Oral pyogenic granuloma: Various concepts of etiopathogenesis

Abstract

Pyogenic granuloma or granuloma pyogenicum is a well-known oral lesion. The name pyogenic granuloma is a misnomer since the condition is not associated with pus and does not represent a granuloma histologically. Pyogenic granuloma of the oral cavity is known to involve the gingiva commonly. Extragingivally, it can occur on the lips, tongue, buccal mucosa, palate, and the like. A history of trauma is common in such sites. The etiology of the lesion is not known, though it was originally believed to be a botryomycotic infection. It is theorized that pyogenic granuloma possibly originates as a response of tissues to minor trauma and/or chronic irritation, thus opening a pathway for invasion of nonspecific microorganisms, although microorganisms are seldom demonstrated within the lesion. Pathogenesis of pyogenic granuloma is still debatable. Medline and PubMed databases were searched under the following key terms: Pathogenesis of oral pyogenic granuloma, pyogenic granuloma, and oral pyogenic granuloma. This search was limited to articles on human/animal studies which were published in English language. After reviewing the searched articles, the relevant articles were selected for the present review. Through this article, we have tried to summarize and present all the concepts of pathogenesis related to this most common and most mysterious oral lesion.

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Journal of Oral and Maxillofacial Pathology Vol. 16 Issue 1 Jan - Apr 2012 79
INTRODUCTION
Soft tissue enlargements of the oral cavity often present a
diagnostic challenge because a diverse group of pathologic
processes can produce such lesions. An enlargement
may represent a variation of normal anatomic structures,
inammation, cysts, developmental anomalies, and neoplasm.
Within these lesions is a group of reactive hyperplasias,
which develop in response to a chronic, recurring tissue
injury that stimulates an exuberant or excessive tissue repair
response. Pyogenic granuloma is of the most common entities
responsible for causing soft tissue enlargements.
Occurrence of pyogenic granuloma in man was rst described
in 1897 by Poncet and Dor. At that time, it was called
botryomycosis hominis. Pyogenic granuloma has been referred
to by a variety of other names such as granuloma pediculatum
benignum, benign vascular tumor, pregnancy tumor, vascular
epulis, Crocker and Hartzell’s disease. It was given its present
name by Crocker in 1903.[1] However, some researchers believe
that Hartzell in 1904 introduced the term “pyogenic granuloma”
that is widely used in the literature, although, it does not express
accurately the clinical or histopathologic features.[2]
Angelopoulos AP proposed the term “hemangiomatous
granuloma” that accurately expresses the histopathologic
picture (hemangioma like) and the inammatory nature
(granuloma) of oral pyogenic granuloma.[2] Cawson et al.
suggested that since the blood vessels are so numerous in oral
pyogenic granuloma, alternative term for pyogenic granuloma
is granuloma telangiectacticum.[3]
Pyogenic granuloma is well known in dermatology as skin
is a common site for this lesion. The term lobular capillary
hemangioma is increasingly gaining favor in the dermatologic
literature.[3]
INCIDENCE AND PREVALENCE
Bhaskar et al. in their study observed that oral pyogenic
granuloma comprized about 1.85% of all oral pathoses,
Oral pyogenic granuloma: Various concepts of
etiopathogenesis
Reet Kamal, Parveen Dahiya1, Abhiney Puri2
Departments of Oral and Maxillofacial Pathology, HPGDC, Shimla Himachal Pradesh, 1Department of Periodontics and 2Oral and Maxillofacial
Pathology, Himachal Institute of Dental Sciences, Paonta Sahib, Sirmour Himachal Pradesh, India
REVIEW ARTICLE
Address for correspondence:
Dr. Reet Kamal,
Department of Oral and Maxillofacial
Pathology, HPGDC, Shimla
Himachal Pradesh - 177 001, India.
E-mail: pareet00@gmail.com
ABSTRACT
Pyogenic granuloma or granuloma pyogenicum is a well-known oral lesion.
The name pyogenic granuloma is a misnomer since the condition is not
associated with pus and does not represent a granuloma histologically.
Pyogenic granuloma of the oral cavity is known to involve the gingiva commonly.
Extragingivally, it can occur on the lips, tongue, buccal mucosa, palate, and
the like. A history of trauma is common in such sites. The etiology of the lesion
is not known, though it was originally believed to be a botryomycotic infection.
It is theorized that pyogenic granuloma possibly originates as a response of
tissues to minor trauma and/or chronic irritation, thus opening a pathway for
invasion of nonspecic microorganisms, although microorganisms are seldom
demonstrated within the lesion. Pathogenesis of pyogenic granuloma is still
debatable. Medline and PubMed databases were searched under the following
key terms: Pathogenesis of oral pyogenic granuloma, pyogenic granuloma,
and oral pyogenic granuloma. This search was limited to articles on human/
animal studies which were published in English language. After reviewing the
searched articles, the relevant articles were selected for the present review.
Through this article, we have tried to summarize and present all the concepts
of pathogenesis related to this most common and most mysterious oral lesion.
Key words: Etiopathogenesis, oral, pyogenic granuloma
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Journal of Oral and Maxillofacial Pathology: Vol. 16 Issue 1 Jan - Apr 2012
Etiopathogenesis of oral pyogenic granuloma Kamal, et al.80
other than caries and gingivitis treated at US Army Institute
of Dental Research.[1] Daley et al. found that pregnancy
epulides accounted for only 42 of the 757 epulides of all
types.[4] According to Cawson et al. oral pyogenic granuloma
is relatively common. It represents 0.5% of all skin nodules in
children. The pregnancy tumor variant of pyogenic granuloma
occurs in up to 5% of pregnancies.[3] Esmeili et al. in their
review stated that hyperplastic reactive lesions represent as
a group the most common oral lesions, excluding caries,
periodontal, and periapical inammatory disease. In this
group, the second most common group is represented by
hyperplastic reactive gingival/alveolar lesions, including
inammatory gingival hyperplasia, oral pyogenic granuloma,
peripheral giant-cell lesion and peripheral cemento-ossifying
broma.[5] Peralles et al. in their clinicopathologic study
conducted on gingival and alveolar hyperplastic reactive
lesions observed that inammatory gingival hyperplasia and
oral pyogenic granuloma were the most common diagnosis.[6]
In an analysis of 244 cases of gingival lesions in south Indian
population, Shamim et al. found that nonneoplastic lesions
accounted for 75.5% of cases with oral pyogenic granuloma
being most frequent lesion, accounting for 52.71% cases.[7]
ETIOPATHOGENESIS
Some authors regard pyogenic granuloma as an “infectious”
entity. Kerr has reported staphylococci and botryomycosis,
foreign bodies, and localization of infection in walls of blood
vessel as contributing factors in the development of the
lesion.[8] Bhaskar et al. observed that bacterial stains have
demonstrated the presence of gram positive and gram negative
bacilli in oral pyogenic granuloma. But they also suggested
that as these organisms were more common in ulcerated than
in non ulcerated lesions and more common near surface than
in deeper aspects that suggest that these organisms may have
been contaminants from oral ora.[1] According to Shafer
et al., oral pyogenic granuloma arises as a result of infection
by either staphylococci or streptococci, partially because it
was shown that these microorganisms could produce colonies
with fungus-like characteristics. They also stated that it is now
generally agreed that oral pyogenic granuloma arises as a result
of some minor trauma to the tissues that provide a pathway for
invasion of nonspecic types of microorganisms. The tissues
respond in a characteristic manner to these organisms of low
virulence by the overzealous proliferation of a vascular type of
connective tissue. They explain the mechanism by suggesting
that tissue response reiterates the well-known biologic
principle that any irritant applied to living tissue may act either
as a stimulus or as a destructive agent or both. If many cells
are present in a small volume of tissue and there is a relative
reduction of blood ow through the area as in inammation,
the concentration of the stimulating substance will be high and
growth will be stimulated. As differentiation and maturation
are attained, the cells become widely separated and the
concentration of the substance falls and little growth occurs.
In this type of inammation that results in the formation of
oral pyogenic granuloma, destruction of xed tissue cells is
slight but stimulus to proliferation of vascular endothelium
persists and exerts its inuence over a long period of time.[9]
Reichart et al. stated that granulation tissue in oral pyogenic
granuloma may become contaminated by ora of oral cavity
and its surface may often become covered by brin which may
mimic pus. However, still suppuration is not a characteristic
of oral pyogenic granuloma to support infectious origin.[10]
Some investigators consider pyogenic granuloma as a
“reactive” or “reparative” tumor process. Regezi et al. suggest
that pyogenic granuloma represents an exuberant connective
tissue proliferation to a known stimulus or injury like calculus
or foreign material within the gingival crevice.[11] Several
“etiologic factors” such as trauma, injury to a primary tooth,
chronic irritation, hormones, drugs, gingival inammation,
preexisting vascular lesions, chronic irritation due to
exfoliation of primary teeth, eruption of permanent teeth,
defective llings in the region of tumor, food impaction, total
periodontitis, toothbrush trauma, etc. have been suggested
as etiological factors where patients presented with these
ndings.[12]
Murata et al. 1997 in their study observed that after any trauma,
the key to wound healing is the formation of granulation
tissue and this includes the migration of inammatory
cells, migration and proliferation of vascular endothelial
cells and broblasts and synthesis of extracellular matrix.
Such processes of wound healing seem to be controlled by
various kinds of cytokines. Out of these cytokines – role
of growth factors, particularly bFGF – a heparin binding
angiogenic protein, has been found to be highly mitogenic
for capillary endothelial cells and to induce angiogenesis.
They studied bFGF immunolocalisation in gingiva and oral
pyogenic granuloma at its various stages of progression.
They suggested that maximum amounts of bFGF are
synthesized and released from some macrophages and mast
cells into extracellular matrix during neovascularisation of
the granulation tissue.[13]
Trauma has also been implicated in etiopathogenesis of
multiple and satellite oral pyogenic granuloma, although,
exact etiopathogenesis that whether it occurs following
treatment or de novo, is not clearly understood. But various
theories have been proposed. Ainamo suggested that trauma
can cause release of various endogenous substances including
angiogenic factors from the tumor cells and it may also cause
disturbances in the vascular system of the affected area. As
there is a site predilection for labial gingiva in the anterior
region of the oral vestibule, some authors have postulated that
habitual tooth brushing may also be considered as a signicant
cause of microtrauma and irritation to the gingiva.[14]
Yung, Richardson, and Krotochvil suggested hormonal
inuence on the basis of the observation that pregnancy
tumor that occurs in the pregnant women also arises from
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Journal of Oral and Maxillofacial Pathology: Vol. 16 Issue 1 Jan - Apr 2012
Etiopathogenesis of oral pyogenic granuloma Kamal, et al.81
the gingiva and has the same microscopic appearance.[15]
Hosseini et al. stated that there are clinical observations that
gingiva may be enlarged during pregnancy and may atrophy
during menopause. On basis of these observations, gingiva
can be regarded as another “target organ” for direct action
of estrogen and progesterone.[16] In Whitaker et al., study, it
was suggested that the quantity of estrogen or progesterone
receptors in oral pyogenic granuloma is not the determining
factor in its pathogenesis of. Rather, such a role could be
attributed to the levels of circulating hormones. The levels of
estrogen and progesterone are markedly elevated in pregnancy
and could therefore exert a greater effect on the endothelium
of oral pyogenic granuloma.[17] Ojanotak-Harri et al. (1991)
stated that it has been shown that pregnancy inhibits the
migration of inammatory cells and broblasts. Hence,
it seems that pregnancy regulates both the metabolism of
progesterone and also inuences migration of inammatory
cells in tissue. The level of progesterone available in the
active form and “dysfunction” of the inammatory cells
may have a role in development of pregnancy gingivitis and
granuloma formation. They suggested co-existence of the
two factors prevent acute type of tissue reaction (which keep
tissues clinically healthy) to plaque, but allows an increased
chronic reaction resulting clinically in an exaggerated
appearance of inammation.[18] But, Bhaskar and Jacoway
observed that pyogenic granuloma occurs almost as often
in males as females; for this reason, a hormonal basis is
doubtful.[1]
Regezi et al. (2003) stated that oral pyogenic granuloma
shows obvious histopathological ndings of prominent
capillary growth in hyperplastic granulation tissue suggesting
a strong activity of angiogenesis.[10]. Kuo, Ying, and Ming
stated the role of two angiogenesis enhancers, that is, VEGF
and bFGF, and two angiogenesis inhibitors, that is, TSP-1
and angiostatin in mechanism for angiogenesis. Vascular
morphogenesis factors Tie-2, angiopoietin-1, angiopoietin-2,
ephrinB2, and ephrinB4 were found upregulated in pyogenic
granuloma compared to healthy gingiva.[19] The importance of
decorin, vascular endothelial growth factor, basic broblast
growth factor, or connective tissue growth factor particularly
in angiogenesis associated with a profound inammation has
been proved by some investigators.[12]
Kelley and Bernard regard pyogenic granuloma as a “Benign,
Acquired, Vascular, Neoplasm”.[20] According to Cawson
et al., pyogenic granuloma represents vascular proliferations
and do not represent a stage in the development of brous
nodules or merely inamed brous nodules. Regarding the
pregnancy pyogenic granuloma, they state that like pyogenic
granulomas in a nonpregnant women, pregnancy tumor may
show minimal or no inammation, but vascular proliferation
is occasionally very active so as to suggest a neoplasm.
Nevertheless, the behavior is benign.[21] Davies et al., found
inclusion bodies in the broblasts suggestive of disordered
protein metabolism.[22]
CLINICAL FEATURES
Oral pyogenic granuloma occurs over a wide age range of 4.5
to 93 years with highest incidence in second and fth decades
and females are slightly more affected than males. Gingiva was
the predominant site followed by lips, tongue, buccal mucosa,
and hard plate. Other sites were the cheek, lips, tongue, palate,
mucobuccal fold, and frenum. Intraorally, it can present with
a wide array of clinical appearances, ranging from a sessile
lesion to an elevated mass. Pyogenic granulomas generally
are soft, painless, and deep red to reddish-purple in color.[1]
RADIOGRAPHIC FEATURES
Radiographic ndings are absent in pyogenic granuloma.
However, angelopoulos AP in his review observed that
localized alveolar bone resorption in rare instances of large
and long standing gingival tumors can be seen.[2]
MICROSCOPIC FEATURES
Pyogenic granuloma is partly or completely covered
by parakeratotic or non-keratinized stratied squamous
epithelium. Major bulk of the lesion is formed by a lobulated or
a non lobulated mass of angiomatous tissue. Usually, lobulated
lesions are composed of solid endothelial proliferation or
proliferation of capillary sized blood vessels. The amount of
collagen in the connective tissue of pyogenic granuloma is
usually sparse. Surface can be ulcerated and in such ulcerated
lesions, edema was a prominent feature and the lesion is
inltrated by plasma cells, lymphocytes and neutrophils.[1]
IMMUNOHISTOCHEMICAL INVESTIGATIONS
Sangueza and Requena stated that pyogenic granuloma lesions
express factor VIII – related antigen positivity in the endothelial
cells lining large vessels, but are negative in the cellular
areas, whereas Ulex europaeus I lectin binds to endothelial
cells in both large vessels and cellular aggregates. Enhanced
expression of the bFGF, Tie-2, anti-CD34 and anti alpha
SMA antibodies, and vascular morphogenesis factors such as
angiopoietin-1, angiopoietin-2, ephrinB2, and ephrinB4. There
is also expression of inducible nitric oxide synthase, increased
expression of vascular endothelial growth factor, low apoptotic
rate expression of Bax/Bcl-2 proteins and strong expression of
phosphorylated mitogen activated protein kinase. Polymerase
chain reaction investigations for human papilloma virus and
human herpes virus type have yielded negative results.[23]
DIFFERENTIAL DIAGNOSIS
Differential diagnosis of pyogenic granuloma includes
peripheral giant cell granuloma, peripheral ossifying broma,
broma, peripheral odontogenic broma, hemangioma,
conventional granulation tissue, hyperplastic gingival
inammation, Kaposi’s sarcoma, bacillary angiomatosis,
angiosarcoma, and nonHodgkin’s lymphoma.[10,24]
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Journal of Oral and Maxillofacial Pathology: Vol. 16 Issue 1 Jan - Apr 2012
Etiopathogenesis of oral pyogenic granuloma Kamal, et al.82
TREATMENT
Surgical excision is the treatment of choice.[10] After surgical
excision of gingival lesions, curettage of underlying tissue is
recommended.[25] Excision with 2 mm margins at its clinical
periphery and to a depth to the periosteum or to the causative
agent. Any foreign body, calculus, or defective restoration
should be removed as part of the excision.[26]
RECURRENCE
Bhaskar and Jacoway has reported recurrence rate of 15.8%
after conservative excision.[1] Vilmann et al. observed that
gingival cases show a much higher recurrence rate than lesions
from other oral mucosal sites. Pyogenic granuloma lacks
inltrative or malignant potential.[27] Sapp et al. stated that oral
pyogenic granulomas have a relatively high rate of recurrence
after simple excision. If patient is pregnant, recurrence is
common. Recurrence after surgery in extragingival sites
is uncommon.[28] Lawoyin et al. observed no recurrence in
cases treated by surgical excision.[29] Al-Khateeb et al. (2003)
observed a recurrence rate of 5.8% in his study.[30]
CONCLUSION
Pyogenic granuloma or granuloma pyogenicum is a
well-known oral lesion. However, etiopathogenesis of oral
pyogenic granuloma is still debatable. This article thus
attempted to review the main theories of etiopathogenesis and
the basis for such observations.
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How to cite this article: Kamal R, Dahiya P, Puri A. Oral pyogenic
granuloma: Various concepts of etiopathogenesis. J Oral Maxillofac
Pathol 2012;16:79-82.
Source of Support: Nil. Conict of Interest: None declared.
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