ARTICLE
Auteur(s) : Toshiyuki YAMAMOTO1, Ichiro
KATAYAMA2, Kiyoshi NISHIOKA1
1 Department of Dermatology, Tokyo Medical and Dental
University, School of Medicine, 1‐5‐45 Yushima, Bunkyo‐ku,
Tokyo 113‐8519, Japan. 2 Department of Dermatology,
Nagasaki University, 1‐7‐1 Sakamoto, Nagasaki 852‐8102,
Japan
Reprints: T. Yamamoto. Fax: (+ 81) 3.5803.0143 E‐mail:
yamamoto.dermmed.tmd.ac.jp
Article accepted on 31\03\2003
Dermatofibroma (DF) is a common, benign dermal nodule which
frequently occurs on the extremities of middle‐aged women [1].
Besides limbs, DF sometimes develops on the shoulders or buttock,
suggesting that DF develops by several stimuli. In most cases, DF
presents as a solitary lesion or occasionally as a few lesions at
most. A recent review demonstrates that multiple DFs occur
associated with autoimmune disorders or in patients under
immunosuppressive therapy, in a relatively short period of time
[2]. In one aspect, DF has been considered as a reactive
hyperplasia rather than a true neoplasm, whereas recent reports
also suggest chromosomal abnormalities in some DFs [3‐5]. Thus, the
etiopathology of DF still remains unsettled. Histologically, DF is
characterized by fibrous proliferation in the mid‐ to lower dermis
accompanied by acanthosis of the overlying epidermis with basal
pigmentation, suggesting the interaction among epidermal cells,
melanocytes and stromal cells via direct\indirect pathways. In this
review we will focus on the significance of mast cells to explain
the histopathological features of DF.
Mast cell infiltration in DF
Mast cells derive from CD34 + hematopoietic precursor
cells residing in the bone marrow and the differentiation stems
from mononuclear cells. Recent evidence demonstrates that mast
cells are a rich source of cytokines or mediators which can affect
fibroblasts, keratinocytes or T cells. Mast cells are often
discussed in association with various skin disorders [6]. Cawley
and Hoch‐Ligeti [7] reported that the mast cell number increases in
the solitary DF lesion. An increased number of mast cells are
detected in the upper portion of DF lesions, or in the layer
between DF lesions and the overlying epidermis, which have been
postulated to play a role in the induction of DF. An intense
staining for factor XIIIa is reported in the majority of tumor
cells in DF [8]. Mast cell degranulation can be implicated in the
upregulation of factor XIIIa [9], suggesting a possible interation
between mast cells and factor XIIIa fibrohistiocytic cells.
DF occasionally develops in multiple forms in patients who are
supposed to be under immunosuppression, including systemic lupus
erythematosus (SLE), myasthenia gravis, pemphigus vulgaris,
ulcerative colitis, AIDS, or in patients under immunosuppressive
therapy [2] (Fig.
1). We confirmed that the mast cell number further
increases in multiple DFs associated with SLE, as compared with
that in solitary DF, and interestingly, mast cells are decreased in
number in a DF under spontaneous regression [10]. Serum of a
patient with SLE and multiple DFs exhibited fibroblast growth
stimulatory activity [11]. The fact that multiple DFs often
disappear spontaneously in patients with SLE strongly suggests that
this type of DF is a localized reactive proliferative disorder, and
mast cells may play an important role in the induction of DFs.
However, the reason why SLE is selectively most common in
association with multiple DFs, as compared with other connective
tissue diseases, is obscure at present.
.
Myxomatous lesions with mucin deposition in the layer between the
DF lesion and the overlying epidermis are occasionally seen, with
abundant mast cells (Fig. 2; A, B). The
characterization (duration from onset, the presence of occult
diseases) of DF with mucin deposition should be determined. We
previously reported this type of DF occurring in a patient with
psoriasis [12]. In addition, a recent report suggests a new variant
of DF, myxoid DF, characterized by marked mucinous stromal changes
[13]. It is supposed that increased numbers of mast cells exist in
the myxoid lesions of this type of DF.
.
Two types of human mast cells are recognized based on differences
in the content of neutral proteases. MCT cells contain tryptase but
little or no chymase in their secretory granules, and MCTC cells
contain substantial quantities of both tryptase and chymase.
Results of immunohistological distribution showed a number of
immunoreactive cells for tryptase in DF (Fig. 3), whereas
chymase‐positive cells were very few.
.
Mast cell‐fibroblast interaction
Mast cells and fibroblasts are strongly suggested to exert
mutual influence. Mast cells have been observed associated with
fibrosis, because increased numbers of mast cells are detected in
fibrotic tissues, including scleroderma, hypertrophic scar or
keloid. Although dermal fibrosis does not occur in systemic
mastocytosis, fibrosis can affect the spleen, liver, and
myocardium. Potential fibrogenic factors which are produced from
mast cells include histamine, tryptase, transforming growth
factor‐β (TGF‐β), basic fibroblast growth factor (bFGF),
interleukin‐4 (IL‐4), and platelet‐derived growth factor (PDGF).
Histamine induces the growth of fibroblasts and the synthesis of
collagen [14, 15]. Tryptase also induces fibroblast proliferation
and collagen synthesis [16]. TGF‐β shows biphasic effects of
fibroblast proliferation, and increases collagen synthesis. bFGF
induces proliferation and chemotaxis of fibroblasts [17], and
IL‐4 also stimulates fibroblasts proliferation, collagen
synthesis as well as chemotaxis [18]. PDGF stimulates fibroblast
proliferation as well as collagen production and secretion by
fibroblasts [19]. A recent report demonstrates that human dermal
mast cells and leukemic mast cells express bFGF at both mRNA and
protein levels [20].
On the other hand, different mediators produced by fibroblasts
have been described to activate mast cells. One of the most
important candidates of mediators released from fibroblasts that
activate mast cells is stem cell factor (SCF), a mast cell growth
factor. SCF is mainly produced by fibroblasts, and also by
endothelial cells and keratinocytes in the skin. The many different
actions of SCF on mast cells include the stimulation of
proliferation, differentiation, adhesion, chemotaxis and inhibition
of apoptosis [21]. It is reported that SCF expression was increased
in the DF lesion at the mRNA [22, 23] and protein [23] levels.
Another candidate is nerve growth factor (NGF). NGF is produced by
many types of cells including fibroblasts, keratinocytes, mast
cells and T cells, and is recently suggested to be involved in the
tissue repair process. The effects of NGF on mast cells include
stimulation of proliferation, differentiation, survival and
mediator secretion. Our immunohistochemical study showed that DF
fibroblasts showed intense expression of NGF (Fig. 4). A recent study
demonstrated that NGF modulated skin fibroblasts phenotype into
myofibroblasts [24]. DF fibroblasts show positive reactivity for
α‐smooth muscle actin, indicating myofibroblast phenotype, which
may be mediated in part by NGF.
.
In vitro, mast cells tightly attach to fibroblasts when
co‐cultured in monolayers [25]. Fibroblasts support mast cell
viability and induce an enhanced release of histamine. Fibroblasts
have been shown to influence mast cell differentiation [25], and
granule synthesis [26], whereas mast cell mediators can stimulate
mitogenic and synthetic activity of fibroblasts. We previously
showed that human mast cell lines, HMC‐1, are incorporated within
the collagen lattices when co‐cultured with fibroblasts in
three‐dimensional collagen lattices, and prominently enhanced gel
contraction [27]. This accerelation of gel contraction was mediated
via cell‐cell interaction through, in part, SCF\c‐kit. Furthermore,
Gailit et al. [28] recently suggested that tryptase is one
of the major mediators of mast cells showing differentiation of
fibroblasts into myofibroblasts and enhancement of collagen gel
contraction.
Mast cell‐keratinocyte interaction
An increased number of mast cells are detected in lichenified
skin in atopic dermatitis [29]. Mast cell‐derived mediators are
suggested to play a part in the induction of epidermal hyperplasia
in atopic dermatitis [30] and mycosis fungoides [31]. As is
well‐recognized, the overlying epidermis of DF lesions is
elongated. It is tempting to suppose that a mast cell‐derived
factor may help keratinocyte proliferation. It is interesting to
determine whether keratinocyte growth factor (KGF), insulin‐like
growth factor (IGF) or epidermal growth factor (EGF), which
potentially induce keratinocyte proliferation, are produced by mast
cells. Human dermal mast cells and also HMC‐1 cells express
heparin‐binding EGF mRNA [20]. In addition, HMC‐1 supernatants
and histamine induced enhanced KGF secretion from dermal
fibroblasts [20]. Thus, it is speculated that mast cells
directly\indirectly play a part in the induction of acanthosis in
DF. On the other hand, we suggested that keratinocyte‐derived SCF
may play a role in the increase of mast cells in DF [22]. Increased
numbers of mast cells are also detected in neurofibromas or
hypertrophic scars, which, nevertheless lack epidermal hyperplasia.
One possible explanation is that released mediators are different
depending on the various diseases.
Mast cell‐melanocyte interaction
DF clinically presents as a brownish nodule, and histological
features show basal pigmentation in the overlying epidermis.
Immunologic activation of mast cells results in the synthesis of
various mediators, including small lipids like platelet activating
factor (PAF), prostaglandins (PGs), and leukotrienes (LTs),
chemokines, cytokines and growth factors. Among them, melanocyte
growth stimulatory activity (MGSA), LTB4 and LTC4 have been
considered to be potent candidates [32].
SCF is critical for the development of melanocytes through c‐kit
receptor. In human beings, SCF injections induce local cutaneous
hyperpigmentation [33]. Shishido et al. [23] suggest that
the mechanism of epidermal hyperpigmentation in DF involves SCF and
hepatocyte growth factor (HGF), which are secreted abundantly by DF
fibroblasts.
Mononuclear cell infiltration
Histologically, patchy cellular infiltration of mononuclear
cells is occasionally seen around the edge of the DF lesion. Recent
studies suggest that mast cells produce several chemokines [34‐36].
It is speculated that mast cell‐derived chemokines may contribute
to mononuclear cell recruitment.
Conclusion
Although the etiology of DF still remains unclear, an
immunoreactive pathogenesis has been suggested [37, 38]. A recent
report suggests that DF represents an abortive immunoreactive
process mediated by dermal dendritic cells [37]. Additionally, mast
cells may also play a role in the reactive process in induction of
DF. DF fibroblasts are supposed to be exposed to certain cytokines
derived from infiltrating cells, which may be responsible for the
phenotypic changes of DF fibroblasts. Possible mediators released
from mast cells, which are supposed to play a part in several
aspects in the induction of DF, are shown in Table I. Further elucidation of mast cells may
clarify the mechanisms of DF.
Table I. Mast cell‐derived mediators and their
potential significance in DF
| Mast cell‐derived mediators |
Potential properties in DF |
IL‐4, TGF‐β, PDGF
bFGF, tryptase, histamine |
Proliferation of fibroblastic cells |
| EGF |
Elongation of overlying epidermis |
| LTB4, LTC4, MGSA, SCF |
Basal pigmentation |
| MCP‐1, MIP‐1α\β, RANTES |
Cellular infiltration |
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