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Diffuse gingival enlargement
CLINICAL
REVIEWS
Diffuse gingival enlargement Pooja Khera, BS, Matthew J. Zirwas, MD, and Joseph C. English III, MD Pittsburgh, Pennsylvania Diffuse gingival enlargement is defined as an excessive growth of periodontal tissue. It can be considered a relatively common finding, as thousands of patients have been described in the literature. Patients may seek medical attention because of pain, tenderness, interference with speech and/or mastication, halitosis, or unsightly appearance, or gingival enlargement may be an unexpected finding on routine physical examination. Diffuse gingival enlargement has numerous causes, including poor dental hygiene, medications, serious systemic illnesses, genetic conditions, other specific physiologic states, or it may be idiopathic. Given the large number of possible underlying conditions, the work-up of a patient presenting with diffuse gingival enlargement may seem daunting. We present a systemic review of diffuse gingival enlargement, including an algorithm that can be used to direct the work-up of patients presenting with this condition. ( J Am Acad Dermatol 2005;52:491-9.)
D
iffuse gingival enlargement is defined as an excessive growth of periodontal tissue (Fig 1). Thousands of patients have been described in the literature, but the actual prevalence is unknown.1 Presenting complaints may include pain, tenderness, interference with speech and/or mastication, halitosis, or unsightly appearance, or the patient may be unaware of the condition.2 Gingival enlargement may be idiopathic, secondary to poor dental hygiene, medications, serious systemic illnesses, genetic conditions, or other specific physiologic states (Table I). The gingiva extends from the extreme cervical area of the clinical crown of the tooth to the mucogingival junction where it meets the alveolar mucosa. The gingiva forms a smooth collar around each tooth and extends as pointed interdental papillae (Fig 2).1 Healthy gingiva is coral pink in whites and often shows physiologic hyperpigmentation in individuals from darkly pigmented races.3,4 The attached gingiva is firm and has fine stippling.3,4 With inflammation, the gingiva becomes red, soft, shiny, and smooth. Inflamed gingiva bleeds easily and is often enlarged because of edema.3 Noninflammatory gingival enlargement classically leads to a reddish-purple color, variable firmness, and loss of stippling, which may be difficult to distinguish from inflammatory enlargement on clinical exam. From the Department of Dermatology, University of Pittsburgh. Funding sources: None. Conflicts of interest: None identified. Reprints not available from the authors. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.09.035
The gingival margins are raised and blunted because of enlargement.3 Gingival hyperplasia, gingival hypertrophy, and gingival enlargement have been used interchangeably in the literature. Gingival enlargement is a term that focuses less on the histological picture and more on the clinical appearance, and this term will be used in the remainder of this article.
ETIOLOGIES Chronic gingivitis Gingivitis is an inflammatory process limited to the soft tissues of the gingiva without any permanent tissue loss. When the inflammation also involves the periodontal ligament and alveolar bone, leading to destruction, the term periodontitis is used.4 The majority of gingivitis cases occur secondary to poor oral hygiene leading to bacterial plaque and calculus formation.3 However, a number of other risk factors for the development of chronic gingivitis and periodontitis have been identified. These include age, male gender, tobacco use,4 habits such as mouth breathing, overcrowded or misaligned teeth, poorly controlled diabetes, HIV, and psychological stress.5 Inflammation of the gingiva may be localized or generalized.3 Chronic inflammation of the gingiva may lead to gingival enlargement. 4 Fortunately, in many cases, gingivitis is a reversible condition. It is important that underlying, contributing factors are eliminated and good oral hygiene is practiced.3 Mechanical removal of plaque in hard-toaccess areas can be aided by chemical products. A recent study by Santos et al6 demonstrated that both 0.12% chlorhexidine (Peridex; Zila Pharmaceuticals, Phoenix, Az) and essential oil (Listerine; Pfizer 491
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Table I. Causes enlargement
Fig 1. Diffuse gingival enlargement.
Consumer Group, Morris Plains, NJ) mouth washes are safe and effective in reducing dental plaque accumulation and gingivitis. The plaque may also be removed by thorough brushing and flossing, sonic, and ultrasonic means.6 In cases of severe gingivitis in which the above means are not successful, gingivectomy should be considered. Conditioned enlargement There are some well-known hormonal and nutritional states that may magnify the usual gingival response to dental plaque leading to conditioned gingival enlargement.7 These conditions include pregnancy, puberty, and vitamin C deficiency. The association between the hormonal changes during pregnancy and generalized gingival enlargement is well known.8,9,10 Hormonal changes that occur during pregnancy are thought to exaggerate the response to local irritants, inducing a hyperplastic response.7,9 Clinically, the enlargement is usually diffuse, and the gingiva is red, shiny, smooth, and bleeds easily.7 Enlargement is much less likely to occur in women with good oral hygiene and little underlying periodontal disease.8 These gingival changes generally resolve spontaneously after delivery.7 Gingival enlargement is occasionally seen in male and female adolescents during puberty.7 The chronic inflammatory enlargement is similar to that seen during pregnancy. The gingival enlargement generally disappears spontaneously after puberty.7 Scurvy is a clinical state arising from dietary deficiency of vitamin C. This results in impaired collagen synthesis of the gingival tissue, which, in turn, results in hemorrhaging into the gums, edema, and loss of teeth. It is the combined effect of inflammation and vitamin C deficiency that leads to the significant gingival enlargement seen in scurvy.7
of
generalized
gingival
Chronic gingivitis Conditioned enlargement Pregnancy Puberty Scurvy Drug-induced Hematologic disorders Leukemias Aplastic anemia Lymphomas Systemic diseases Wegener’s granulomatosis Sarcoidosis Crohn’s disease von Recklinghausen’s neurofibromatosis Primary amyloidosis Kaposi’s sarcoma Acromegaly Congenital Idiopathic
Drug-induced gingival enlargement Drug-induced gingival enlargement (DIGE) was first described by Kimball11 in 1939 when he noted the correlation between the use of phenytoin and gingival changes. The vast majority of cases of DIGE are caused by phenytoin, calcium channel blockers, and cyclosporin. Gingival enlargement because of these drugs generally manifests within 1 to 3 months of initiating treatment.2 In the past few decades, gingival enlargement has been noted to be an adverse effect of other drugs in small clinical trials or case reports (Table II). Clinically and histologically, the gingival enlargement because of the various classes of drugs is nearly identical.12 It usually affects the interdental papillae on the labial side of the lower anterior teeth, around the maxillary molars and/or interdental gingiva rather than the lingual or palatal sides. The gingiva is soft and tends to bleed easily. Occasionally, the overgrowth can progress to cover the crowns of the teeth.12 Histologically, there is an excessive growth of connective tissue with an increase in ground substance produced by fibroblasts.11 The size of the cells and the ratio of cells to matrix is unchanged. For this reason, the term gingival hyperplasia is not appropriate to describe these changes.11 A number of risk factors for the development of DIGE have been identified. Oral hygiene and health. Dental plaque formation and gingivitis secondary to poor oral hygiene are established risk factors for gingival enlargement.11,12 It has been proposed that the plaque may
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Fig 2. Normal gingiva.
act as a reservoir not only for numerous bacteria and food particles, but also for the drug, thereby enhancing the drug-fibroblast interaction.11 In a study of patients who were treated with cyclosporin posttransplant, it was found that gingival enlargement was greatest in areas of dental plaque and gingivitis.15 Thus, the role of quintessential oral hygiene can not be overemphasized. Poor oral hygiene is the causative factor of gingivitis and periodontitis. In addition, it is one of, if not the major factor in DIGE. Age, sex, race. With regard to the commonly used drugs such as phenytoin and cyclosporin, there is a greater incidence of DIGE in children than in adults.11,12 It has been suggested that this may be because of the increased sensitivity of immature fibroblasts to various drugs.12 Most studies have not noted a racial or sexual predilection for DIGE. However, a few studies contradict these results. For example, Tyldesley and Rotter found that cyclosporin-induced gingival enlargement was 3 times higher in female renal transplant recipients than in male recipients.16 Another recent study demonstrated that males are 3 times more likely than females to demonstrate nifedipine-induced gingival enlargement.17 The investigators stated that in prior studies, nifidepine was shown to increase the conversion of testosterone to 5a dihydrotestosterone (5a DT) when added to in vitro fibroblasts. They deduced that 5a DT may be responsible for inducing fibroblast proliferation.17 Genetic predisposition. Not all individuals taking these drugs develop gingival enlargement. This may suggest an underlying genetic predisposition. It has been demonstrated that individuals’ fibroblasts demonstrate heterogeneity in response to different drugs and their metabolites.11 In addi-
tion, phenytoin, dihydropyridines, and cyclosporine are all metabolized by cytochrome P450 enzymes. Genetic polymorphisms of these enzymes may help account for differences in susceptibility.11 Genetic differences in human leukocyte antigen expression have also been hypothesized to account for some of this susceptibility. 11 Drug pharmacokinetics. While some studies suggest a correlation of the dosage, duration, and serum level of the drug with the degree of gingival enlargement, other studies have not supported this correlation.18-23 In a recent study, Hefti et al18 found that in a group of multiple sclerosis patients treated with cyclosporin, the presence of gingival enlargement was positively correlated with drug levels in the saliva and serum. In contrast, Varga et al19 reported no direct correlation between serum cyclosporin levels and the degree of gingival overgrowth in patients who received cyclosporin treatment after renal transplantation. Similarly, there is conflicting evidence regarding the relationship of the doses of phenytoin20,21 and nifedipine22,23 with severity of gingival enlargement. Combination of drugs. Studies indicate that by combining drugs known to induce gingival enlargement, the incidence and severity of the changes increase.12 Specific combinations that have been implicated include cyclosporin and calcium channel blockers such as nifedipine. This combination is often prescribed to patients post-transplant since nifedipine can reduce cyclosporin-mediated nephrotoxicity and hypertension.24 Thomason et al24 demonstrated that the prevalence and severity of gingival enlargement were significantly greater in cardiac transplant patients treated with both cyclosporin and nifedipine than with cyclosporin alone.
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Table II. Drugs enlargement Drugs
Anticonvulsants
associated
with
Common*
Phenytoin (50%)2
Calcium channel blockers
Nifidepine (38%)2 Diltiazem (20%)2 Verapamil (4%-19%)2 Amlodipine (3%)2,14 Immunosuppressants Cyclosporine (13-85%)2 Antimicrobials
Antidepressants Miscellaneous
gingival Uncommon
Barbiturates2 Carbamazepine2 Succinimides2 Valproic acid2 Primidone13 Ethosuximide13 Lamotrigine13 Vigabatrin13 Topiramate13 Felodipine2 Nitrendipine2 Oxodipine12
Tacrolimus12 Erythromycin13 Cotrimoxazole13 Ketoconazole13 Sertaline13 Lithium13
Oral contraceptives13
*Percentages refer to the incidence of gingival enlargement among patients taking each drug. When two drugs known to cause gingival enlargement are used concurrently, the frequency and severity of enlargement may be increased.12
The concomitant use of phenytoin in conjunction with either carbamazepine, phenobarbital, or primidone was shown to increase the risk of gingival enlargement in the pediatric population.25 A recently conducted study in adults revealed no synergistic effect of phenytoin with the same 3 anticonvulsants on gingival enlargement.26 This discrepancy may be caused by the increased susceptibility to DIGE in children because of the immaturity of their fibroblasts.12 Majola et al27 recently investigated the importance of various risk factors on phenytoin-induced gingival enlargement. The factors included age, the presence of bacterial plaque and gingivitis, serum drug levels, the concurrent use of other anticonvulsant drugs, tobacco use, and alcohol consumption. Except for the presence of dental plaques, no other variable on its own was found to have a significant association with DIGE. However, using a multifactorial regression analysis, the investigators noted that some of these factors, when considered in combination, in-
creased the risk of gingival enlargement.27 Interestingly, smoking and alcohol use may be associated with lower rates of phenytoin-induced gingival enlargement.27 It was hypothesized that alcohol users are able to metabolize phenytoin faster because of increased activity of the Cytochrome P450 enzymes, thereby decreasing the amount of drug available to induce gingival changes.27 Discontinuing the offending drug generally leads to a regression of the gingival enlargement.2 If it is possible, other drugs should be considered for the patient’s condition. For example, in terms of calcium channel blockers, switching from nifedipine to isradipine in hypertensive patients has been effective in reducing the incidence of gingival enlargement.12 Two randomized controlled studies have demonstrated that the conversion from cyclosporine to oral tacrolimus in renal transplant recipients results in a reduction of gingival enlargement.28,29 However, among pediatric renal transplant patients, neuropsychological and behavioral side effects may occur with therapeutic levels of tacrolimus and these adverse effects are often under-recognized in this population.30 In a double-blind, randomized crossover trial of renal transplant recipients, Nash and Zaltzman31 reported a reduction in cyclosporin-induced gingival enlargement and gum bleeding with a 5-day course of the macrolide antibiotic, azithromycin. The patients tolerated the medication well, and no adverse effects were reported. In another study of 31 patients who developed cyclosporin-induced gingival enlargement, all improved with a 3-day course of azithromycin.32 Thus, a short course of azithromycin can be considered in cases of DIGE in which it is not possible to discontinue or switch the offending drug and in cases that do not respond to improved oral hygiene. Surgical procedures are necessary in severe, refractory cases. 6,23 Hematologic conditions Gingival enlargement may be the presenting feature of acute leukemia or a later finding.33,34 In some cases, the enlargement is the result of infiltration of the gingival soft tissues by malignant white blood cells, in other cases it is caused by an inflammatory reactive hyperplasia without evidence of infiltration.34 Gingival changes are seen in 3% to 5% of patients with acute myelogenous leukemia and are most commonly seen in acute monomyelocytic and monocytic leukemias (M4 and M5 subtypes).33 Recently, however, two cases of leukemic infiltration were found in patients with mixed lineage leukemia.34 Interestingly, gingival enlargement is not seen in edentulous
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patients, suggesting that the presence of teeth is somehow involved in the pathogenesis of this condition.33 Clinically, the gingiva may appear diffusely enlarged or there may be a tumor-like nodule. The enlarged gingiva is red, swollen, without stippling, and has a tendency to bleed easily.33 In a patient presenting with gingival enlargement in whom leukemia is suspected, a biopsy should be performed with caution or avoided altogether because of the risk of bleeding and infection secondary to pancytopenia. A recent study demonstrated that fine needle aspiration cytology may be a simpler and safer diagnostic screening procedure.34 In most cases, the gingival enlargement resolves, at least partially, with chemotherapy. However, involvement of the gingiva often predicts a poorer overall prognosis for patients.33 In a review of 79 patients with aplastic anemia, Brennan et al35 noted that gingival enlargement was present in 16% of the patients with aplastic anemia and in none of the control subjects. Upon performing a logistic regression analysis, it was found that 12 of the 13 patients with gingival enlargement had been treated with cyclosporin within the previous 6 months. Thus, the gingival changes may have been drug-induced and not a manifestation of the aplastic anemia.35 There has been another case report, however, that suggested that gingival enlargement was secondary to underlying aplastic anemia.36 Haytac et al37 recently described a 14-year-old patient who presented with gingival enlargement and alveolar bone loss as the first signs of Burkitt cell type acute lymphoblastic leukemia (ALL-L3). Although no biopsy was performed, it was hypothesized that the enlargement was secondary to the infiltration of neoplastic cells in the gingiva, periodontal ligament, and alveolar bone.37 Nicolatou-Galitis et al38 reported a case of gingival enlargement, premature root resorption, and alveolar bone loss as a manifestation of stage IVB Hodgkin’s lymphoma. Treatment with a number of chemotherapeutic agents led to the regression of the lymphoma as well as the gingival enlargement. The authors hypothesized that the mechanism of gingival enlargement was the excessive activation of the transcription factor nuclear factor (NF)-kB.38
Systemic diseases Gingival enlargement may be an accompanying or even presenting feature of several systemic diseases. These include Wegener’s granulomatosis, sarcoidosis, Crohn’s disease, von Recklinghausen neurofibromatosis, and primary amyloidosis.
Wegener’s granulomatosis (WG) is characterized by a necrotizing and granulomatous vasculitis affecting primarily the upper respiratory tracts, lungs, and kidneys.39,40 Patients who are not treated may rapidly experience multi-organ failure. Cytoplasmic anti-neutrophilic cytoplasmic antibody (C-ANCA) titers are often elevated in WG; however, they have variable sensitivities and specificities and may not be useful early in the disease.39 The prevalence of oral lesions, including gingival enlargement, has been reported to range from 10% to 62% in patients with WG.40 In fact, gingival changes may be the presenting sign in 7% of cases.39 ‘‘Strawberry gingival hyperplasia’’ can be an early pathognomonic finding in Wegener’s granulomatosis.39 The changes initially appear in the interdental papillae as bright red, friable papules that resemble small strawberries.39 Although not pathognomonic, pseudoepitheliomatous hyperplasia, microabscesses, and multinucleated giant cells seen on a biopsy specimen are suggestive of WG.40 Early use of immunosuppressive drugs has produced prolonged remissions in up to 75% of patients.39 Sarcoidosis is a systemic noncaseating granulomatous disease of unknown etiology that usually begins in young adulthood and leads to secondary derangement of normal tissue or organ anatomy and function.41 Sarcoidosis may affect any organ or tissue, including the gingiva. The gingiva tends to be diffusely enlarged and erythematous.7 To confirm the diagnosis, a biopsy of the affected site is generally performed. In the literature, a case was reported in which gingival enlargement was the presenting sign of generalized sarcoidosis. The patient’s gingival enlargement resolved with oral prednisolone.42 Crohn’s disease is another inflammatory granulomatous disease that affects young adults. It may affect any part of the digestive tract from the mouth to the anal region. A case was reported in which an 8-year-old patient presented with abdominal complaints, and on physical examination, she was found to have oral ulcerations as well as erythematous and enlarged gingiva.43 A colonoscopy with several biopsies revealed histological changes consistent with Crohn’s disease. Oral prednisone and azathioprine prevented the lip and oral lesions from recurring. 43 Occasionally, gingival enlargement can occur because of neoplastic infiltration of Schwann and perineural cells, as in von Recklinghausen neurofibromatosis.44 Neurofibromatosis I is a neurocutaneous condition in which patients present with cutaneous findings such as cafe´-au-lait spots and multiple skin neurofibromas, osseous abnormalities, and tumors of the central nervous system. Bekisz et al44 recently reported a case in which an
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Fig 3. Algorithm for diagnosis of diffuse gingival enlargement.
8-year-old patient was noted by her dentist to have diffuse, unilateral gingival enlargement in addition to 16 cafe´-au-lait spots. The gingival enlargement resulted in a delayed eruption of teeth. Histologic examination of a gingival biopsy revealed a prolifer-
ation of perineural and Schwann cells.44 Amyloidosis is the result of several unrelated disease processes that leads to the deposition of proteinaceous fibrils in various tissues and organs.45 Infiltration of the tongue leading to macroglossia is the most characteristic oral
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lesion, occurring in 20% of cases of primary amyloidosis.46 However, many other sites within the oral cavity may also be affected including the palate, gingival and buccal mucosa, and salivary glands. 45 Two reports described several patients who presented with gingival enlargement which was diffuse and appeared as pink, waxy masses that were painless and did not bleed easily.47,48 Upon histologic exam, amorphous deposits of an eosinophilic material were noted. Surprisingly, however, the deposits did not demonstrate green bifringence with Congo red staining.47,48 The authors suggested that the lack of bifringence may be because the disease process was in the early stages or because the material was not amyloid, but amyloid-like.47,48 Kaposi’s sarcoma is a vascular neoplasm frequently observed in patients with AIDS. Kaposi’s sarcoma typically affects the skin; however, oral lesions of the palate, gingiva, and tongue have been well described in the literature.49-52 The lesions typically appear focally as reddish-blue macules which progress to form purple nodules.51 In severe cases, as was described by Petit et al,49 the gingival lesions may spread, resulting in diffusely erythematous and edematous gingiva. Although intraoral Kaposi’s sarcoma is most commonly seen in patients with AIDS, a recent case report described an HIV-negative, renal transplant patient who presented with erythematous, nodular lesions that covered her maxillary and mandibular teeth.52 Gingival enlargement has also been seen in patients with acromegaly, an endocrine disorder characterized by increased and unregulated growth hormone production. Acromegaly typically results in the overgrowth of cartilage, muscles, and organs. Capoglu et al53 examined 11 patients with acromegaly and reported that 8 of them demonstrated diffuse gingival enlargement. Interestingly, nearly all the patients with gingival changes also had prognathism.53 Congenital The differential diagnosis of severe gingival enlargement in children should include hereditary and metabolic disorders. In children, the primary functional concern is delayed eruption of permanent teeth. Congenital causes of generalized gingival enlargement include: hereditary fibromatosis, I-cell disease, mucopolysaccharidoses I-H, fucosidosis, aspartyl glycosaminuria, Pfeiffer’s syndrome, infantile systemic hyalinosis, and primary amyloidosis.49 Congenital causes of localized gingival enlargement include: Fabry’s syndrome, Cowden’s syndrome, tuberous sclerosis, Sturge-Weber angiomatosis, and congenital gingival granular cell tumor.49
Hereditary gingival fibromatosis is a condition of unknown etiology with an autosomal dominant inheritance pattern.7 Unlike drug-induced gingival enlargement which is typically limited to the gingival margin and interdental papillae, gingival fibromatosis also affects the attached gingiva. The gingiva is pink, firm, and has a characteristic pebbled appearance.7 This condition may occur as an isolated finding or may be part of a syndrome. For example, recent case reports have described a syndrome of diffuse gingival enlargement, generalized hypertrichosis, epilepsy, and mental retardation.54,55 Children often present with excessive hair growth at birth or early infancy, although in up to 50% of cases, the excess hair is noticed at puberty.54 Gingival enlargement is generally noted when the teeth are late to erupt.54 Patients typically need repeated surgical procedures to ensure proper and timely eruption of the teeth.54,55 I-cell disease is a rare metabolic disorder resulting from the deficiency of a lysosomal enzyme. Patients typically present before 1 year of age with physical and mental retardation and oral manifestations including gingival enlargement. The enlargement of the gingiva and alveolar process is progressive after 4 months of age, causing the mouth to appear ‘‘fishlike.’’56 The overall prognosis of I-cell disease is poor with death often occurring secondary to recurrent respiratory tract infections.56
CONCLUSION Gingival enlargement may come to attention as a presenting complaint or as an incidental finding. In addition to its potential functional and cosmetic effects, its primary importance lies in its potential association with systemic diseases. Since there are a large number of diseases, medications, and physiologic states reported in association with gingival enlargement, the diagnostic work-up must be pursued in a logical, step-wise approach. To that end, we present a diagnostic algorithm in Fig 3. In general, treatment should be directed at any underlying disease that is identified. In cases of chronic inflammatory enlargement, exquisite dental hygiene is typically effective. In addition, a short course of oral antibiotics to decrease the oral bacterial load may be considered. When gingival enlargement is medication-related, discontinuation or substitution of the offending medication is the gold standard. Specifically, a different anticonvulsant can be substituted for phenytoin, or a different immunosuppressant can be substituted for cyclosporine. If cyclosporine cannot be discontinued, or if the enlargement persists off the
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cyclosporine, a trial of macrolide antibiotics may be considered. In cases of idiopathic enlargement which persists despite aggressive oral hygiene, consideration can be given to surgical reduction of the gingiva. This should be considered as a last line measure. REFERENCES 1. Brunet L, Miranda J, Farre M, Berini L, Mendieta C. Gingival enlargement induced by drugs. Drug Safety 1996;15:219-31. 2. Meraw SJ, Sheridan PJ. Medically induced gingival hyperplasia. Mayo Clin Proc 1998;73:1196-9. 3. Periodontal diseases. In: Neville BW, Damm DD, Allen CM, Bouquot JE, editors. Oral and Maxillofacial Pathology. 1st ed. Philadelphia, PA: W.B. Saunders Company; 1995. p. 122-33. 4. Research, Science and Therapy Committee of the American Academy of Periodontology. Treatment of plaque-induced gingivitis, chronic periodontitis, and other clinical conditions. J Periodontol 2001;72:1790-800. 5. Nunn ME. Understanding the etiology of periodontitis: an overview of periodontal risk factors. Periodontol 2000 2003;32:11-23. 6. Santos A. Evidence-based control of plaque and gingivitis. J Clin Periodontol 2003;30:13-6. 7. Carranza FA, Hogan EL. Gingival enlargement. In: Newman MG, Takei HH, Carranza FA, editors. Clinical Periodontology. 9th ed. Philadelphia, PA: W.B.Saunders Company; 2002. p. 279-96. 8. Barak S, Oettinger-Barak O, Oettinger M, Machtei EE, Peled M, Ohel G. Common oral manifestations during pregnancy: a review. Obstet Gynecol Survey 2003;58:624-8. 9. Gungormus M, Akgul HM, Yilmaz AB, Dagistanli S, Erciyas K. Generalized gingival hyperplasia occurring during pregnancy. J Int Med Res 2002;30:353-5. 10. Di Placido G, Tumini V, D’Archivio D, Di Peppe G. Gingival hyperplasia in pregnancy. II. Etiopathogenic factors and mechanisms. Minerva Stomatologica 1998;47:223-9. 11. Seymour RA, Thomason JM, Ellis JS. The pathogenesis of druginduced gingival overgrowth. J Clin Periodontol 1996;23:165-75. 12. Varnfield M, Botha SJ. Drug-induced gingival hyperplasiaea review. SADJ 2000;55:632-41. 13. Abdollahi M, Radfar M. A review of drug-induced oral reactions. J Contemp Dent Pract 2003;4:10-31. 14. Routray SN, Mishra TK, Pattnaik UK, Satapathy C, Mishra CK, Behera M. Amlodipine-induced gingival hyperplasia. J Assoc Physicians India 2003;51:818-9. 15. Tyldesley WR, Rotter E. Gingival hyperplasia induced by cyclosporin-A. Br Dent J 1984;157:305-10. 16. Ellis JS, Seymour RA, Steele JG, Robertson P, Butler TJ, Thomason JM. Prevalence of gingival overgrowth induced by calcium channel blockers: a community-based study. J Periodontol 1999;70:63-7. 17. Somacarrera ML, Hernandez G, Acero J, Moskow MS. Localization of gingival overgrowth in heart transplant patients undergoing cyclosporin therapy. J Periodontol 1994;65: 666-70. 18. Hefti AF, Eshenaur AE, Hassell TM, Stone C. Gingival overgrowth in cyclosporine A treated multiple sclerosis patients. J Periodontol 1994;65:744-9. 19. Varga E, Lennon MA, Mair LH. Pre-transplant gingival hyperplasia predicts severe cyclosporin-induced gingival overgrowth in renal transplant patients. J Clin Periodontol 1998; 25:225-30.
20. Perlik F, Kolinova M, Zvarova J, Patzelova V. Phenytoin as a risk factor in gingival hyperplasia. Ther Drug Monitoring 1995; 17:445-8. 21. Ball DE, McLaughlin WS, Seymour RA, Kamali F. Plasma and saliva concentrations of phenytoin and 5-(4-hydroxyphenyl)5-phenylhydantoin in relation to the incidence and severity of phenytoin-induced gingival overgrowth in epileptic patients. J Periodontol 1996;67:597-602. 22. Barak S, Engelberg IS, Hiss J. Gingival hyperplasia caused by nifedipine. Histopathologic findings. J Periodontol 1987;58: 639-42. 23. Nery EB, Edson RG, Lee KK, Pruthi VK, Watson J. Prevalence of nifedipine-induced gingival hyperplasia. J Periodontol 1995; 66:572-8. 24. Thomason JM, Seymour RA, Ellis JS, Kelly PJ, Parry G, Dark J, Idle JR. Iatrogenic gingival overgrowth in cardiac transplantation. J Periodontol 1995;66:742-6. 25. Maguire JH, Greenwood RS, Lewis D. Phenytoin-induced gingival overgrowth is dependent upon co-medication. J Dent Res 1986;65:249. 26. Kamali F, McLaughlin WS, Ball DE, Seymour RA. The effect of multiple anticonvulsant therapy on the expression of phenytoin-induced gingival overgrowth. J Clin Periodontol 1999; 26:802-5. 27. Majola MP, McFadyen ML, Connolly C, Nair YP, Govender M, Laher MH. Factors influencing phenytoin-induced gingival enlargement. J Clin Periodontol 2000;27:506-12. 28. Thorp M, DeMattos A, Bennett W, Barry J, Norman D. The effect of conversion from cyclosporine to tacrolimus on gingival hyperplasia, hirsutism and cholesterol. Transplantation 2000;69:1218-20. 29. Kohnle M, Lutkes P, Zimmermann U, Philipp T, Heemann U. Conversion from cyclosporine to tacrolimus in renal transplant recipients with gum hyperplasia. Transplantation Proc 1999; 31:44S-5S. 30. Kemper MJ, Sparta G, Laube GF, Miozzari M, Neuhaus TJ. Neuropsychologic side-effects of tacrolimus in pediatric renal transplantation. Clin Transplantation 2003;17:130-4. 31. Nash MM, Zaltzman JS. Efficacy of azithromycin in the treatment of cyclosporine-induced gingival hyperplasia in renal transplant recipients. Transplantation 1998;65:1611-5. 32. Gomez E, Sanchez-Nunez M, Sanchez JE, Corte C, Aguado S, Portal C, Baltar J, Alvarez-Grande J. Treatment of cyclosporininduced gingival hyperplasia with azithromycin. Nephrol Dial Transplantation 1997;12:2694-7. 33. Cooper CL, Loewen R, Shore T. Gingival hyperplasia complicating acute myelomonocytic leukemia. J Can Dent Assoc 2000;66:78-9. 34. Abdullah BH, Yahya HI, Kummoona RK, Hilmi FA, Mirza KB. Gingival fine needle aspiration cytology in acute leukemia. J Oral Pathol Med 2002;31:55-8. 35. Brennan MT, Sankar V, Baccaglini L, Pillemer SR, Kingman A, Nunez O, Young NS, Atkinson JC. Oral manifestations in patients with aplastic anemia. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontics 2001;92:503-8. 36. Luker J, Scully C, Oakhill A. Gingival swelling as a manifestation of aplastic anemia. Oral Surg Oral Med Oral Pathol 1991;71:55-6. 37. Haytac MC, Antmen B, Dogan MC, Sasmaz I. Severe alveolar bone loss and gingival hyperplasia as initial manifestation of Burkitt cell type acute lymphoblastic leukemia. J Periodontol 2003;74:547-51. 38. Nicolatou-Galitis O, Papadaki T, Moshovi M, Kamma JJ, van Vliet-Constantinidou C, Tsoumakas C, Kattamis A, TzortzatouStathopoulou F. Gingival overgrowth as the initial paraneoplastic manifestation of Hodgkin’s lymphoma in a child. A case report. J Periodontol 2001;72:107-12.
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39. Knight JM, Hayduk MJ, Summerlin DJ, Mirowski GW. ‘‘Strawberry’’ gingival hyperplasia: a pathognomonic mucocutaneous finding in Wegener granulomatosis. Arch Dermatol 2000;136: 171-173. 40. Manchanda Y, Tejasvi T, Handa R, Ramam M. Strawberry gingiva: a distinctive sign in Wegener’s granulomatosis. J Am Acad Dermatol 2003;49:335-7. 41. English JC 3rd., Patel PJ, Greer KE. Sarcoidosis. J Am Acad Dermatol 2001;44:725-43. 42. Sloan PJ, O’ Neil TC, Smith CJ, Holdsworth CD. Multisystem sarcoid presenting with gingival hyperplasia. Br J Oral Surg 1983;21:31-5. 43. Stricker T, Braegger CP. Images in clinical medicine. Oral manifestations of Crohn’s disease. N Engl Med 2000;342:1644. 44. Bekisz O, Darimont F, Rompen EH. Diffuse but unilateral gingival enlargement associated with von Recklinghausen neurofibromatosis: a case report. J Clin Periodontol 2000;27:361-5. 45. Stoopler ET, Sollecito TP, Chen SY. Amyloid deposition in the oral cavity: a retrospective study and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontics 2003;95:674-80. 46. Smith A, Speculand B. Amyloidosis with oral involvement. Br J Oral Maxillofac Surg 1985;23:435-44. 47. Gunhan O, Celasun B, Perrini F, Covani U, Perrini N, Ozdemir A, Bostanci H, Finci R. Generalized gingival enlargement due to accumulation of amyloid-like material. J Oral Pathol Med 1994;23:423-8.
48. Gokbuget AY, Mutlu S, Scully C, Efeoglu A, Porter SR, Speight P, Erseven G, Karacorlu M. Amyloidaceous ulcerated gingival hyperplasia: a newly described entity related to ligneous conjunctivitis. J Oral Pathol Med 1997;26:100-4. 49. Petit JC, Ripamonti U, Hille J. Progressive changes of Kaposi’s sarcoma of the gingiva and palate. J Periodontol 1986;57:15963. 50. Chapple IL, Rout PG, Basu MK. Gingival Kaposi’s Sarcoma: the first indication of HIV infection. Dent Update 1992;19:296, 298-301. 51. Shiboski CH, Winkler JR. Gingival Kaposi’s sarcoma and periodontitis. A case report and suggested treatment approach to the combined lesions. Oral Surg Oral Med Oral Pathol 1993;76:49-53. 52. Bowie SA Jr, Bach D. Oral Kaposi’s sarcoma in a non-AIDS patient. Gen Dent 1999;47:413-5. 53. Capoglu I, Yilmaz AB, Unuvar N, Orbak R, Aksoy H, Yesilyurt H. Gingival enlargement in acromegaly. Endocr 2002;18:207-10. 54. Vashi RA, Mancini AJ, Paller AS. Primary generalized and localized hypertrichosis in children. Arch Dermatol 2001; 137:877-84. 55. Guevara-Sangines E, Villalobos A, Vega-Memije ME, MosquedaTaylor A, Canun-Serrano S, Lacy-Niebla RM. Congenital generalized terminal hypertrichosis with gingival hyperplasia. Pediatr Dermatol 2003;19:114-8. 56. Lee W, O’Donnell D. Severe gingival hyperplasia in a child with I-cell disease. International J Paediatr Dent 2003;13:41-5.
REVIEWS
Diffuse gingival enlargement Pooja Khera, BS, Matthew J. Zirwas, MD, and Joseph C. English III, MD Pittsburgh, Pennsylvania Diffuse gingival enlargement is defined as an excessive growth of periodontal tissue. It can be considered a relatively common finding, as thousands of patients have been described in the literature. Patients may seek medical attention because of pain, tenderness, interference with speech and/or mastication, halitosis, or unsightly appearance, or gingival enlargement may be an unexpected finding on routine physical examination. Diffuse gingival enlargement has numerous causes, including poor dental hygiene, medications, serious systemic illnesses, genetic conditions, other specific physiologic states, or it may be idiopathic. Given the large number of possible underlying conditions, the work-up of a patient presenting with diffuse gingival enlargement may seem daunting. We present a systemic review of diffuse gingival enlargement, including an algorithm that can be used to direct the work-up of patients presenting with this condition. ( J Am Acad Dermatol 2005;52:491-9.)
D
iffuse gingival enlargement is defined as an excessive growth of periodontal tissue (Fig 1). Thousands of patients have been described in the literature, but the actual prevalence is unknown.1 Presenting complaints may include pain, tenderness, interference with speech and/or mastication, halitosis, or unsightly appearance, or the patient may be unaware of the condition.2 Gingival enlargement may be idiopathic, secondary to poor dental hygiene, medications, serious systemic illnesses, genetic conditions, or other specific physiologic states (Table I). The gingiva extends from the extreme cervical area of the clinical crown of the tooth to the mucogingival junction where it meets the alveolar mucosa. The gingiva forms a smooth collar around each tooth and extends as pointed interdental papillae (Fig 2).1 Healthy gingiva is coral pink in whites and often shows physiologic hyperpigmentation in individuals from darkly pigmented races.3,4 The attached gingiva is firm and has fine stippling.3,4 With inflammation, the gingiva becomes red, soft, shiny, and smooth. Inflamed gingiva bleeds easily and is often enlarged because of edema.3 Noninflammatory gingival enlargement classically leads to a reddish-purple color, variable firmness, and loss of stippling, which may be difficult to distinguish from inflammatory enlargement on clinical exam. From the Department of Dermatology, University of Pittsburgh. Funding sources: None. Conflicts of interest: None identified. Reprints not available from the authors. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.09.035
The gingival margins are raised and blunted because of enlargement.3 Gingival hyperplasia, gingival hypertrophy, and gingival enlargement have been used interchangeably in the literature. Gingival enlargement is a term that focuses less on the histological picture and more on the clinical appearance, and this term will be used in the remainder of this article.
ETIOLOGIES Chronic gingivitis Gingivitis is an inflammatory process limited to the soft tissues of the gingiva without any permanent tissue loss. When the inflammation also involves the periodontal ligament and alveolar bone, leading to destruction, the term periodontitis is used.4 The majority of gingivitis cases occur secondary to poor oral hygiene leading to bacterial plaque and calculus formation.3 However, a number of other risk factors for the development of chronic gingivitis and periodontitis have been identified. These include age, male gender, tobacco use,4 habits such as mouth breathing, overcrowded or misaligned teeth, poorly controlled diabetes, HIV, and psychological stress.5 Inflammation of the gingiva may be localized or generalized.3 Chronic inflammation of the gingiva may lead to gingival enlargement. 4 Fortunately, in many cases, gingivitis is a reversible condition. It is important that underlying, contributing factors are eliminated and good oral hygiene is practiced.3 Mechanical removal of plaque in hard-toaccess areas can be aided by chemical products. A recent study by Santos et al6 demonstrated that both 0.12% chlorhexidine (Peridex; Zila Pharmaceuticals, Phoenix, Az) and essential oil (Listerine; Pfizer 491
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Table I. Causes enlargement
Fig 1. Diffuse gingival enlargement.
Consumer Group, Morris Plains, NJ) mouth washes are safe and effective in reducing dental plaque accumulation and gingivitis. The plaque may also be removed by thorough brushing and flossing, sonic, and ultrasonic means.6 In cases of severe gingivitis in which the above means are not successful, gingivectomy should be considered. Conditioned enlargement There are some well-known hormonal and nutritional states that may magnify the usual gingival response to dental plaque leading to conditioned gingival enlargement.7 These conditions include pregnancy, puberty, and vitamin C deficiency. The association between the hormonal changes during pregnancy and generalized gingival enlargement is well known.8,9,10 Hormonal changes that occur during pregnancy are thought to exaggerate the response to local irritants, inducing a hyperplastic response.7,9 Clinically, the enlargement is usually diffuse, and the gingiva is red, shiny, smooth, and bleeds easily.7 Enlargement is much less likely to occur in women with good oral hygiene and little underlying periodontal disease.8 These gingival changes generally resolve spontaneously after delivery.7 Gingival enlargement is occasionally seen in male and female adolescents during puberty.7 The chronic inflammatory enlargement is similar to that seen during pregnancy. The gingival enlargement generally disappears spontaneously after puberty.7 Scurvy is a clinical state arising from dietary deficiency of vitamin C. This results in impaired collagen synthesis of the gingival tissue, which, in turn, results in hemorrhaging into the gums, edema, and loss of teeth. It is the combined effect of inflammation and vitamin C deficiency that leads to the significant gingival enlargement seen in scurvy.7
of
generalized
gingival
Chronic gingivitis Conditioned enlargement Pregnancy Puberty Scurvy Drug-induced Hematologic disorders Leukemias Aplastic anemia Lymphomas Systemic diseases Wegener’s granulomatosis Sarcoidosis Crohn’s disease von Recklinghausen’s neurofibromatosis Primary amyloidosis Kaposi’s sarcoma Acromegaly Congenital Idiopathic
Drug-induced gingival enlargement Drug-induced gingival enlargement (DIGE) was first described by Kimball11 in 1939 when he noted the correlation between the use of phenytoin and gingival changes. The vast majority of cases of DIGE are caused by phenytoin, calcium channel blockers, and cyclosporin. Gingival enlargement because of these drugs generally manifests within 1 to 3 months of initiating treatment.2 In the past few decades, gingival enlargement has been noted to be an adverse effect of other drugs in small clinical trials or case reports (Table II). Clinically and histologically, the gingival enlargement because of the various classes of drugs is nearly identical.12 It usually affects the interdental papillae on the labial side of the lower anterior teeth, around the maxillary molars and/or interdental gingiva rather than the lingual or palatal sides. The gingiva is soft and tends to bleed easily. Occasionally, the overgrowth can progress to cover the crowns of the teeth.12 Histologically, there is an excessive growth of connective tissue with an increase in ground substance produced by fibroblasts.11 The size of the cells and the ratio of cells to matrix is unchanged. For this reason, the term gingival hyperplasia is not appropriate to describe these changes.11 A number of risk factors for the development of DIGE have been identified. Oral hygiene and health. Dental plaque formation and gingivitis secondary to poor oral hygiene are established risk factors for gingival enlargement.11,12 It has been proposed that the plaque may
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Fig 2. Normal gingiva.
act as a reservoir not only for numerous bacteria and food particles, but also for the drug, thereby enhancing the drug-fibroblast interaction.11 In a study of patients who were treated with cyclosporin posttransplant, it was found that gingival enlargement was greatest in areas of dental plaque and gingivitis.15 Thus, the role of quintessential oral hygiene can not be overemphasized. Poor oral hygiene is the causative factor of gingivitis and periodontitis. In addition, it is one of, if not the major factor in DIGE. Age, sex, race. With regard to the commonly used drugs such as phenytoin and cyclosporin, there is a greater incidence of DIGE in children than in adults.11,12 It has been suggested that this may be because of the increased sensitivity of immature fibroblasts to various drugs.12 Most studies have not noted a racial or sexual predilection for DIGE. However, a few studies contradict these results. For example, Tyldesley and Rotter found that cyclosporin-induced gingival enlargement was 3 times higher in female renal transplant recipients than in male recipients.16 Another recent study demonstrated that males are 3 times more likely than females to demonstrate nifedipine-induced gingival enlargement.17 The investigators stated that in prior studies, nifidepine was shown to increase the conversion of testosterone to 5a dihydrotestosterone (5a DT) when added to in vitro fibroblasts. They deduced that 5a DT may be responsible for inducing fibroblast proliferation.17 Genetic predisposition. Not all individuals taking these drugs develop gingival enlargement. This may suggest an underlying genetic predisposition. It has been demonstrated that individuals’ fibroblasts demonstrate heterogeneity in response to different drugs and their metabolites.11 In addi-
tion, phenytoin, dihydropyridines, and cyclosporine are all metabolized by cytochrome P450 enzymes. Genetic polymorphisms of these enzymes may help account for differences in susceptibility.11 Genetic differences in human leukocyte antigen expression have also been hypothesized to account for some of this susceptibility. 11 Drug pharmacokinetics. While some studies suggest a correlation of the dosage, duration, and serum level of the drug with the degree of gingival enlargement, other studies have not supported this correlation.18-23 In a recent study, Hefti et al18 found that in a group of multiple sclerosis patients treated with cyclosporin, the presence of gingival enlargement was positively correlated with drug levels in the saliva and serum. In contrast, Varga et al19 reported no direct correlation between serum cyclosporin levels and the degree of gingival overgrowth in patients who received cyclosporin treatment after renal transplantation. Similarly, there is conflicting evidence regarding the relationship of the doses of phenytoin20,21 and nifedipine22,23 with severity of gingival enlargement. Combination of drugs. Studies indicate that by combining drugs known to induce gingival enlargement, the incidence and severity of the changes increase.12 Specific combinations that have been implicated include cyclosporin and calcium channel blockers such as nifedipine. This combination is often prescribed to patients post-transplant since nifedipine can reduce cyclosporin-mediated nephrotoxicity and hypertension.24 Thomason et al24 demonstrated that the prevalence and severity of gingival enlargement were significantly greater in cardiac transplant patients treated with both cyclosporin and nifedipine than with cyclosporin alone.
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Table II. Drugs enlargement Drugs
Anticonvulsants
associated
with
Common*
Phenytoin (50%)2
Calcium channel blockers
Nifidepine (38%)2 Diltiazem (20%)2 Verapamil (4%-19%)2 Amlodipine (3%)2,14 Immunosuppressants Cyclosporine (13-85%)2 Antimicrobials
Antidepressants Miscellaneous
gingival Uncommon
Barbiturates2 Carbamazepine2 Succinimides2 Valproic acid2 Primidone13 Ethosuximide13 Lamotrigine13 Vigabatrin13 Topiramate13 Felodipine2 Nitrendipine2 Oxodipine12
Tacrolimus12 Erythromycin13 Cotrimoxazole13 Ketoconazole13 Sertaline13 Lithium13
Oral contraceptives13
*Percentages refer to the incidence of gingival enlargement among patients taking each drug. When two drugs known to cause gingival enlargement are used concurrently, the frequency and severity of enlargement may be increased.12
The concomitant use of phenytoin in conjunction with either carbamazepine, phenobarbital, or primidone was shown to increase the risk of gingival enlargement in the pediatric population.25 A recently conducted study in adults revealed no synergistic effect of phenytoin with the same 3 anticonvulsants on gingival enlargement.26 This discrepancy may be caused by the increased susceptibility to DIGE in children because of the immaturity of their fibroblasts.12 Majola et al27 recently investigated the importance of various risk factors on phenytoin-induced gingival enlargement. The factors included age, the presence of bacterial plaque and gingivitis, serum drug levels, the concurrent use of other anticonvulsant drugs, tobacco use, and alcohol consumption. Except for the presence of dental plaques, no other variable on its own was found to have a significant association with DIGE. However, using a multifactorial regression analysis, the investigators noted that some of these factors, when considered in combination, in-
creased the risk of gingival enlargement.27 Interestingly, smoking and alcohol use may be associated with lower rates of phenytoin-induced gingival enlargement.27 It was hypothesized that alcohol users are able to metabolize phenytoin faster because of increased activity of the Cytochrome P450 enzymes, thereby decreasing the amount of drug available to induce gingival changes.27 Discontinuing the offending drug generally leads to a regression of the gingival enlargement.2 If it is possible, other drugs should be considered for the patient’s condition. For example, in terms of calcium channel blockers, switching from nifedipine to isradipine in hypertensive patients has been effective in reducing the incidence of gingival enlargement.12 Two randomized controlled studies have demonstrated that the conversion from cyclosporine to oral tacrolimus in renal transplant recipients results in a reduction of gingival enlargement.28,29 However, among pediatric renal transplant patients, neuropsychological and behavioral side effects may occur with therapeutic levels of tacrolimus and these adverse effects are often under-recognized in this population.30 In a double-blind, randomized crossover trial of renal transplant recipients, Nash and Zaltzman31 reported a reduction in cyclosporin-induced gingival enlargement and gum bleeding with a 5-day course of the macrolide antibiotic, azithromycin. The patients tolerated the medication well, and no adverse effects were reported. In another study of 31 patients who developed cyclosporin-induced gingival enlargement, all improved with a 3-day course of azithromycin.32 Thus, a short course of azithromycin can be considered in cases of DIGE in which it is not possible to discontinue or switch the offending drug and in cases that do not respond to improved oral hygiene. Surgical procedures are necessary in severe, refractory cases. 6,23 Hematologic conditions Gingival enlargement may be the presenting feature of acute leukemia or a later finding.33,34 In some cases, the enlargement is the result of infiltration of the gingival soft tissues by malignant white blood cells, in other cases it is caused by an inflammatory reactive hyperplasia without evidence of infiltration.34 Gingival changes are seen in 3% to 5% of patients with acute myelogenous leukemia and are most commonly seen in acute monomyelocytic and monocytic leukemias (M4 and M5 subtypes).33 Recently, however, two cases of leukemic infiltration were found in patients with mixed lineage leukemia.34 Interestingly, gingival enlargement is not seen in edentulous
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patients, suggesting that the presence of teeth is somehow involved in the pathogenesis of this condition.33 Clinically, the gingiva may appear diffusely enlarged or there may be a tumor-like nodule. The enlarged gingiva is red, swollen, without stippling, and has a tendency to bleed easily.33 In a patient presenting with gingival enlargement in whom leukemia is suspected, a biopsy should be performed with caution or avoided altogether because of the risk of bleeding and infection secondary to pancytopenia. A recent study demonstrated that fine needle aspiration cytology may be a simpler and safer diagnostic screening procedure.34 In most cases, the gingival enlargement resolves, at least partially, with chemotherapy. However, involvement of the gingiva often predicts a poorer overall prognosis for patients.33 In a review of 79 patients with aplastic anemia, Brennan et al35 noted that gingival enlargement was present in 16% of the patients with aplastic anemia and in none of the control subjects. Upon performing a logistic regression analysis, it was found that 12 of the 13 patients with gingival enlargement had been treated with cyclosporin within the previous 6 months. Thus, the gingival changes may have been drug-induced and not a manifestation of the aplastic anemia.35 There has been another case report, however, that suggested that gingival enlargement was secondary to underlying aplastic anemia.36 Haytac et al37 recently described a 14-year-old patient who presented with gingival enlargement and alveolar bone loss as the first signs of Burkitt cell type acute lymphoblastic leukemia (ALL-L3). Although no biopsy was performed, it was hypothesized that the enlargement was secondary to the infiltration of neoplastic cells in the gingiva, periodontal ligament, and alveolar bone.37 Nicolatou-Galitis et al38 reported a case of gingival enlargement, premature root resorption, and alveolar bone loss as a manifestation of stage IVB Hodgkin’s lymphoma. Treatment with a number of chemotherapeutic agents led to the regression of the lymphoma as well as the gingival enlargement. The authors hypothesized that the mechanism of gingival enlargement was the excessive activation of the transcription factor nuclear factor (NF)-kB.38
Systemic diseases Gingival enlargement may be an accompanying or even presenting feature of several systemic diseases. These include Wegener’s granulomatosis, sarcoidosis, Crohn’s disease, von Recklinghausen neurofibromatosis, and primary amyloidosis.
Wegener’s granulomatosis (WG) is characterized by a necrotizing and granulomatous vasculitis affecting primarily the upper respiratory tracts, lungs, and kidneys.39,40 Patients who are not treated may rapidly experience multi-organ failure. Cytoplasmic anti-neutrophilic cytoplasmic antibody (C-ANCA) titers are often elevated in WG; however, they have variable sensitivities and specificities and may not be useful early in the disease.39 The prevalence of oral lesions, including gingival enlargement, has been reported to range from 10% to 62% in patients with WG.40 In fact, gingival changes may be the presenting sign in 7% of cases.39 ‘‘Strawberry gingival hyperplasia’’ can be an early pathognomonic finding in Wegener’s granulomatosis.39 The changes initially appear in the interdental papillae as bright red, friable papules that resemble small strawberries.39 Although not pathognomonic, pseudoepitheliomatous hyperplasia, microabscesses, and multinucleated giant cells seen on a biopsy specimen are suggestive of WG.40 Early use of immunosuppressive drugs has produced prolonged remissions in up to 75% of patients.39 Sarcoidosis is a systemic noncaseating granulomatous disease of unknown etiology that usually begins in young adulthood and leads to secondary derangement of normal tissue or organ anatomy and function.41 Sarcoidosis may affect any organ or tissue, including the gingiva. The gingiva tends to be diffusely enlarged and erythematous.7 To confirm the diagnosis, a biopsy of the affected site is generally performed. In the literature, a case was reported in which gingival enlargement was the presenting sign of generalized sarcoidosis. The patient’s gingival enlargement resolved with oral prednisolone.42 Crohn’s disease is another inflammatory granulomatous disease that affects young adults. It may affect any part of the digestive tract from the mouth to the anal region. A case was reported in which an 8-year-old patient presented with abdominal complaints, and on physical examination, she was found to have oral ulcerations as well as erythematous and enlarged gingiva.43 A colonoscopy with several biopsies revealed histological changes consistent with Crohn’s disease. Oral prednisone and azathioprine prevented the lip and oral lesions from recurring. 43 Occasionally, gingival enlargement can occur because of neoplastic infiltration of Schwann and perineural cells, as in von Recklinghausen neurofibromatosis.44 Neurofibromatosis I is a neurocutaneous condition in which patients present with cutaneous findings such as cafe´-au-lait spots and multiple skin neurofibromas, osseous abnormalities, and tumors of the central nervous system. Bekisz et al44 recently reported a case in which an
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Fig 3. Algorithm for diagnosis of diffuse gingival enlargement.
8-year-old patient was noted by her dentist to have diffuse, unilateral gingival enlargement in addition to 16 cafe´-au-lait spots. The gingival enlargement resulted in a delayed eruption of teeth. Histologic examination of a gingival biopsy revealed a prolifer-
ation of perineural and Schwann cells.44 Amyloidosis is the result of several unrelated disease processes that leads to the deposition of proteinaceous fibrils in various tissues and organs.45 Infiltration of the tongue leading to macroglossia is the most characteristic oral
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lesion, occurring in 20% of cases of primary amyloidosis.46 However, many other sites within the oral cavity may also be affected including the palate, gingival and buccal mucosa, and salivary glands. 45 Two reports described several patients who presented with gingival enlargement which was diffuse and appeared as pink, waxy masses that were painless and did not bleed easily.47,48 Upon histologic exam, amorphous deposits of an eosinophilic material were noted. Surprisingly, however, the deposits did not demonstrate green bifringence with Congo red staining.47,48 The authors suggested that the lack of bifringence may be because the disease process was in the early stages or because the material was not amyloid, but amyloid-like.47,48 Kaposi’s sarcoma is a vascular neoplasm frequently observed in patients with AIDS. Kaposi’s sarcoma typically affects the skin; however, oral lesions of the palate, gingiva, and tongue have been well described in the literature.49-52 The lesions typically appear focally as reddish-blue macules which progress to form purple nodules.51 In severe cases, as was described by Petit et al,49 the gingival lesions may spread, resulting in diffusely erythematous and edematous gingiva. Although intraoral Kaposi’s sarcoma is most commonly seen in patients with AIDS, a recent case report described an HIV-negative, renal transplant patient who presented with erythematous, nodular lesions that covered her maxillary and mandibular teeth.52 Gingival enlargement has also been seen in patients with acromegaly, an endocrine disorder characterized by increased and unregulated growth hormone production. Acromegaly typically results in the overgrowth of cartilage, muscles, and organs. Capoglu et al53 examined 11 patients with acromegaly and reported that 8 of them demonstrated diffuse gingival enlargement. Interestingly, nearly all the patients with gingival changes also had prognathism.53 Congenital The differential diagnosis of severe gingival enlargement in children should include hereditary and metabolic disorders. In children, the primary functional concern is delayed eruption of permanent teeth. Congenital causes of generalized gingival enlargement include: hereditary fibromatosis, I-cell disease, mucopolysaccharidoses I-H, fucosidosis, aspartyl glycosaminuria, Pfeiffer’s syndrome, infantile systemic hyalinosis, and primary amyloidosis.49 Congenital causes of localized gingival enlargement include: Fabry’s syndrome, Cowden’s syndrome, tuberous sclerosis, Sturge-Weber angiomatosis, and congenital gingival granular cell tumor.49
Hereditary gingival fibromatosis is a condition of unknown etiology with an autosomal dominant inheritance pattern.7 Unlike drug-induced gingival enlargement which is typically limited to the gingival margin and interdental papillae, gingival fibromatosis also affects the attached gingiva. The gingiva is pink, firm, and has a characteristic pebbled appearance.7 This condition may occur as an isolated finding or may be part of a syndrome. For example, recent case reports have described a syndrome of diffuse gingival enlargement, generalized hypertrichosis, epilepsy, and mental retardation.54,55 Children often present with excessive hair growth at birth or early infancy, although in up to 50% of cases, the excess hair is noticed at puberty.54 Gingival enlargement is generally noted when the teeth are late to erupt.54 Patients typically need repeated surgical procedures to ensure proper and timely eruption of the teeth.54,55 I-cell disease is a rare metabolic disorder resulting from the deficiency of a lysosomal enzyme. Patients typically present before 1 year of age with physical and mental retardation and oral manifestations including gingival enlargement. The enlargement of the gingiva and alveolar process is progressive after 4 months of age, causing the mouth to appear ‘‘fishlike.’’56 The overall prognosis of I-cell disease is poor with death often occurring secondary to recurrent respiratory tract infections.56
CONCLUSION Gingival enlargement may come to attention as a presenting complaint or as an incidental finding. In addition to its potential functional and cosmetic effects, its primary importance lies in its potential association with systemic diseases. Since there are a large number of diseases, medications, and physiologic states reported in association with gingival enlargement, the diagnostic work-up must be pursued in a logical, step-wise approach. To that end, we present a diagnostic algorithm in Fig 3. In general, treatment should be directed at any underlying disease that is identified. In cases of chronic inflammatory enlargement, exquisite dental hygiene is typically effective. In addition, a short course of oral antibiotics to decrease the oral bacterial load may be considered. When gingival enlargement is medication-related, discontinuation or substitution of the offending medication is the gold standard. Specifically, a different anticonvulsant can be substituted for phenytoin, or a different immunosuppressant can be substituted for cyclosporine. If cyclosporine cannot be discontinued, or if the enlargement persists off the
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cyclosporine, a trial of macrolide antibiotics may be considered. In cases of idiopathic enlargement which persists despite aggressive oral hygiene, consideration can be given to surgical reduction of the gingiva. This should be considered as a last line measure. REFERENCES 1. Brunet L, Miranda J, Farre M, Berini L, Mendieta C. Gingival enlargement induced by drugs. Drug Safety 1996;15:219-31. 2. Meraw SJ, Sheridan PJ. Medically induced gingival hyperplasia. Mayo Clin Proc 1998;73:1196-9. 3. Periodontal diseases. In: Neville BW, Damm DD, Allen CM, Bouquot JE, editors. Oral and Maxillofacial Pathology. 1st ed. Philadelphia, PA: W.B. Saunders Company; 1995. p. 122-33. 4. Research, Science and Therapy Committee of the American Academy of Periodontology. Treatment of plaque-induced gingivitis, chronic periodontitis, and other clinical conditions. J Periodontol 2001;72:1790-800. 5. Nunn ME. Understanding the etiology of periodontitis: an overview of periodontal risk factors. Periodontol 2000 2003;32:11-23. 6. Santos A. Evidence-based control of plaque and gingivitis. J Clin Periodontol 2003;30:13-6. 7. Carranza FA, Hogan EL. Gingival enlargement. In: Newman MG, Takei HH, Carranza FA, editors. Clinical Periodontology. 9th ed. Philadelphia, PA: W.B.Saunders Company; 2002. p. 279-96. 8. Barak S, Oettinger-Barak O, Oettinger M, Machtei EE, Peled M, Ohel G. Common oral manifestations during pregnancy: a review. Obstet Gynecol Survey 2003;58:624-8. 9. Gungormus M, Akgul HM, Yilmaz AB, Dagistanli S, Erciyas K. Generalized gingival hyperplasia occurring during pregnancy. J Int Med Res 2002;30:353-5. 10. Di Placido G, Tumini V, D’Archivio D, Di Peppe G. Gingival hyperplasia in pregnancy. II. Etiopathogenic factors and mechanisms. Minerva Stomatologica 1998;47:223-9. 11. Seymour RA, Thomason JM, Ellis JS. The pathogenesis of druginduced gingival overgrowth. J Clin Periodontol 1996;23:165-75. 12. Varnfield M, Botha SJ. Drug-induced gingival hyperplasiaea review. SADJ 2000;55:632-41. 13. Abdollahi M, Radfar M. A review of drug-induced oral reactions. J Contemp Dent Pract 2003;4:10-31. 14. Routray SN, Mishra TK, Pattnaik UK, Satapathy C, Mishra CK, Behera M. Amlodipine-induced gingival hyperplasia. J Assoc Physicians India 2003;51:818-9. 15. Tyldesley WR, Rotter E. Gingival hyperplasia induced by cyclosporin-A. Br Dent J 1984;157:305-10. 16. Ellis JS, Seymour RA, Steele JG, Robertson P, Butler TJ, Thomason JM. Prevalence of gingival overgrowth induced by calcium channel blockers: a community-based study. J Periodontol 1999;70:63-7. 17. Somacarrera ML, Hernandez G, Acero J, Moskow MS. Localization of gingival overgrowth in heart transplant patients undergoing cyclosporin therapy. J Periodontol 1994;65: 666-70. 18. Hefti AF, Eshenaur AE, Hassell TM, Stone C. Gingival overgrowth in cyclosporine A treated multiple sclerosis patients. J Periodontol 1994;65:744-9. 19. Varga E, Lennon MA, Mair LH. Pre-transplant gingival hyperplasia predicts severe cyclosporin-induced gingival overgrowth in renal transplant patients. J Clin Periodontol 1998; 25:225-30.
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