|Year : 2014 | Volume
| Issue : 2 | Page : 118-125
Peripheral giant cell granuloma: A comprehensive review of an ambiguous lesion
Kaustubh P Patil1, Ketki P Kalele2, Vinayak D Kanakdande1
1 Department of Periodontics and Oral Implantology, Dr. D.Y. Patil Dental College and Hospital, Pune, Maharashtra, India
2 Department of Oral and Maxillofacial Pathology and Microbiology, V.Y.W.S. Dental College and Hospital, Amravati, Maharashtra, India
|Date of Web Publication||28-Oct-2014|
Ketki P Kalele
Department of Oral and Maxillofacial Pathology and Microbiology, V.Y.W.S. Dental College and Hospital, Amravati - 444 607, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Peripheral giant cell granuloma (PGCG) is a non-neoplastic, tumor-like reactive lesion occurring exclusively on gingiva/alveolar crest. It is thought to arise from the periodontal ligament or the periosteum. Clinically, it bears resemblance to pyogenic granuloma, peripheral ossifying fibroma and many other peripheral lesions seen in the oral cavity, thereby histopathology is mandatory for the diagnosis of this lesion. The lesion although being relatively common, but still carries a lot of ambiguity. The ambiguity is in terms of its etiology, growth potential, biological behavior (recurrence), histogenesis of its cells and its treatment. The entity further holds significance because of its notorious behavior and its high tendency to recur. The present paper describes recurrent PGCG with a comprehensive insight of the literature on its etiology, clinical, radiological, histological, ultrastructural and molecular aspects. Special attention is given on the histogenesis of cells and their types as also on the differential diagnosis and treatment of this lesion.
Keywords: Giant cell lesion, mononuclear stromal cells, multinucleated giant cells, myeloid tumor, osteoclast, peripheral giant cell granuloma
|How to cite this article:|
Patil KP, Kalele KP, Kanakdande VD. Peripheral giant cell granuloma: A comprehensive review of an ambiguous lesion
. J Int Clin Dent Res Organ 2014;6:118-25
|How to cite this URL:|
Patil KP, Kalele KP, Kanakdande VD. Peripheral giant cell granuloma: A comprehensive review of an ambiguous lesion
. J Int Clin Dent Res Organ [serial online] 2014 [cited 2018 Dec 17];6:118-25. Available from: http://www.jicdro.org/text.asp?2014/6/2/118/143501
| Introduction|| |
Peripheral giant cell granuloma (PGCG) about more than a 100 years ago.  Jaffe through his research affirmed that the giant cell tumors occurring at other areas of the body were poles apart from the giant cells found in the jaws and termed them (giant cells found within the jaws) as giant cell reparative granuloma. 
Bernier Cahn suggested that these lesions should be called as either a peripheral or central giant cell reparative granuloma.  Today the term PGCG is universally accepted.  Waldron and Shafer found that the intra-osseous lesions did not contain any reparative characteristics and histologically did not differ from any other benign giant cell tumor of bone.  Bhaskar et al. in 1959 subdivided giant cell granuloma into central and peripheral types. 
A non-neoplastic lesion by nature, the Giant cell granuloma is distinctive in its histologic makeup. It contains multinucleated giant cells embedded in a stromal environment composed of mononuclated stromal cells along with ovoid to spindle-shaped nuclei. 
Giant cell granulomas occurring within the bone are called central giant cell granuloma (CGCG) and those occurring on edentulous alveolar processes or gingivae are called PGCG. Although the CGCG is rare in nature, making up 7% of total benign lesions of the jaws it is at times uncompromising in nature, especially in young patients. , Contrary to that, PGCG is a more common giant cell lesion of the jaw and can arise either in response to local irritation or from the connective tissue of the gingiva, periodontal membrane or from the periosteum of the alveolar ridge. 
Conventionally, although the term "PGCG" is now a worldwide designated and acknowledged terminology, but still certain parameters regarding this lesion such as its etiology, recurrent nature, proliferative potential and derivative roots of multinucleated giant cells and mononuclear stromal cells remain obscure. 
In 1962, Gottsegen  proposed that PGCG arose postperiodontal surgery while others claimed that they developed in response to local irritating factors. ,, One of the predisposing factors causing PGCG is poor oral hygiene, and it is most commonly found in people belonging to the lower socioeconomic strata.  PGCG occurs exclusively on the gingiva or edentulous alveolar ridge. The lesion mimics other reactive lesions occurring on the gingiva clinically, however, it has significantly higher rate of recurrence than other reactive lesions and thus has to be treated with caution with complete excision and clearing of the lesion.
The present paper offers a review of the literature to define the etiology, clinical, radiological, histological, ultrastructural and molecular aspects of PGCG. Special emphasis is given on the histogenesis of cells and their types as also on the differential diagnosis and treatment of this lesion.
Etiopathogenesis of peripheral giant cell granuloma
Etiology of this lesion is not very clear, and many authors have put forth different causes.
Chronic local irritation of the gingiva can lead to the manifestation of spectrum of reactive lesions, one of which is PGCG that is thought to either originate from the periodontal membrane surrounding the tooth or from the periosteum of the bone. Since it is known that periodontium responds to the similar irritants in a different way, it is postulated that PGCG is a more intense response of periosteum to the irritation factors than that associated with the formation of the more common lesion that is pyogenic granuloma. ,
Sood et al. stated that PGCG is presumably a reactive lesion caused in response to local irritation or trauma. The predisposing factors include trauma, badly finished restorations, plaque, calculus, chronic infections and impacted food.  Bodner et al. suggested that these lesions comprise of an abnormal proliferative response to aggregation. 
Previous literature has shown some occurrence rate of PGCG postextraction, but the fact that extraction might lead to the development of PGCG is still not clear. Mighell et al. reported a case, where there was an occurrence of PGCG 2 months post theorthodontic extraction of a deciduous molar. They suggested that a healing socket rich in growth factors could possibly have stimulated the PGCG growth and eventual lesion development. 
Bodner et al.  found in his study that there was significantly higher percentage of reports of large PGCG's (>2 cm) in people with xerostomia (oral dryness). The pathophysiology as shown in [Figure 1].
|Figure 1: Flowchart depict pathogenesis of xerostomia induced peripheral giant cell granuloma|
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Vittek et al. in 1982 found progesterone and estrogen receptors on human gingiva.  A study conducted by Matter et al. suggested that PGCG was propagated by pregnancy rather than being "pregnancy dependent." He stated that the lesion entirely was not hormone dependent, but was a result of various combinations of causative factors such as an immunosuppressive action of hormones along with hyper responsiveness of the gingiva to these hormones. The response of gingiva can be linked to the finding that estrogen metabolism in unhealthy gingiva is 3 times more than normal gingiva and the activity of responsible enzyme of these reactions increased gingival inflammation. Furthermore, marked female predilection of PGCG suggests a possible hormonal influence. Thus, it can be concluded that ovarian hormones influence the growth of this lesion, however the effect is secondary. 
Rare occurrence of PGCG as an oral manifestation of hyperparathyroidism without any significant bone involvement is reported in the literature. Although this is not a common initial presentation, hyperparathyroidism should be considered as an etiological factor when multiple lesions are present and in recurrent cases that already have undergone various treatment modalities with no effective remission. An unwarranted production of the parathyroid hormone as seen in parathyroid tumor and chronic renal disease also initiates the formation of a giant cell lesion.
Furthermore, children with X-linked hypophosphatemic rickets, a condition that is associated with subclinical hyperparathyroidism, have an increased probability for developing this entity. ,
| Clinical features|| |
Amongst all reactive growths found orally the incidence rate of PGCG varies from 5.1% to 43.6%. 
Many authors have conducted various studies to know relative frequencies of reactive lesions. Buchner et al.  in his study concluded that PGCG was the least encountered lesion among all the reactive lesions, comprising of about (18.7%), and was (1.25%) of all the biopsies included in his study.
PGCG is known to occur at any age but occurs most commonly (40%) in the fourth to sixth decade of life. PGCG is found more commonly in females (65%) than in males (35%). , Although the reason for this predilection remains obscure other lesions with a similar sex predilection have postulated the positive influence of estrogen and progesterone in leading to a higher incidence rate of the lesion thus justifying a positive hormonal influence.  The postulated male to female ratio is about 1:1.5 or 1:2. ,
In children, reactive oral lesions such as the PGCG can demonstrate a rapid growth rate and reach significant size within several months of initial diagnosis. These soft tissue nodules then can instigate bone resorption and can also interfere with eruption and may also cause slight tooth mobility. 
PGCG affects mandible (55%) more than the maxilla; mandibular to maxillary predilection is 2.4:1. , Tyagi et al.  in their review affirmed the maxillary to mandibular site predilection ratio of this lesion to be (1:4). While Pindborg stated that the preferential location for the lesion is the premolar and molar area. 
It is manifested clinically as a painless, soft, nodular mass, usually red to reddish-blue in color.  As opposed to other superficial reactive lesions that present in a similar areas such as a fibroma or pyogenic granuloma that closely resemble PGCG, the PGCG seems to arise from deeper tissues and presents as a sessile or pedunculated lesion.  Clinical characteristics of PGCG are very similar to pyogenic granuloma. However, PGCG has a typical bluish - red hue in contrast to pyogenic granuloma that has a characteristic bright red color. 
The lesion is usually asymptomatic; however, repeated trauma due to occlusion can lead to its growth with eventual ulceration and secondary infection. Rarely, the lesion is painful in nature.  A secondarily infected lesion presents a 'yellow zone' caused due to the aggregation of a fibrin clot at the ulcer site. 
The lesions in edentulous patients may display as either a granular mass of tissue that grows along the slopes of the edentulous ridge or as a swelling on the crest of the ridge. It can either be vascular, ovoid or fusiform in nature, but the color in both in edentulous or dentulous patients is comparable. 
PGCG has shown to have an extensive array of range in sizes, that is, lesions can range anything from small papules to large masses. The lesion exhibits the unique ability of rapid growth and can reach a significant size within several months of its primary diagnosis.  These lesions have a reported average diameter of less than 20 mm, but the extent of their growth capacity is not well-known, but usually is approximately about 0.5-1.5 cm.  Rarely the lesions attain a size of about 2 cm.  However, Kaya et al.  reported 2 cases of huge giant cell granulomas of about 40 mm × 20 mm in diameter that even lead to bone resorption. PGCG's of about 5 cm are also reported in the literature. 
According to a study conducted by Bodner et al.  following are the factors that contribute to the growth of PGCG:
- Compromised systemic health
- Poor oral hygiene
- Oral dryness
- Ill-fitting dentures.
Also, the study showed that females are more likely to have larger lesions than males and the mean age at which lesions >2 cm occurred was elderly age group that is about 50 years.
Radiographic features of peripheral giant cell granuloma
As PGCG is a soft tissue lesion that presents on gingival and alveolar mucosa; X-ray features are thereby nonspecific. Occasionally, bone involvement beneath the lesion has been seen that presents as superficial bone resorption and thus it can be discerned easily on periapical radiographs. Widening of the periodontal ligament space is also seen which is often accompanied by mobility of associated teeth. Alveolar crest region or margin at interdental bone level of the lesion and associated teeth also exhibits resorption. 
In some cases, a detailed examination of this lesion reveals vertically oriented bony spicules at the base of the lesion; this can be attributed to the foci of the bone metaplasia in some cases.  PGCG being a type of reactive lesion, radiographs occasionally demonstrate irritating factors such as subgingival calculus. 
When the lesion involves edentulous areas the cortical bone exhibits a concave resorption beneath the lesion, this typical feature is known as "leveling" effect.  This feature is also referred to as "cupping" resorption by many authors. Apart from the factors mentioned above, X-rays are also important for distinguishing whether the lesion is of gingival (i.e., peripheral) origin or of bone (central) origin that spread towards the surface. 
Oral cavity shows different types of focal overgrowths and proliferation of different components of connective tissue of the periodontium which includes the fibers, bone, cementum, blood vessels or any particular cell. 
Differential diagnosis of PGCG holds importance as there is a variety of other lesions on the list that mimics PGCG; and that are associated with a difference in their treatment and their prognosis.
The spectrum of focal proliferative growths occurring on gingival tissue that have a close resemblance with PGCG includes pyogenic granuloma, hemangioma, CGCG, peripheral ossifying fibroma (POF) and metastatic carcinomas. 
Eversole and Rovin had postulated that, although there are similar clinical and histologic features, sex and site predilection for pyogenic granuloma, PGCG and POF, these lesions vary in their histologic response to irritation  as shown in [Table 1]. ,,, Thus, histopathological evaluation should be undertaken to establish a definitive diagnosis.
|Table 1: Demonstrates the clinical differentiating features in between various entities that resemble PGCG|
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Microscopic examination of the section shows the presence of hyperplastic parakertinized stratified squamous epithelium.
Histopathology of PGCG centers around 3 main features:
- Presence of numerous young proliferating fibroblasts.
- Vascularized fibrocellular stroma with numerous capillaries.
- Abundant multinucleated giant cells. 
Fibroblasts in the stroma form a basic element of the lesion and are plump oval to spindle-shaped. Multinucleated giant cells comprising of variable shapes and sizes are scattered all throughout the connective tissue stroma. Many giant cells are found in association with and within the lumen of the blood vessels. 
This has led to the name of this lesion as "giant cell sarcoma" or, in some cases, "myeloid sarcoma." Spicules of newly formed osteoid or bone are commonly present scattered throughout the lesion. 
The presence of giant cells has been linked to various causes and many authors have put forth different schools of thoughts, as some of them believe them to be a phagocytic response to hemorrhage in a preexisting granulation tissue, others believe that they may arise from the endothelial cells of the capillaries, periosteum, periodontal ligament, or connective tissue of the gingiva. 
Different theories that have been proposed to explain the origin of these cells [Table 2]. a traumatic mechanism on one hand and a proliferative origin on the other, in which the lesion does not arise as a consequence of prior trauma, but secondary to alterations of the vascular endothelium.
|Table 2: Various theories proposed by different authors regarding origin of multinuclear giant cells|
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Multinucleated giant cells
Two types of giant cells are seen in the lesional tissue, which is consistent with the literature as follows:
- Type I cells: These consists of multiple large, ovoid cells with vesicular, somewhat translucent nuclei, ranging 5to 15 in numbers, with prominent nucleoli, and the nuclear chromatin is located peripherally on distinct nuclear membrane. They vary in size, often exceeding 100 μ in diameter. These represent metabolically active cells.
- Type II cells: These are fewer in number, have smaller and more irregular nuclei than type I giant cells. The nucleoli are not easily seen and the cytoplasm stains deeply eosinophilic and granular. These represent the dying cells. 
According to Sapp et al.
Morphologically giant cells are of three types  [Figure 2]:
|Figure 2: Schematic representation of various types of giant cells found in peripheral giant cell granuloma|
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- Type I: They contain clusters of vesicular nuclei with prominent nucleoli that appear to arise out of a background full of distinct mononuclear cells.
- Type II: Majority of cells is type II cells that are distinctly separated from the background stromal cells with deeply staining eosinophilic cytoplasm and often with nuclei clustered in one part of the cell. Clear round vacuoles with central dark areas are evident in the cytoplasm of these cells.
- Type III: These were less in number and represented dying cells.
A zone of dense connective tissue representing a pseudocapsule "Grenz zone" is seen separating the giant cell proliferation from superficial epithelial surface.
Along with the above mentioned features; connective tissue stroma also reveals high vascularity with endothelial proliferations and numerous vascular spaces with mild inflammatory cell infiltrate. In addition, hemosidrin pigments are seen in the stroma of the majority of the sections of PGCG. ,
Ultrastructure of the cells in PGCG
These are according to the investigations of Sapp et al. 
Mononuclear cells ultrastructurally are of three types 
- Type I: Cells possessing clear ovoid nuclei with a smooth outline and prominent nucleoli. Their cytoplasm contains numerous organelles, especially rough endoplasmic reticulum, mitochondria, free polyribosomes and membrane-bound vacuoles.
- Irregular cytoplasmic processes are present in some of these cells, often showing interdigitation with similar cells and apparent cell fusion.
- Type II: These cells possess more dense elongated nuclei with deep invagination of the nuclear membrane and inconspicuous nucleoli. Dilated cisternae of rough endoplasmic reticulum, mitochondria and clear vacuoles are seen in the cytoplasm of these cells. Traces of phagocytosed collagen fibers are also evident in the cell.
- Type III: In this type of cell Birbeck granules, with characteristic tennis-racket morphology and transverse striations is present.
- The more prominent cytoplasmic organelles found in these cells were endoplasmic reticulum, mitochondria, intermediate-sized filaments, polyribosomes and lysosomes.
Multinucleated giant cells
Ultrastructurally, giant cells show distinct cytoplasmic characteristics:
- Portions of the cytoplasmic membrane are modified into an even villous border that extends 2-3 microns beyond the surface.
- Pseudopodic extensions of the cytoplasm are seen that are interpreted as representing either the phagocytic attempt of the cell or an expression of mobility of the cell.
- Peripherally the cell contains dilated cisternae of RER, and these contain granular material of unknown composition.
- Some giant cells appear to be engulfing or phagocytizing some undifferentiated stromal cells.
Electron microscopy also shows the presence of intracytoplasmic actin filaments, proof of phenotypical changes from fibroblast - myofibroblast, in the samples from the investigated cases. Myofibroblasts situated at the same level have an intense activity of the synthetic and secretors organelle. These cells secrete a large amount of collagen (Type I and III). 
Histogenesis of cells in PGCG
Origin of the cells in PGCG is again the subject of controversy and many studies are done regarding this aspect which is tabulated in the following table.
[Table 3] and [Table 4] depicts certain immunohistochemical and ultrastructural properties with emphasis on histogenesis of mononuclear stromal cells and multinucleated giant cells in PGCG.
|Table 3: Ultrastructural and immunohistochemical studies on mononuclear stromal cells in PGCG|
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|Table 4: Immunohistochemical and ultrastructural studies on multinucleated giant cells in PGCG|
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Some molecular aspects
Souza et al. concluded in their study that, Ki67 (proliferative marker) is expressed through G1, S, G2 and M phase of the cell cycle and its demonstration indicates proliferative stage of the cell. Ki67 positive cells were more in PGCG.
Thus, according to Souza et al. although CGCG is more aggressive, however, PGCG is more proliferative than CGCG. 
Filioreanu et al. have shown that the expression of α-SMA which is a cytoskeletal marker is highly correlated with myofibroblasts in the granulation tissue of PGCG. This denotes increased fibroblastic activity of the lesion. 
The study conducted by Amaral et al. have found that giant cell lesions that include PGCG, CGCG, and cherubism presents increased levels of NFATc1, overexpression of which increases osteoclasts fusion as well their differentiation. The study concluded that the development and progression of giant cell lesions of the jaws was possibly mediated by overexpression of NFAT in the nucleus of multinucleated giant cells. Thus, targeting this pathway can be a potential source of future molecular therapy in treating these lesions. 
The treatment of PGCG comprises of excision and suppression of underlying etiological factors with elimination of the entire base of the lesion. There are reports of lesion being eliminated using various methods ranging from conventional blade, an electric scalpel to cryosurgery using liquid nitrogen or cryoprobe and lasers. , The laser resection is highly advantageous that it causes less intraoperative bleeding, sterilizes the wound, requires no suturing and affords improved postoperative patient comfort.  If resection is only superficial, the growth may recur. Most lesions respond satisfactorily to thorough surgical resection, with exposure of all the bone walls.
This great variation is probably attributable to the surgical technique used since recurrences re-excised up to the periosteum have not recurred thereafter. 
When the periodontal membrane is affected, extraction of the adjacent teeth may prove necessary to ensure full resection, though this is initially contraindicated.
Recurrence rate of 5.0-70.6% (average 9.9%) has been reported in various epidemiologic studies  A recurrence rate of 5% has been reported by Giansanti and Waldron  while a study by Eversole and Rovin showed a recurrence of 11%.  Recurrences are believed to be related to lack of inclusion of the periosteum or periodontal ligament in the excised specimen.  A re-excision must be performed for these cases.  Aggressive tendencies or malignant transformation of these lesions has never been reported. ,
PGCG lesions are self-limiting.  Hence, recommended management of PGCG aims at elimination of the entire base of the growth accompanied by eliminating any local irritating factors. 
| Conclusion|| |
PGCG is a routinely encountered lesion in dental practice. However, this entity is under lot of ambiguity in terms of its histogenesis, etiology and other aspects. We have made an attempt to review the literature regarding all aspects of PGCG. Thorough knowledge and identification of etiopathogenesis and biologic behavior of this lesion will lead to a reduction in occurrence and recurrence rates of PGCG. Digging into hidden molecular aspect of this lesion will aid us to design target therapies against PGCG thereby providing optimal patient care. A definite diagnosis of PGCG on the basis of clinical, radiographical, and histopathological examination allows us to do conservative management with minimal risk to the adjacent hard tissue.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]