histochemical techniques are able to detect partially
degranulated mast cells, which still contain enough
tryptase (31). Moreover it has been shown that basoph-
ils, like MC have the capacity to release tryptase in vivo,
and that anti-tryptase antibodies cannot be used to
distinguish these two cell types from one another (32).
We therefore used staining of CDD 117, and consider
that staining of CDD 117 may be more sensitive for
detection of MC, since the existing data showed a strong
membrane reactivity for CD l17 is identified in MC, that
may be useful in the diagnosis of MC disorders (33).
J Oral Pathol Med
In a similar recent study MC were more frequently
found in periapical cysts than in granulomas (25). Our
findings have shown that the incidence of MC is greater
in cysts than in granulomas. de Oliveira et al. (25) found
that MC were more frequently found in periapical cysts
than in granulomas based on the expression of mast cell
tryptase in both lesions. However we did not find any
difference in semi-quantitative intensity of presence of
MC between granulomas and cysts. In both granulomas
and cysts a there is a functional relationship between
MC and inflammatory infiltrate. It is possible that MC
are more frequently found in cysts – as their longstand-
ing lesions composed of fibrous capsule – contain more
MC than granulomas. Mast cells are implicated in
inflammatory processes in the cyst wall, and may be
implicated in fibrous tissue formation as well. Mast cells
are long-living cells that have the property to be
repeatedly activated and to re-synthesize their mediators
(34), reflecting possible effects on T-cells (35), and other
neighboring cells.
Intensity of presence of MC in periapical lesions in
our study may be regarded as low as their intensity was
predominantly mild (47%) and moderate (16%) in the
majority of periapical lesions. This is in agreement with
results of previous study in which MC have been found
to be of low frequency in periapical lesions (36).
Although their number is small when compared with
other inflammatory cells (28), their interrelation to other
cells may be multiple and bidirectional. A comparison of
cytokine production with the cellular composition of
periapical lesions showed that MC seem to be predom-
inantly involved in the effector immune mechanisms
mediated by T-helper cells (28). Our findings have
shown that MC were present in both inflammatory
infiltrate and fibrous areas of periapical lesions. A
presence of degranulated cells suggests that MC have an
active role in periapical lesions. A similar finding was
reported by Marton and Kiss (36), whereas the same
authors in another study reported that MC were absent
in granulation tissue, but they were numerous in the
fibrous capsule of periapical lesions (17, 27). Our study
also proved presence of MC in fibrous area of periapical
lesions.
It is considered that MC contribute to a fibrous
tissue formation by production of hyaluronic acid (37).
In addition, there are presumptions that mast-cells
intensify the growth of collagen fibers by effects of
heparin (38). It has been shown that MC activate
fibroblasts through tryptase that stimulate collagen
messenger ribonucleic acid synthesis and promotes
fibroblast (19).
CD117 is an important cell surface marker. Binding
of stem cell factor by CD117 leads to receptor
activation of its tyrosine kynase activity (21). A
number of signal transduction pathways have been
implicated in mediating CD117 functions in mast cells,
including cellular proliferation and differentiation,
resistance to apoptosis, mobility and chemotaxis,
adhesion to fibronectin and enhancement of serotonin
and histamine release (39–41). Mast cells can adhere to
fibronectin, whereas fibroblasts adhere to fibronectin

too, through the classical fibronectin integrin receptor
(42, 43). This interaction may have possible roles in
processes such as wound healing and fibrosis (42).
Apart of this linkage adhesion of mast cells to
fibroblasts is mediated by different receptors than
adhesion to common extracellular matrix substrates
(44). Moreover it has been shown that the administra-
tion of the mast cell stabilizers nedocromil or disodium
cromoglycate can delay or attenuate fibrous tissue
formation in peritoneal adhesions (45). There are
proofs that MC participate in both: at the onset of
fibrosis and at later stages formation of peritoneal
adhesions (46). Tryptase, chymase, histamine, heparin,
TNF-a, and TGF-b have been shown to influence lung
or skin fibroblast proliferation (47, 48). In addition,
TNF-a has been found to be fibrogenic factors for
human fibroblasts (47). Mast cells are reported to
specifically influence granulation tissue organization
during wound repair (45, 49). The presence of degran-
ulated MC in a proximity of fibroblasts in our study,
may allow us to initiate a speculation about their
possible role in fibrous tissue formation.
Periapical inflammatory granulation tissue formation
is a consequence of constant inflow of irritants from
root canals that are usually caused of endodontic
treatment failure. Perpetuation of the inflammatory
processes and consequent inability host defenses to
win, results in forming of a circumscribed barrier
composed of granulation tissue and the peripheral
fibrous tissue that represents a dynamic balance
between microorganisms and the host-defense mecha-
nisms. Induction of a strong inflammatory response
and consequent tissue damage, also seem to start tissue
repair. TNF-a released from preformed stores of MC
(50), and produced by other cells, may be activator of
either osteoclast activity (16), and ⁄ or proliferation of
fibroblasts as well (47). Mast cells contain a wide range
of cytoplasmic granules that are responsible for var-
ious stages of their functional activity, and multiple
interactions between mast cells and other cells involved
in the immune response.
Taking together our and previously discussed results,
it could be presumed that mast cells are implicated in
regulation of cellular immune mechanisms balancing
between inflammatory and reparatory processes in
inflamed periapical tissue.
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Acknowledgements
Authors wish to thank to the entire staff of Department of Pathology
Faculty of Dentistry, and Department of Pathology, Faculty of Medicine,
University of Belgrade for their help in performing this study.
Funding
None.
Competing interests
None declared.