Gingival enlargement

Introduction:

Gingival enlargement or gingival overgrowth is the increase the size of gingival to cover part of the crown. It is a common clinical condition usually seen in acute and chronic gingival inflammation. The enlargement of gingival tissue may occur due to many other reasons also which include drug intake related, conditioned, neoplastic or false enlargements. Many genetic conditions have gingival enlargement as one of their clinical feature. In the following sections we shall study in detail about the gingival enlargement. Readers are advised to go through “Immunology of periodontal diseases” and “Host response in periodontal disease” before we start the following discussion.

Classification of gingival enlargement:

According to the etiology & pathologic changes:

1) Inflammatory enlargement:

                       Chronic.          

                       Acute.

2) Fibrotic enlargement:

                        Drug-induced.

                        Idiopathic.

3) Combined enlargement (fibrotic + inflammatory)

4) Enlargement associated with systemic diseases/conditions

         A) Conditioned enlargement:

                        Pregnancy.

                        Puberty.

                        Vit. C deficiency.

                        Plasma cell gingivitis.

                        Nonspecific conditioned enlargement.

          B) Systemic diseases causing gingival enlargement:

                       Leukemia.

                       Granulamatous diseases ( wegener’s granulamatosis,sarcoidosis)

5) Genetic Disorders associated with Gingival Enlargement

6) Neoplastic enlargement (gingival tumor):

                       Benign tumors.

                       Malignant tumors.

7) False enlargement.

According to location & distribution:

                      Localized: single tooth or group of teeth.

                      Generalized: involving gingiva throughout the mouth.

                      Papillary: confined to the interdental papilla.

                      Marginal: confined to the marginal gingival.

                      Diffuse: involving the marginal & attached gingivae & papillae.

                      Discrete: isolated sessile or pedunculated (tumor like) enlargement.

1) Inflammatory gingival enlargement:

Gingivitis and periodontitis are two common conditions found in majority of population. The commonest sign of either gingivitis or periodontitis is bleeding gums which can be provoked by tooth-brushing, flossing, and eating hard foods but can also be spontaneous. Inflammation in gingival tissue can cause enlargement of gingiva that is called as inflammatory gingival enlargement. More accurately it is edematous gingival enlargement as it is caused by accumulation of fluids in the inflamed gingival connective tissue. The fluid is primarily serum that has emerged from blood vessels with increased permeability because of local inflammation.

a) Chronic inflammatory enlargement:

Chronically inflamed gingiva can present with enlargement in following forms,

Localized or generalized:

It originates as a slight ballooning of the interdental papilla or gingival margin. In early stages it appears as a life saver-like, bulge around the involved teeth. Later on the interdental papilla and gingival margin increase in size until it covers part of crown. This process progress slowly and painlessly unless it is complicated by infection or trauma. Later on it may progress to achieve generalized form.

Inflammatory gingival enlargement

Inflammatory gingival enlargement

Discrete (tumor like):

It occurs as sessile or pedunculated mass in the Interproximal or on marginal or attached gingival. It grows slowly. A painless or painful ulceration in the fold between the mass & gingival may appear. It may undergo spontaneous reduction, may be followed by exacerbation & continued enlargement.

Gingival changes associated with mouth breathing:

Mouth breathers usually present with gingival enlargement. The gingiva is red and edematous with diffuse shiny surface. The maxillary anterior region is the common site and the altered gingiva is clearly demarcated from adjacent normal gingival. The exact manner in which breathing affect gingiva in not known, but its harmful effect is generally attributed to irritation from surface dehydration.

b) Acute gingival enlargement:

Acute gingival enlargement if generally due to gingival abscess. It is a localized painful condition which has local signs and symptoms of acute inflammation. The swelling in the involved area may increase rapidly in size due to accumulation of  abscess.  Initially the surface of the swelling is smooth and shiny but with due course of time it becomes fluctuant. Later on there is formation of an orifice from which the purulent fluid is released. Usually, this condition arises from forceful embedding of foreign substance like tooth brush bristle or bony spicule etc.  Condition resolves with removal of irritant.

2) Fibrotic enlargement:

A) Drug-induced gingival enlargement:

“Gingival enlargement” or “gingival overgrowth” is the preferred term for all medication-related gingival lesions previously termed “gingival hyperplasia” or “gingival hypertrophy” 1. This condition is characterized by an accumulation of extracellular matrix within the gingival connective tissue, particularly the collagenous component, with various degrees of chronic inflammatory inflammation 2. Drug induced gingival enlargement was first reprted in 1939 by Kimball 3. Another drug found responsible for gingival overgrowth was Cyclosporin which is an immunosuppressant 4-5. The calcium channel antagonists can also cause gingival enlargement. Nifedipine induced gingival overgrowth was first reported in 1984 6-7. The dihydropyridines (e.g. nifedipine, felodipine, amlodipine) tend to be more commonly associated with gingival enlargement as compared to other sub groups of calcium channel blockers.

The accurate determination of the prevalence rate in each drug category is difficult but it has been reported that the prevalence rate of this disorder for phenytoin varies from 10% to 50% 8-12 ; 8% to 70% for cyclosporine A 13-17; and 0.5% to 83% for nifedipine 18-21. Currently, there are over 20 medications from three pharmaceutical categories including anticonvulsants, calcium channel blockers and immunosuppressants that are associated with gingival enlargement  22 . Few of them are listed below,

Drugs causing gingival enlargement

CATEGORY

DRUGS

Anti-epileptics

Phenytoin
Phenobarbitone
Primidone
Valproic acid

Immunosuppressants

Cyclosporine A

Calcium Channel Blockers

Nifedipine
Amlodipine
Felodipine
Nitrendipine
Nicardipine
Verapamil

Phenylalkylamin

Diltiazem

Miscellaneous

Erythromycin
Sertraline

Following is the discussion of some major drugs responsible for gingival enlargement:

Anti epileptic drugs induced gingival enlargement:

Phenytoin is the drug of choice for treatment of grand mal, temporal lobe and psychomotor seizures. Gingival overgrowth is a common adverse effect of therapy with Phenytoin, having important medical and cosmetic implications. Poor periodontal hygiene is an important risk factor for severity of  Phenytoin-induced gingival overgrowth (PIGO), which is a time-dependent process. As already stated, prevalence of gingival enlargement with phenytoin (Dilantin®) use has been shown to be up to 50%, while other anticonvulsants such as valproic acid, Phenobarbital® and Tegretol® have been shown to be rarely associated with the disorder.   The pathogenesis and exact mechanisms responsible for gingival overgrowth are not fully understood.

Phenytoin is primarily metabolized to the inactive hydroxyphenytoin, 5-(4′-hydroxyphenyl)-5-phenylhydantoin or p-HPPH  by cytochrome P450 (P450) enzymes, which may be further metabolized to a catechol that spontaneously oxidizes to semiquinone and quinone species that covalently modify proteins.

Phenytoin induced gingival enlargement

Phenytoin induced gingival enlargement

Calcium Channel Blockers:

Calcium has a central role in cellular physiology. Calcium channel blocker group are used extensively as antihypertensive drugs. As discussed earlier, nifedipine was first reported in 1984 to be causatively associated with gingival enlargement. Dihydropyridines can directly affect gingival connective tissue cells (fibroblast-like cells) causing overgrowth of connective tissue. Gingival enlargement with calcium channel blockers has been reported with verapamil, nifedipine, diltiazem and amlodipine 23-25.

Nifedipine induced gingival enlargement

Nifedipine induced gingival enlargement

Cyclosporine A:

Cyclosporin A (CsA) is widely used for prevention of transplant rejection as well as for management of a number of autoimmune conditions such as rheumatoid arthritis 26-27. Research has demonstrated that CsA increases both IL-6 and TGF-β1 levels. IL-6 or TGF-β1 treatment induces gingival fibroblast proliferation and inhibition of these cytokine resulted in the suppression of CsA-induced proliferation. Intracellular signalling mechanism has also been described to demonstrate the fibroblast proliferation 28. Prevalence of this side effect is more in patients taken nifedipine in combination with cyclosporine. Other risk factors include age, sex, dose, duration of the therapy, gingival inflammation and serum creatinine concentration 29.

Cyclosporin A induced gingival enlargement

Cyclosporin A induced gingival enlargement

Mechanisms involved in gingival enlargement/overgrowth:

1) Direct effect on Fibroblasts:

Fibrobalsts are responsible for collagen production as well as degradation. Studies have been done to find out the direct effect of phenytoin, nifedipine, and cyclosporin A on fibroblasts. These studies have investigated collagenous and non-collagenous extracellular matrix metabolism by gingival fibroblasts 30-33. Cyclosporin A was found to increase glycosaminoglycan secretion by fibroblasts 32 and nifedipine and phenytoin increased heparan levels 34. But many in vitro studies failed to report any differences 35-37. So, these findings suggest that this may not be the primary mechanism responsible for gingival overgrowth.

2) Synthesis and degradation of type I collagen:

Collagen is the most abundant protein in mammals. Its synthesis and degradation is precisely balanced by the regulatory mechanisms. It has been proposed that gingival overgrowth occurs due to loss of homeostasis of the synthesis and degradation of collagen fibers, especially type I collagen, resulting in the excess accumulation of collagen fibers 38

The immunohistochemical analysis of drug-induced gingival overgrowth in rat models have shown the excessive accumulation of type I collagen in gingival connective tissue 39-40. This may be due to various degrees of gingival inflammation because of which the production of inflammatory cytokines, such as interleukin 1β. This cytokine is known to stimulate the gingival fibroblast proliferation and has a potential influence on collagen metabolism of fibroblasts 41-43. Individuals taking these drugs can be divided as “responders” and “non-responders”. Studies have shown excessive cell proliferation and collagen synthesis rate by gingival fibroblasts isolated from human drug-induced overgrown gingiva as compared to those isolated from non-responder exposed to nifedipine or phenytoin in vitro 44-45.

Collagen degradation occurs via two methods, an extracellular pathway involving the secretion of collagenase 46  and an intracellular pathway involving phagocytosis by fibroblasts 47. Researchers have shown the stimulating effect of cyclosporine A on type I collagen synthesis in human gingival fibroblasts 48. However, in vitro studies have given conflicting results on cell proliferation and/or collagen synthesis 49-52.

Under normal conditions the collagen degradation occurs via phagocytic activity in gingival fibroblasts. Collagenase-mediated degradation occurs during inflammation. Studies have shown decreased collagen phagocytosis of fibroblast isolated from human phenytoin-induced gingival overgrowth than healthy gingiva, and direct inhibitory effects of nifedipine and phenytoin were also shown on the collagen phagocytosis of fibroblasts 53.

3) Role of cytokines:

As we know that subclinical inflammation is always present in gingival sulcus because of which gingiva is always in a process of repair and remodelling. Collagen turnover is unusually high in periodontal tissues 54-55. Various cytokines and other chemical mediators are involved in this process.  Research work has demonstrated that there may be an imbalance between these cytokines in gingival overgrowth. Cytokines and growth factors found at elevated levels in human drug-induced gingival overgrowth include interleukin-6 (IL-6), IL-1β, platelet-derived growth factor-B (PDGF-B), fibroblast growth factor-2 (FGF-2), transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) 56-63. The exact mechanism how these drugs cause cytokine imbalance is still being studied, but the proposed mechanisms indicate the immunomodulatory effects of these drugs.

4) Role of α 2 Integrins:

Integrins are heterodimeric transmembrane cellular receptors responsible for signalling  mechanism from exterior to interior of cells. Each heterodimer consists of an a and b subunit. There are approximately 17α and 8β subunits in mammals, and through different combinations, they can form approximately 40 different integrins 64-67. The α1β1 and α2β1 integrins are cell surface receptors for collagens, and cells expressing the α1β1 integrin preferentially adhere to type IV collagen, whereas cells expressing α2β1 preferentially adhere to type I collagen. The α2β1 integrins have been shown to serve as specific receptors of type I collagen in fibroblasts 68. Research work has shown that initial binding step of collagen phagocytosis relies on adhesive interaction between fibroblasts and collagen. The α2 integrin plays a critical role in the phagocytic regulation of collagen internalization 69-70. Studies done on rat models have shown significantly decreased collagen phagocytosis by fibroblasts and α2 integrin expression suppressed in fibroblasts isolated from overgrown gingiva compared to the control 39, 71.

The above findings suggest that one of the important factors to be considered in pathogenesis of gingival overgrowth is the inhibition of collagen phagocytosis because of reduced α2 integrin expression leading to decreased fibroblast binding to collagen.

5) Calcium and collagen phagocytosis:

Calcium is an important molecule that participates in the intracellular signalling. All the drugs which are shown to cause gingival enlargement in one or other way disturb the intracellular calcium flux. The Calcium channel blockers are able to block the influx of calcium ions into cells and to reduce oxygen consumption 72-73, Phenytoin act as a calcium channel antagonist and inhibit calcium ion flux 74 and Cyclosporin A is reported to inhibit the release of calcium from intracellular stores, including endoplasmic reticulum and mitochondria 75.

As we know that α2β1 integrins are important molecules responsible for fibroblast attachment to collagen fibers, their expression requires intracellular signalling which in turn requires calcium ions 76. So, one another proposed pathway of pathogenesis of drug induced gingival overgrowth is the disturbance of calcium flux in the cell causing reduced expression of α2β1 integrins and reduced fibroblast attachment and phagocytosis.

6) Alterations in role of Matrix Metalloproteinase (MMP):

As already discussed, calcium has an important role in intracellular homeostasis and drugs responsible for gingival overgrowth have been shown to have inhibitory effects on calcium ion influx across cell membranes. So, it was proposed that this may lead to decreased synthesis and function of intracellular collagenases 77. In vitro studies have shown that treatment of fibroblasts with Cyclosporine A caused significantly reduced levels of MMP-1 and MMP-3 secretion which can be related to accumulation of extracellular matrix components 78.

7) Fibroblast Subpopulations:

Within normal connective tissue, fibroblasts appear similar at the light-microscopic level; however, a lot of evidence indicates that such cells are functionally different 79-81. Discrete and phenotypically stable subpopulations of fibroblasts exist within gingiva and other connective tissues; these subpopulations are characterized by dramatic differences in protein synthesis, collagen production, glycosaminoglycan accumulation, replicative life span in culture, proliferation rate, cell size distribution and response to exogenously added substances 82-85. Fibroblast cell subpopulations that are responsive to the drugs responsible for gingival overgrowth are called as “responder cells” 82.

8) Role of androgen metabolism:

One proposed mechanism of drug induced gingival overgrowth is activation of gingival fibroblast subpopulation by these drugs as a result the conversion of androgens to their active metabolites. For example it has been shown that monolayer cultures of gingival fibroblasts readily metabolise labelled testosterone to its active metabolite 5α-dihydro testosterone (5α-DHT). Addition of phenytoin/cyclosporin to this culture further promotes the formation of active metabolites. Now, these active metabolites can act on a “target fibroblast cell population” and can activate these cells to produce more collagen fibers or decrease collagenases activity 86-87.

9) Genetic factors:

The group of drugs which have been shown to be responsible gingival overgrowth are metabolised in body by cytochrome P450 enzyme family. Dihydropyridines and cyclosporin are metabolised by CYP3A4 88 and phenytoin is metabolised by CYP2C9 89. Genetic polymorphism is found in Cyt P450 genes. This polymorphism may lead to the variations in inter individual drug metabolism. Although, the exact mechanism is not clear but this may be one of the machanisms involved in drug induced gingival overgrowth.

Another evidence for genetic factors involved in gingival overgrowth comes from the human leukocytic antigen (HLA) expression. One investigation done on patients taking cyclosporin and/or dihydropyridine has elucidated  that HLA-DR1 +ve patients had significantly lower gingival overgrowth as compared to HLA-DR2 +ve patients 90. So, higher frequency of HLA-DR2 expression is associated with moderate to severe gingival overgrowth.

Prevention and management of drug induced gingival overgrowth:

Maintenance of good oral hygiene by patient and professional help in achieving it are two major factors in minimizing gingival overgrowth. Gingival overgrowth increases the amount of plaque accumulation because of formation of pseudopockets. It further increases the gingival inflammation and hence inflammatory gingival hyperplasia. Investigations have shown that aggressive plaque control and routine oral hygiene help in maintaining gums but may not prevent the onset of gingival overgrowth in some individuals 91. A frequent follow up of patient (bi-weekly) is also helpful in preventing or limiting gingival overgrowth.

The treatment consists of stopping the drug responsible for gingival overgrowth. But, in many cases it may not be possible (organ transplant patients taking immunosuppressants). So, therapy consists of maintenance of stringent oral hygiene. Use of 0.2% chlorhexidine mouthwash has been shown to be highly beneficial 92. Administration of folic acid systemic or local has also been shown to be helpful, but its specific role has not clearly been established 93.

Azathioprine and prednisolone  administration to patients with drug induced gingival overgrowth has been shown to be beneficial. This may be due to antiinflammatory effect  of prednisolone and azathioprine 94. Azithromycin concentrates in fibroblasts and phagocytes and transported to area of inflammation due to its chemotactic effect on phagocytes.

Surgical excision of overgrown gingiva by gingivectomy proceadure is the treatment of choice in these patients.

B) Idiopathic gingival enlargement:

As the name suggests, these enlargements are due to some unidentified cause. Common terms used for these enlargemens include terms as gingivomatosis, elephantiasis, idiopathic fibromatosis, hereditary gingival hyperplasia, and congenital familial fibromatosis.

Hereditary Gingival Fibromatosis (HGF):

It represents a heterogeneous group of disorders characterized by progressive enlargement of the gingiva. It may appear as an isolated entity i.e. as autosomal dominant Gingival Fibromatosis or as part of a syndrome.

Clinical presentation:

Clinically Hereditary Gingival Fibromatosis develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. In severe cases the gingiva may cover the entire crown of the tooth. Both sexes are equally affected by this condition. The onset of gingival overgrowth is usually along with the eruption of permanent incisors but in some cases it starts with eruption of primary dentition. In localized form of Hereditary Gingival Fibromatosis, maxillary tuberosity and the labial surface around mandibular molars are usually affected, whereas in generalized form the labial, lingual, and palatal gingiva is the most commonly affected. The colour of the enlarged gingiva may be normal or erythematous and is firm and nodular on palpation. Enlarged gingiva causes formation of pseudo-pockets and patient has difficulties in maintaining an effective level of oral hygiene. Other major patient complaint is regarding esthetics. Enlarged gingiva may create diastemas, impede or delay tooth eruption, and create changes in facial appearance as a result of lip protrusion. In case of sever gingival overgrowth patient may have difficulty in speech, crowding of tongue, difficulty in mastication and difficulty in lip closure 95-96.

Hiostology:

A peculiar histopatological finding in this condition is the accumulation of excess extracelluar matrix (ECM). The histologic section of gingiva presents as dense, hyperkeratotic epithelium with elongated rete ridges. Epithelial hyperplasia can also occur as a consequence of acanthosis, but this was found only in areas of chronic inflammation 97-98. Increased numbers of bundles of collagen fibers are found randomly in all directions with few fibroblasts and blood vessels 99-100. There is also accumulation of elastic and oxytalan fibers 101-102.

Inflammatory infiltrate is found only where there are local factors (like plaque) present due to formation of pseudo pockets. Researchers have demonstrated two types of fibroblast population in the histological sections, one with little cytoplasm around the nucleus, which is associated with dense collagen bundles and the other contains prominent cytoplasm with well developed organelles. These fibroblasts have been considered inactive and active, respectively 103-104.

Studies have demonstrated increased expression of Transforming growth factor (TGF) 105. It may lead to excessive production of extra cellular matrix. Along with this there is reduced expression of matrix metalloproteinases and increased expression of tissue inhibitors of matrix metalloproteinases, which further supports accumulation of extra cellular matrix 106.

3) Combined enlargement (fibrotic + inflammatory):

Gingival enlargement is associated with false pocket formation. Due to more accumulation of local factors like plaque, gingival inflammation occurs. The pre exisiting fibrotic gingival enlargement now becomes a combined enlargement due to combination of fibrotic and inflammatory components.

Combined gingival enlargement

Combined gingival enlargement

4) Enlargement associated with systemic diseases/conditions:

Conditioned enlargement:

A) Pregnancy Associated Gingival Enlargement:

The clinical manifestation of plaque-induced gingival inflammation is modulated by the hormonal imbalances during pregnancy. Hormonal changes can significantly potentiate the effects of local irritants on gingival connective tissue 107.  Research has shown that by the end of third trimester, progesterone and estrogen reach peak plasma levels of 100 and 6ng/ml respectively, which represent 10 and 30 times the levels observed during the menstrual cycle 108. The levels of sex steroid hormones in saliva also increase during pregnancy 109Incidence of gingivitis in pregnancy varies from around 50% to 100% 110. The gingival inflammation typically begins in the second month and reach the maximal level during the eighth month of pregnancy 111-112It is important to note that pregnancy does not cause the condition, but the altered tissue  metabolism in pregnancy accentuates the response to local irritants and pregnancy associated gingival enlargement does not occur without clinical evidence of local irritation 113.

Kornman & Loesch (1980) have reported that the subgingival flora changes to a more anaerobic flora as pregnancy progresses 114. Microbilogical investigations show that the only microorganism that increases significantly during pregnancy is Prevotella intermedia and this increase is associated with elevations of levels of systemic estradiol and progesterone. These hormones are used as growth factors by these organisms as a substitute for vit. K 115.

Studies have also shown the altered tissue response to plaque is due to depression of the maternal T-lymphocyte 116.

Marginal gingival enlargement:

It is a consequence of exaggeration of existing inflammation in  pregnant patient. The clinical presentation may vary with patient to patient. It is usually generalized with involvement of interdental papilla regions more commonly as compared to other regions of gingiva. The involved gingiva is usually bright red or bluish in colour (depending upon vascularity) with smooth and shiny surface. Bleeding may occur spontaneously or with slight provocation due to high vasularity.

Localized gingival hyperplasia associated with pregnancy:

It is also known as pyogenic granuloma or pregnancy tumor or pregnancy epulides. It manifests as a painless, sessile or pedunculated, ulcerated lesion sized a few millimeters to several centimeters with a smooth or lobulated surface and purplish red to deep blue color according to the vascularity 117-118.It appears often during 2nd or 3rd month of pregnancy, presenting clinically as a tumor like gingival enlargement due to an exaggerated conditioned response to minor trauma 119This lesion occurs most commonly on maxillary anterior region with interdental papilla region being most commonly affected 120.

Pregnancy tumor

Case I

Pregnancy tumor

Case II

Pregnancy tumor

B) Gingival enlargement in puberty:

Puberty involves a complex process of sexual maturation and it is responsible for changes in physical appearance and behavior that are related to increased levels of the steroid sex hormones, testosterone in males and estradiol in females 121.  The incidence and severity of gingivitis in adolescents are influenced by a variety of factors, including plaque levels, dental caries, mouth breathing, crowding of the teeth and tooth eruption. Puberty associated gingival enlargement is present sometimes in females as well as males and is characterized by the onset of exuberant inflammation of the marginal and, by direct extension, adjacent attached gingiva, especially in the interdental papillae 122-123.  Bleeding from gingiva is usually the chief complaint of the patient. The enlargement is primarily present on the buccal/labial surfaces and lingual surface is usually unaffected 124. The main reason for this condition along with poor oral hygiene is the changes in subgingival microbiota 125-126

Microbiological investigations have demonstrated an increase in P. intermedia in subgingival plaque. This bacteria has been shown to substitute estrogen and progesterone for vitamin K, an essential bacterial growth factor 127-128. Other microbial species that have been shown to be increased in subgingival plaque include spirochetes, Capnocytophagia sp., Actinomycetes sp. and Eikenella corrodens 129-130.  The increased gingival bleeding has been associated with capnocytophaga species 131.   

C) Vit. C deficiency:

Deficiency of Vit. C causes scurvy which is characterised by general weakness, anaemia, gingivitis and skin haemorrhages caused by a prolonged deficiency of vitamin C (ascorbic acid) in the diet. Avitaminosis-C is associated primarily with defective collagen synthesis, causing tissue dysfunction such as impaired wound healing and ruptured capillaries because of insufficient support of the capillary walls by the connective tissues 132This vascular fragility leads to a bleeding tendency which produces petechiae and ecchymoses and is confmned by a positive Hess test. The oral signs of avitaminosis C include fetid odour and loosened teeth with swollen, tender, spongy bleeding – putrid gingiva 133. In severe cases of scurvy gingivae are boggy, ulcerated and bleed. The interdental and marginal gingiva becomes bright red, smooth, swollen and shiny  134.

The histological features are dilated subepithelial blood vessels engorged with red blood cells. The vessel walls are thin, and in some areas there is haemorrhage into the surrounding connective tissue where the vessels have ruptured. There is periodontal breakdown which includes alveolar bone resorption, with loosening and loss of teeth 135. The alveolar blood vessels lose support and develop capillary fragility which allows easy haemorrhage, caused by even minor trauma such as chewing soft food 136.

Regeneration of collagen to maintain the integrity of the tooth attachment elements is especially important for periodontal health. Administration of Vit C supplements can reverse the condition.

D) Plasma cell gingivitis:

Plasma cell gingivitis (synonyms:  Plasmacytosis of the gingiva, Plasma cell-gingivostomatitis, Allergic gingivitis, Atypical gingivitis) 137. It is a rare benign inflammatory condition of unknown aetiology 138. Most of the times this condition has been associated with an allergic response to allergens like mint, cinnamon which is present in the toothpaste and chewing gum. Other categories of this disease can be neoplastic lesions or lesions of unknown causes 139.

This condition is characterized by a sharply demarcated, erythematous, oedematous, diffuse gingivitis which often extends into the mucogingival junction 138. Usually, a sharp demarcation along the mucogingival border is evident.  Three categories of plasma cell gingivitis have been proposed based upon the aetiology of the condition 140,

  • Lesions caused by an allergen.
  • Neoplastic lesions.
  • Lesions of unknown cause.

This condition is not associated with attachment loss but stippling is absent in the involved area of gingiva. The lesion is friable and frequently bleeds with minimal trauma 141Histopathological evaluation of the lesion demonstrates psoriasiform hyperplasia and spongiosis of the surface epithelium, with intense exocytosis and neutrophilic microabscesses. The underlying lamina propria contained numerous dialated vascular channels and an extremely dense chronic inflammatory infiltrate that is composed predominantly of plasma cells. The removal of allergen from diet usually resolves the condition. If condition does not resolve, then extensive allergy testing and elimination diet can be undertaken.

F) Nonspecific conditioned enlargement: (Pyogenic Granuloma)

Pyogenic granuloma is a relatively common, soft tissue tumor of oral cavity that is belived to be reactive and not neoplastic in nature. The name pyogenic granuloma is a misnomer since the condition is not associated with pus and does not represent a granulma histologically 142. It is also called as  “Granuloma gravidarum,” and “Pregnancy tumor”, when it occurs in a pregnant woman. It is a reactive inflammatory process filled with proliferating vascular channels, immature fibroblastic connective tissue and scattered inflammatory cells. This lesion most frequently develops on the buccal gingiva in the interproximal tissue between teeth. Females are far more susceptible than males because of the hormonal changes that occur in women during puberty, pregnancy, and menopause. Clinically, it appears as smooth or lobulated exophytic lesion manifesting as small red erythematous plaque on a pedunculated or sometimes as a sessile base, which is usually haemorrhagic and compressible.

Pyogenic granuloma

Pyogenic granuloma

Microscopic examination reveals a highly vascular proliferation that resembles granulation tissue. Numerous small and large blood vessels are seen engorged with red blood cells. This feature makes this lesion highly vascular and it bleeds profusely after trauma or during surgical excision. There is presence of ulcerated mucosa covering a core of cellular fibrous connective tissue admixed with proliferating vascular channels and a mixed inflammatory infiltrate. Although pyogenic granuloma an be diagnosed clinically with considerable accuracy, radiographic and histopathological investigations, aid in confirming the diagnosis and treatment.

Gingival enlargement associated with systemic diseases:

A) Leukemic gingival enlargement:

Leukemia is a malignant neoplasm resulting from proliferation of abnormal haemopoietic stem cells with uncoordinated differentiation, regulation and apoptosis 143. Leukemia is characterized into acute or chronic forms, according to its clinical behavior, and characterized as lymphocytic and myelocytic, according to its histogenetic origin. The basic forms are: acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML). Acute lymphoid leukaemia (ALL) and acute myeloid leukemia (AML) are further subdivided within the French-American British (FAB) classification according to their degree of differentiation along cell lines and extent of cell maturation. Acute myeloblastic leukemia (AML) is commonly classified under 8 subgroups according to the French-American-British (FAB) classification system.

AML is the most serious condition associated with gingival enlargement. The leukemic infiltrates have been reported in the kidneys, lungs, bowels, breasts, testes, eyes, meninges, lymph nodes, liver, prostate, skin, and oral cavity 144. Gingival tissues are considered more susceptible to leukemic cell infiltration because of their microanatomy and expression of endothelial adhesion molecules which enhance infiltration of leukocytes 145Gingival enlargement is more frequently seen in the context of acute rather than chronic leukemia 146-147. Oral manifestation in patient with leukemia have been described in all subtypes of AML, chronic myeloid leukemia, acute lymphocytic leukemia, and chronic lymphocytic leukemia 148. Gingival infiltration of leukemic cells is most commonly seen in acute monocytic leukemia (M5) and acute myelomonocytic leukemia (M4) 149-150. It is present in about 30% of patients at diagnosis with these AML subtypes 151. Patient usually presents with a high white blood cell count and may also have skin infiltrates, meningeal infiltrates or hepatosplenomegaly  secondary to leukaemic blasts infiltration.

Pathogenesis of periodontal involvement in leukaemia:

Investigations have demonstrated that leukaemic gingival enlargement is mostly due to plaque-induced inflammation, since stringent plaque control appears to resolve the swelling 152. The gingival connective tissue is infiltrated by leukemic cells that create gingival pockets where bacterial plaque accumulates. It causes the initiation of secondary inflammatory lesion that contributes also to the enlargement of the gingiva. Gingival bleeding which is commonly seen in these patients is due to thrombocytopenia.

Clinical findings:

Include enlarged gingiva with rounded margins. Gingiva appears swollen, devoid of stippling and pale red to deep purple in colour. In severe cases the interdental papilla are involved with gingival enlargement partially covering crowns of the teeth. Mucosal hemorrhages, ulcerative gingivitis, infectious gingivitis and odontalgia may be observed 153-154. Spontaneous hemorrhage, petechiae and ulceration have been described to occur more frequently in acute than chronic leukemia 155.

Microscopic features:

Microscopic examination of gingival demonstrates dense, diffuse infiltration of predominantly immature leukocytes which tend to displace the normal connective tissue components of the gingiva.  These cells are characterized by abundant mitotic figures. The lamina propria is densely packed with leukemia cells extending from the basal cell layer of the epithelium into the gingiva, thereby altering the normal anatomy. The blood vessels are distended and contain predominantly leukemic cells, and the RBCs are reduced in number. Epithelium covering the connective tissue may become thin or hyperplastic.

B) Granulamatous diseases

Wegener’s granulomatosis:

It is a rare disease, in which the blood vessels and other tissues become inflamed. The hallmarks of this potentially fatal disorder are necrotizing granulomatous inflammation involving the upper and lower respiratory tract, glomerulonephritis, and vasculitis 156-159. It was first described by Klinger in 1933. In 1936 Wegener reported three patients with similar clinical features and published his findings on their distinct clinical and histopathologic findings. He postulated term ‘septic’ vasculitis 160In Wegener’s granulomatosis, the most characteristic oral lesion is hyperplastic gingivitis, which is typically red to purple with many petechiae (strawberry gingivitis). These lesions may remain localized in the oral cavity for unusually long periods of time before multi-organ involvement occurs 161-162.

Histopathologically, diffuse mixed inflammatory cell infiltrate comprising mostly neutrophils which forms subepithelial abscesses can be seen. Scattered multinucleated giant cells, some resembling Langhan-type giant cells with horse-shoe arrangement of their nuclei can also be seen.                                                                

5) Genetic Disorders Associated with Gingival Enlargement:

Many genetic syndromes have gingival enlargement as one of their clinical feature.  For the ease of understanding these conditions can be divided into four categories: hereditary gingival fibromatosis associated with syndromes, lysosomal storage disorders, vascular disorders and genetic dental abnormality disorders. Although each of these conditions is not discussed in detail here, following is the list of genetic disorders associated with gingival enlargement, 

Genetic Disorders associated with Gingival Enlargement

Hereditary gingival fibromatosis associated with syndromes

Lysosomal storage disorders

Vascular disorders

Genetic dental abnormality disorders

Rutherfurd syndrome Hurler syndrome Sturge Weber Syndrome Regional Odontodysplasia
Zimmerman – Laband Syndrome Hunter syndrome
Niemann – Pick disease Klippel- Trenaunay syndrome Goltz syndrome
Neurofibromatosistype I Scheie syndrome Wilson syndrome
Aspartylglucosaminuria
Costello syndrome Cowden syndrome
Cross Syndrome Ligneous periodontitis
Ramon syndrome Alpha Mannosidosis
Schinzel – Giedion Syndrome Menkes Kinky hair Disease
Jones syndrome Maroteaux-Lamy syndrome
Gingival fibromatosis,hypertrichosis and mental retardation.

6) Neoplastic enlargement (gingival tumor):

The benign or malignant tumors of gingiva are also responsible for gingival enlargement. Only a brief description of some benign and malignant gingival enlargements is given here, for their detailed description readers are advised to go through oral pathology books/articles.

Benign tumors:

Fibroma:

Fibromas are benign tumors that are composed of fibrous or connective tissue. They are the most common“tumour” of the oral cavity. Other synonyms for this condition are irritational Fibroma/Traumatic  Fibroma/Focal Fibrous Hyperplasia/Fibrous Nodule/Fibroepithelial Polyp. Most fibromas are sessile, although some are pedunculated. They range in size from tiny lesions that are only a couple of millimeters in diameter to large masses that are several centimeters across. Histopathologic examination shows nodular mass of fibrous connective tissue covered by stratified squamous epithelium. The collagen bundles may be arranged in a radiating, circular or haphazard fashion. The covering epithelium often demonstrates atrophy of the rete ridges because of the underlying fibrous mass. Surgical excision is the treatment of choice in this condition.

Fibroma present on palate

Fibroma

Papilloma.

It is a benign proliferation of the stratified squamous epithelium, which results in a papillary or verrucous exophytic mass induced by human papilloma virus (HPV) 163-164. Most commonly papillomas are induced by HPVs 6 and 11 subtypes of HPV. It may occur anywhere in the mouth with a predilection for the ventral tongue and frenum area, palate, and mucosal surface of the lips. Nonkeratinized lesions appear coral pink; if keratinized, they are white. Some have a cauliflower surface whereas others have discrete finger-like projections.

Cementoossifying fibroma:

Cemento-ossifying fibroma is a benign fibro-osseous lesion. It is most commonly seen between the third and fourth decades of life 165-167, and is more frequent in women than in men (4:1). The most common location is the mandible, with 70-90% of all cases 168. It starts as a slow-growing intrabony mass that is normally well delimited and asymptomatic – though over time the lesion may become large enough to cause facial deformation. Radiographically it appears as a well delimited unilocular lesion containing variable amounts of radiopaque material. Histologically, a well vascularized fibrocellular tissue with the capacity to form immature bone trabeculae and cementoid tissue can be seen.

Peripheral Giant Cell Granuloma:

Peripheral Giant cell granuloma is a benign hyperplastic lesion of the gingiva arising interdentally or from the gingival margin, and may be sessile or pedunculated. It is also known as giant cell epulis/  giant cell reparative granuloma/ osteoclastoma/ giant cell hyperplasia. It is a reactive exophytic growth of gingiva and alveolar ridge which originates from the Periosteum or periodontal ligament. Histological features reveal a non-capsulated mass of tissue containing a large number of young connective tissue cells and multinucleated giant cells. Hemorrhage, hemosiderin, inflammatory cells, and newly formed bone or calcified material may also be seen throughout the cellular connective tissue.

Leukoplakia:

It is defined as a white patch or plaque which cannot otherwise be characterized clinically or pathologically as any other disease. It appears white usually because of three main factors alone or in combination: hyperkeratosis or excessive production of keratin (the white flakes that come off when you scratch your skin), thickening of the surface layer of cells, or the presence of pre-cancer (“dysplasia”) or cancer. One article has given detailed description of leukoplakia 169.  Readers are referred to read this article for details. 

Malignant Tumors:

Carcinoma:

Oral Squamous cell carcinoma (SCC) is most common malignant tumor of oral cavity. It accounts for about 90% of oral cancers, and affects mostly adult males, predominantly alcohol and tobacco users, between the sixth and seventh decades of life 170. The most affected sites in decreasing order are the tongue, oropharynx, lip, floor of mouth, gingiva, hard palate, and buccal mucosa 171-173. The clinical characteristics of SCC vary from case to case and include the exophytic (verrucous or papillary), endophytic, ulcerated, leukoplastic, erythroplastic or erythroleukoplastic forms. Depending on their extent and/or location, these lesions may cause painful symptoms and resorption of adjacent bone seen as a “moth-eaten” appearance on radiographs.

In most cases histopathological analysis shows malignant neoplasia of epithelial origin characterized by invasive proliferation of nests and cords of neoplastic epithelial cells. These neoplastic cells show characteristics like intense cellular and nuclear pleomorphism, nuclear hyperchromatism, loss of cells cohesion, multiple and clearly visible nucleoli, individual cell keratinization, atypical mitoses, and formation of keratin pearls.

Malignant Melanoma:

Malignant melanoma is a cancer of pigmented cells called melanocytes. Melanocytes are neural crest-derived cells that migrate to the skin, mucous membranes and several other sites. The most frequently primary sites in the oral cavity are the palate and maxillary gingiva 174-175. Mucosal melanomas are considered to be more aggressive tumors compared with cutaneous melanomas and they are more inclined to metastasize into regional and distant sites, recur locally or regionally resulting in a high rate of disease specific-death.

Histopathological analysis shows proliferation of atypical melanocytes characterized through hyperchromatic and angular nuclei with infrequent mitotic activity. The melanocytes may be arranged irregularly at the epithelial connective tissue-interface or may be distributed in aggregates. Invasive pattern in which the melanoma extend into the connective tissue is represented in 30% of oral melanoma cases.

Sarcomas:

These are cancers of mesenchymal cell origin. They are rarely found in oral cavity. However, Kaposi sarcoma has become more prevalent due to increased cases of AIDS. The details of these lesions can be studied in oral pathology books.

7) False enlargement:

As the name indicates false enlargements are those that do not originate from gingiva but from underlying tissue. The gingiva is healthy and normal in size but the enlargement is present due to underlying tissues like bone. These enlargements may be of osseous or dental origin. Most common osseous condition is tori and exostoses. Other less common conditions include Paget’s disease, fibrous dysplasia, cherubism, central giant cell granuloma, ameloblastoma, osteoma, and osteosarcoma.

False gingival enlargement caused by mandibular tori

Mandibular Tori

False gingival enlargement caused by osteoma

False gingival enlargement caused by osteoma

Dental conditions include “developmental enlargement”. During eruption of teeth the gingival covering of the gingiva gives a false gingival enlargement appearance. This is not a pathological condition and is resolved with complete eruption of crown of the tooth.

8) Conclusion:

Gingival enlargement/overgrowth is a common finding in patients. The correct diagnosis of gingival enlargement is of great importance because as discussed above, many local and systemic causes may cause gingival enlargement. Drug induced gingival enlargement is a common side effect of some medications. Research work is going on to find out the exact mechanism of drug induced gingival overgrowth, so that once we are clear with its pathogenesis, the treatment modalities can be worked upon. 

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Know more……………..

Drug induced gingival enlargement/overgrowth/hyperplasia/hypertrophy terminologies:

Hyperplasia: It is defined as abnormal increase in the number of normal cells in normal arrangement in an organ or tissue, which increases its volume.

Hypertrophy: It is defined as nontumorous enlargement of an organ or a tissue as a result of an increase in the size rather than the number of constituent cells.

The drug-induced gingival overgrowth was previously termed as gingival hypertrophy or gingival hyperplasia by finding an increased number of fibroblasts in gingival connective tissue with histological analysis 176-177.

But histological analysis of gingiva did not accurately reflect “hypertrophy” or “hyperplasia”. It was not the increased proliferation of gingival fibroblasts, but the severe accumulation of extracellular matrix within the gingival connective tissue, particularly collagenous components, which was observed in human gingival overgrowth 178-179.

Because there was no evidence of increase in size or number of constituent cell in the tissue the terms gingival hyperplasia or hypertrophy were replaced with terms gingival enlargement or overgrowth.

Conditions with usually generalized or localized gingival involvement:

Generalized

  • Hyperplastic gingivitis
  • Mouth-breathing gingivitis
  • Drug-induced gingival overgrowth
  • Gingival overgrowth in pregnancy
  • Gingival overgrowth due to leukemia
  • Hereditary gingival fibromatosis
  • Scurvy
  • Wegener granulomatosis
  • Acanthosis nigricans

Localized

  • Pyogenic granuloma
  • Peripheral giant-cell granuloma
  • Peripheral ossifying fibroma
  • Granular-cell tumor of the newborn
  • Periodontal abscess
  • Parulis
  • Multiple exostoses
  • Gingival cyst
  • Eruption cyst

 

References:

Please contact author for references

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