CLINICAL PRACTICE DIAGNOSTIC CHALLENGE

Gingival enlargement

Gregory A. Pette, DMD, MS; Michael A. Siegel, DDS, MS, FDS RCSEd; William B. Parker, DDS

THE CHALLENGE scribed valproic acid. Approximately eight A 29-year-old woman visited the postgraduate months after the patient ceased taking pheny- periodontics clinic at the College of Dental Medi- toin, she visited the postgraduate periodontal cine, Nova Southeastern University, Fort clinic. The patient’s was poor and Lauderdale-Davie, Fla., for a consultation in June she had received no professional prophylaxis or 2009 because she was experiencing gingival deep scaling since her last dental appointment enlargement. The periodontist (G.A.P.) elicited a five years earlier. history of grand mal epilepsy. The onset of the Initial therapy consisted of deep scaling and epilepsy occurred at the time of puberty. The root planing in four quadrants followed by the patient reported having no other medical condi- at-home use of gluconate 0.12 per- tions. She indicated that she had four to five grand cent for a two-week period. The periodontist re- mal seizures per year coincident with her men- evaluated her condition six weeks later (Figure strual cycle. She also reported that her seizures 2). Excessive fibrotic gingival tissue remained, were preceded by auras. She had been under the with mild to moderate pseudopocketing and care of a neurologist since the onset of her moderate to severe loss of attachment. The epilepsy. The neurologist had prescribed a regimen periodontist performed guided tissue regenera- of phenytoin to treat the patient’s seizures. tion with a recombinant platelet-derived growth Before the patient sought care at the postgrad- factor and beta tricalcium phosphate in the uate periodontics clinic, a general dentist in pri- maxillary right and left posterior sextants, then vate practice, who was a family friend, noted the performed open flap curettage with apically approximately five years positioned flaps at all other sites. All perio- after the onset of the seizures and encouraged the dontal surgery took place with the patient patient’s private-practice neurologist of record to under enteral sedation with lorazepam (2 mil- perform an oral examination (Figure 1). The ligrams by mouth). During periodontal surgery, patient had not seen a dentist during this five-year the periodontist removed excess gingival tissue period, so the periodontist (G.A.P.) could not ascer- and subsequently sent it for microscopic evalu- tain whether the gingival en largement predated ation and interpretation (Figure 3). As of this the onset of the seizure disorder. The neurologist writing, the patient is undergoing orthodontic discontinued the phenytoin treatment, because it therapy while she remains on a three-month is known to cause gingival enlargement, and pre- periodontal maintenance schedule (Figure 4).

Figure 1. Initial presentation, Figure 2. Presentation after Figure 3. Photomicrograph Figure 4. Presentation after showing marked inflammation initial periodontal therapy, showing marked increase in surgical therapy. There is an and displacement of teeth. showing significant improve- collagen fibers with a mixed absence of inflammation and a ment in gingival color and inflammatory infiltration, acan- marked improvement in the architecture. thosis and elongated rete pegs gingival architecture. (hematoxylin-eosin, original magnification ×5).

Can you make the diagnosis? A. Drug-influenced gingival enlargement C. Leukemic infiltration B. Hereditary gingival enlargement D. Tuberculosis © 2011 American Dental Association. Republished by Medical Online Publication SAL with permission of American JADA 142(11) http://jada.ada.org November 2011 1265 Dental Association. All rights reserved. JADA 2011, Volume 142, No 11, Page 1265-1268

JADA Middle East vol 3 No 1 Jan-Feb 2012 55 CLINICAL PRACTICE DIAGNOSTIC CHALLENGE

THE DIAGNOSIS

A. drug-influenced gingival enlargement

“Drug-influenced gingival enlargement” and increased number of fibroblasts histologically.8,19 “drug-induced gingival overgrowth” are the pre- These findings indicate that, at a molecular ferred terms for what previously was referred to level, one etiologic factor of drug-induced gin- as “gingival hyperplasia,” “gingival hypertrophy,” gival enlargement may be the inhibition of col- “gingival fibromatosis” and “elephantiasis gin- lagen phagocytosis by means of reducing the 6 givae.” The medications commonly associated expression of α2 β1 integrins. Research suggests with drug-influenced gingival enlargement that integrins transduce information from the include antihypertensive agents such as the cal- extracellular matrix to the inside of the cell by cium channel blockers (including nifedipine, dilti- triggering intracellular signaling pathways.6 azem and verapamil, as well as antiseizure med- Antiepileptic, immunosuppressant, antidepres- ications such as phenytoin, sodium valproate, sant and calcium channel blocker drugs are valproic acid, phenobarbital and primidone.1-13 known to act as calcium antagonists. Intracel- Immunosuppressants such as cyclosporin A also lular calcium plays a role in the regulation of

are implicated in gingival enlargement. While α2 β1 integrin-mediated collagen phagocytosis by some spontaneous resolution has been associated altering integrin affinity. Furthermore, the with discontinuing the use of certain medications actin-binding protein gelsolin is considered an such as nifedipine, this generally is not the rule.13 important factor in gingival enlargement. Gel- At this patient’s initial visit to the neurologist, solin contributes to the maintenance of normal she was receiving only phenytoin treatment. tissue integrity by regulating collagen phagocy- Therefore, her history supports a diagnosis of tosis through its integrin-binding affinity to phenytoin-influenced gingival enlargement. How- collagens.6 ever, because the gingival enlargement did not Treatment. Risk factors associated with appear to improve after the elimination of the phenytoin-induced gingival enlargement may phenytoin, one also must consider sodium val- have a synergistic effect, and bacterial plaque proate as a cause of the drug-influenced gingival appears to be the most important determinant enlargement.14 of severe phenytoin-influenced gingival enlarge- The information in the patient’s medical, ment.9 Still, to date, the most effective long- dental and drug histories and the clinical presen- term treatment for gingival enlargement is drug tation usually are sufficient to attain a diagnosis withdrawal.5 In addition to discontinuation of of drug-influenced gingival enlargement; there- drug treatment, periodontal therapy often is fore, a biopsy is not necessarily mandated. How- recommended in conjunction with oral hygiene ever, to demonstrate such a diagnosis more defin- instructions. Dannewitz and colleagues20 itively, a biopsy procedure certainly is preferred. showed that in patients who were receiving cal- The clinician must consider a biopsy if there are cium channel blockers, nonsurgical therapy for signs and symptoms that suggest a serious gingival enlargement consisting of full-mouth underlying etiology such as leukemia or tubercu- gross , and losis. The typical features of drug-influenced gin- short-term (two weeks’) use of 0.12 percent gival overgrowth include an increase in collagen chlorhexidine gluconate mouthrinse resulted fibers, inflammatory infiltration, acanthosis and in only 6 percent of teeth’s requiring surgical elongated rete pegs.14,15 intervention. The prevalence of gingival enlargement in healthy populations has been estimated to be DIFFERENTIAL DIAGNOSIS between 4.0 and 7.5 percent.10,12 Prevalence has Hereditary gingival enlargement. Patients been known to vary from 10 to 50 percent in with hereditary gingival enlargement exhibit populations of patients receiving phenytoin clinical signs identical to those of the patient therapy.7,11,16,17 Although the pharmaceutical described here. This diagnosis can be excluded effect and primary target tissues of antiepileptic, by questioning the patient about whether his or immunosuppressant, antidepressant and cal- her family members have similar gingival cium channel blocker medications are different, enlargement. As an isolated abnormality, gin- they act similarly on gingival connective tissue, gival enlargement is inherited as an autosomal causing fibrous gingival enlargement.18 In cases dominant trait or, rarely, as an autosomal reces- involving gingival enlargement, gingival connec- sive trait.21,22 Gingival enlargement may arise tive tissue does not necessarily exhibit an owing to a spontaneous gene mutation, so a neg-

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ative family history alone cannot dismiss appropriate diagnostic testing such as blood hereditary gingival enlargement from the differ- testing or biopsy must be considered. Patients ential diagnosis completely. Gingival enlarge- with gingival enlargement should undergo ment has been associated rarely with a number appropriate laboratory testing to ensure that of syndromes such as inclusion-cell disease any underlying disorders are diagnosed and (mucolipidosis II), acanthosis nigricans, Borrone treated at the earliest possible time. ■ di Rocco Crovato syndrome, Cantu syndrome 21 When this article was written, Dr. Pette was a second-year resi- and Winchester syndrome. In this patient, dent in the postgraduate program in , Department of there were no systemic signs of a syndromatic Periodontology, College of Dental Medicine, Nova Southeastern Uni- versity, Fort Lauderdale-Davie, Fla. He now is in private practice in presentation. However, as this patient did not Fort Myers, Fla. have any siblings and we do not know whether the gingival enlargement predated her receipt of Dr. Siegel is a professor and the chair, Department of Diagnostic Sciences, College of Dental Medicine, Nova Southeastern University, antiseizure medications, the isolated genetic 3200 S. University Drive, Fort Lauderdale-Davie, Fla. 33328-2018, form of the gingival enlargement cannot be e-mail “[email protected]”. He also is a coeditor of the Diagnostic ruled out definitively. Challenge section. Address reprint requests to Dr. Siegel. Leukemic infiltration. Leukemic infiltra- Dr. Parker is an associate professor and the chair, Department of tion can be varied in appearance, but it almost Periodontology, College of Dental Medicine, Nova Southeastern Uni- always involves gingival enlargement. The versity, Fort Lauderdale-Davie, Fla. tissue often is purple-red, a condition that also Disclosure. None of the authors reported any disclosures. can be seen in other forms of gingival enlarge- ment with secondary inflammation. Leukemic Diagnostic Challenge is published in collaboration with the American Academy of Oral and Maxillofacial Pathology and the infiltration usually features an acute onset of American Academy of Oral Medicine. hemorrhagic gingival oozing.23 Considering that the duration of the patient’s gingival enlarge- 1. Brown RS, Beaver WT, Bottomley WK. On the mechanism of drug- ment was at least eight months, it is likely that induced gingival hyperplasia. J Oral Pathol Med 1991;20(5):201-209. 2. Brown RS, Sein P, Corio R, Bottomley WK. Nitrendipine-induced she would have exhibited other signs and symp- gingival hyperplasia: first case report. Oral Surg Oral Med Oral toms of leukemia such as bleeding tendencies, Pathol 1990;70(5):593-596. 3. Brunet L, Miranda J, Farre M, Berini L, Mendieta C. Gingival lymphadenopathy, recurrent infections, weight enlargement induced by drugs. Drug Saf 1996;15(3):219-231. loss, lethargy or a combination of these. 4. Brunet L, Miranda J, Roset P, Berini L, Farre M, Mendieta C. Tuberculosis. Tuberculosis and other granu- Prevalence and risk of gingival enlargement in patients treated with anticonvulsant drugs. Eur J Clin Invest 2001;31(9):781-788. lomatous diseases—including orofacial granulo- 5. Dongari-Bagtzoglou A; Research, Science and Therapy Com- matosis, Crohn disease and sarcoidosis24—can mittee, American Academy of Periodontology. Drug-associated gin- mimic drug-influenced gingival enlargement gival enlargement. J Periodontol 2004;75(10):1424-1431. 25 6. Kataoka M, Kido J, Shinohara Y, Nagata T. Drug-induced gin- clinically. In the case of the patient we describe, gival overgrowth: a review. Biol Pharm Bull 2005;28(10):1817-1821. the generalized nature of the gingival enlarge- 7. Lundström Å, Eeg-Olofsson O, Hamp SE. Effects of anti-epileptic drug treatment with carbamazepine or phenytoin on the oral state of ment suggests that it was not tuberculosis or children and adolescents. J Clin Periodontol 1982;9(6):482-488. another granulomatous disease. Also, the results 8. Lucas RM, Howell LP, Wall BA. Nifedipine-induced gingival of the histologic examination did not show gran- hyperplasia: a histochemical and ultrastructural study. J Periodontol 1985;56(4):211-215. uloma formation or an inflammatory process but 9. Majola MP, McFadyen ML, Connolly C, Nair YP, Govender M, were consistent with drug-influenced gingival Laher MH. Factors influencing phenytoin-induced gingival enlarge- enlargement. ment. J Clin Periodontol 2000;27(7):506-512. 10. Miranda J, Brunet L, Roset P, Berini L, Farre M, Mendieta C. Prevalence and risk of gingival enlargement in patients treated with CONCLUSION nifedipine. J Periodontol 2001;72(5):605-611. 11. Nishikawa S, Nagata T, Morisaki I, Oka T, Ishida H. Pathogen- Gingival enlargement is not always associated esis of drug-induced gingival overgrowth: a review of studies in the with a patient’s medication regimen. The differ- rat model. J Periodontol 1996;67(5):463-471. ential diagnosis for a patient with gingival 12. Steele RM, Schuna AA, Schreiber RT. Calcium antagonist- induced gingival hyperplasia. Ann Intern Med 1994;120(8):663-664. enlargement should include hereditary influ- 13. Harel-Raviv M, Eckler M, Lalani K, Raviv E, Gornitsky M. ences, leukemic infiltration and granulomatous Nifedipine-induced gingival hyperplasia: a comprehensive review diseases such as tuberculosis. The clinician and analysis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79(6):715-722. should obtain an in-depth medical history to 14. Tan H, Gürbüz T, Dagsuyu IM. Gingival enlargement in chil- investigate a diagnosis of hereditary gingival dren treated with antiepileptics. J Child Neurol 2004;19(12):958-963. 15. Anderson HH, Rapley JW, Williams DR. Gingival overgrowth with enlargement, although there is always the possi- valproic acid: a case report. ASDCJ Dent Child 1997;64(4):294-298. bility that the gingival changes can arise 16. Angelopoulos AP, Goaz PW. Incidence of diphenylhydantoin gin- because of a spontaneous gene mutation. If gival hyperplasia. Oral Surg Oral Med Oral Pathol 1972;34(6):898-906. 17. Girgis SS, Staple PH, Miller WA, Sedransk N, Thompson T. there are signs and symptoms suggesting a sys- Dental root abnormalities and gingival overgrowth in epileptic patients temic disease such as leukemia or tuberculosis, receiving anticonvulsant therapy. J Periodontol 1980;51(8):474-482.

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18. Kato T, Okahashi N, Kawai S, et al. Impaired degradation of 22. Hassell TM, Burtner AP, McNeal D, Smith RG. Oral problems matrix collagen in human gingival fibroblasts by the antiepileptic and genetic aspects of individuals with epilepsy. Periodontology 2000 drug phenytoin. J Periodontol 2005;76(6):941-950. 1994;6:68-78. 19. Deliliers GL, Santoro F, Polli N, Bruno E, Fumagalli L, 23. Overholser CD, Peterson DE, Williams LT, Schimpff SC. Perio- Risciotti E. Light and electron microscopic study of cyclosporin A- dontal infection in patients with acute nonlymphocytic leukemia: induced gingival hyperplasia. J Periodontol 1986;57(12):771-775. prevalence of acute exacerbations. Arch Intern Med 1982;142(3): 20. Dannewitz B, Krieger JK, Simon I, Dreyhaupt J, Staehle HJ, 551-554. Eickholz P. Full-mouth disinfection as a nonsurgical treatment 24. Sciubba JJ, Said-Al-Naief N. Orofacial granulomatosis: presen- approach for drug-induced gingival overgrowth: a series of 11 cases. tation, pathology and management of 13 cases. J Oral Pathol Med Int J Periodontics Restorative Dent 2010;30(1):63-71. 2003;32(10):576-585. 21. Gorlin RJ, Cohen MM, Hennekam RCM. Syndromes of the Head 25. Gill JS, Sandhu S, Gill S. Primary tuberculosis masquerading and Neck. 4th ed. New York City: Oxford University Press; 2001:1093. as gingival enlargement. Br Dent J 2010;208(8):343-345.

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