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A. Gingival overgrowth or enlargement is a common side effect and unwanted outcome of certain systemic medications. Drug‐influenced gingival enlargement refers to an abnormal growth of the gingiva secondary to use of systemic medication and is classified by the 2017 World Workshop as a form of dental plaque‐induced gingival disease modified by medications [1]. Currently three pharmaceutical categories of medication (anticonvulsants, immunosuppressants, and calcium channel blockers) are associated with gingival enlargement. However, a strong association has been noted only with phenytoin (when used in a chronic regimen to control epileptic seizures), cyclosporine (powerful immunoregulator drug primarily used in the prevention of organ transplant rejection), and nifedipine (commonly prescribed as an antihypertensive, antiarrhythmic, and antianginal agent). The prevalence of gingival overgrowth varies widely: the prevalence related to use of phenytoin is approximately 50%, whereas cyclosporine and nifedipine produce significant gingival changes in about 25% of the patients treated.

Among the non‐plaque‐induced gingival lesions, gingival fibromatosis of genetic origin has been also described as associated with gingival overgrowth [3]. Hereditary gingival fibromatosis (HGF) is an uncommon disorder that can occur as an isolated finding or as part of a genetic syndrome. HGF is most frequently reported to be transmitted as an autosomal dominant trait, but autosomal recessive inheritance has also been reported [4]. The clinical presentation of HGF is variable, both in the distribution (number of teeth involved) and in the degree (severity) of expression [4]. Affected individuals have a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of the oral masticatory mucosa [5]. A mutation in the SOS1 (Son of Sevenless‐1) gene was reported to cause HGF type 1 [5]. HGF usually develops before the person reaches 10 years of age, often at or about the time of eruption of the permanent incisors. However, cases have been reported to occur during the eruption of the deciduous dentition and even to appear at birth [4].

Gingival enlargement has been found to be one of the oral manifestations associated with acute leukemias [6], in addition to cervical adenopathy, petechiae, mucosal ulcers, and gingival inflammation. Gingival bleeding is a common and usually the initial oral sign and/or symptom in 17.7% and 4.4% of patients with acute and chronic leukemias, respectively [6]. Gingival inflammation in leukemic patients presents as swollen, glazed, and spongy tissues that are red to deep purple in appearance [7]. Gingival enlargement has been associated with leukemia beginning at the interdental papilla and extending to the marginal and attached gingiva [7].

Questions important in the development of a differential diagnosis include the following.

 When did your gingiva start to swell?

 Did anybody in your family describe a similar pattern of gingival enlargement?

 Are you taking any medication?

 How long have you been taking the specific medication?

 Do your gums bleed easily?

B. As detailed in Mariotti [8], the common clinical characteristics of drug‐related gingival enlargement include variation in interpatient and intrapatient pattern (such as genetic predisposition), predilection for anterior and facial segments, higher prevalence in children (due to phenytoin most often used in young patients and having the highest prevalence of all medication‐induced gingival enlargement), onset within one to three months of drug use, change in gingival contour leading to modification of gingival size, enlargement starting at the interdental papilla, change in gingival color, pronounced inflammatory response of gingiva in association with bacterial plaque and reduction in severity with decrease in dental plaque, bleeding upon provocation, increased gingival exudate, and found in gingiva with or without bone loss but is not associated with attachment loss. Patients with this diagnosis are usually taking one of the following: phenytoin, cyclosporine, or certain channel blocker drugs.

C. The probing depth is the distance from the gingival margin to the base of the gingival sulcus. The normal sulcus, measuring between 1 and 3 mm, is normally measured to the nearest millimeter by means of a graduated periodontal probe with a standardized tip diameter of approximately 0.4–0.5 mm. The measurements recorded clinically with the periodontal probe have generally been considered a reasonably accurate estimate of sulcus or pocket depth. A probing of the sulcus depth (PPD) of ≥4 mm suggests a diseased state and represents a true periodontal pocket. A “true” periodontal pocket is the measurement from the gingival margin to the bottom of the pocket, recording an increased value (PPD ≥4 mm) beyond that found in the normal gingival sulcus. This depth increase is the result of apical migration of the junctional epithelium subsequent to alveolar bone resorption in patients with periodontitis.

Pocket depths of more than 3–4 mm may also be caused by the swelling of the gingiva without concomitant apical migration of dentogingival epithelium from the cementoenamel junction (CEJ), as in the case of gingival enlargement. This increase in pocket depth is called a “pseudo‐pocket” because it is not associated with bone loss or apical migration of the junctional epithelium.

Probing depth is, in fact, a histologic term expressing the distance from the gingival margin to the most coronal level of the junctional epithelium. Clinical probing depth measured from the gingival margin seldom corresponds to sulcus or pocket depth. The discrepancy is least in the absence of inflammation and increases with increasing degrees of inflammation [9]. In the presence of periodontitis the probe tip passes through the inflamed tissues to stop at the level of the most coronal intact dentogingival fibers, approximately 0.3–0.5 mm apical to the apical termination of the junctional epithelium. Decreased probing depth measurements following periodontal therapy may be in part due to decreased penetrability of the gingival tissues by the probe. Therefore, a distinction should be made between the histologic and the clinical PPD to differentiate between the actual depth of anatomic defect and the measurement recorded by the periodontal probe [9].

D. Gingival enlargement is usually associated with certain medications (i.e. phenytoin, nifedipine, cyclosporine), and the clinical presentation is typically characteristic: papillary and free marginal gingiva is enlarged, mostly localized in anterior facial segments, increased probing depth with normal bone levels generally; possibly there are signs of inflammation.

Periodontitis is characterized by plaque‐induced inflammation localized at the marginal gingiva, with bleeding on probing, increased probing depth and loss of periodontal tissues (cementum, periodontal ligament and crestal bone resorption) – therefore displaying “true” periodontal pockets. Depending on the degree of clinical attachment loss, periodontitis can be mild, moderate, or severe.

Diagnosis of each disease type is critical due to the distinct treatment that is needed to restore form and function and/or stabilize the periodontal disease progression, as mainly in the case of periodontitis.

E. The biologic origins for gingival overgrowth are complex. Recent studies indicate that molecular markers and clinical features of gingival overgrowth differ in their response to medication and that multiple genetic loci are linked to the inherited forms of gingival overgrowth [10].

Multiple hypotheses have been suggested and tested to better understand the molecular mechanisms underlying the clinical features of drug‐induced gingival overgrowth. One leading theory is that substances that cause gingival overgrowth may do so by altering the normal balance of cytokines in gingival tissues, because abnormally high levels of specific cytokines were found in enlarged gingival tissues. Among the cytokines and growth factors found to be at elevated levels in human drug‐induced gingival overgrowth are interleukin (IL)‐6, IL‐1β, platelet‐derived growth factor‐B, fibroblast growth factor‐2, transforming growth factor‐β, and connective tissue growth factor [10].

Connective tissue growth factor (CTGF, or CCN2), is a 38‐kDa secreted protein belonging to the CCN family of growth factors. It has been shown to promote the synthesis of various components of the extracellular matrix, and its overexpression is associated with the onset and progression of fibrosis in many organs including human gingiva [11]. Moreover, fibrotic human gingival tissues express CTGF/CCN2 in both epithelium [12] and connective tissues [13], suggesting that interactions between epithelial and connective tissues could contribute to gingival fibrosis.

It has also been suggested that variations in the balance between cell proliferation and apoptosis contribute to the etiology of gingival overgrowth. Increased fibroblast proliferation and a simultaneous decrease in apoptosis were found to contribute to gingival overgrowth [14].

F. Short clinical crowns associated with healthy‐appearing gingiva can be due to gingival tissue located more incisally or occlusally on the anatomic crown. Volchansky and Cleaton‐Jones described this condition as delayed passive eruption [15,16]. They reported an incidence of 12% of patients examined demonstrating delayed passive eruption. Goldman and Cohen [17] also described this condition where the gingival margin fails to recede to the CEJ during tooth eruption as altered (retarded) passive eruption.

G. The treatment of patients with drug‐induced gingival enlargement consists of oral hygiene instructions, supragingival and subgingival scaling and polishing, and referral to the primary care physician for possible substitution of one medication for another (i.e. phenytoin can be replaced with carbamazepine or valproic acid, cyclosporine with tacrolimus, and nifedipine with one of many dihydropteridines) not as strongly associated with gingival overgrowth. If the previously described treatment does not result in significant resolution of gingival enlargement, surgical excision of the excessive gingiva is performed using a classic external bevel gingivectomy or an internal bevel gingivectomy approach [18] (see Chapter 3, Case 1). The internal bevel approach provides primary closure and reduction of postoperative bleeding, discomfort, and infection. More recently, a carbon dioxide laser has been used for surgical excision and provides rapid hemostasis and compatibility with a host with underlying medical conditions. It also has been reported to reduce surgical time [18].

Having the patient in a rigorous home plaque control regimen as well as regular three‐month periodontal maintenance are strongly recommended [19] and may considerably reduce the risk of recurrence. In a study of 38 individuals, 18 months after surgical therapy, the recurrence rate of gingival overgrowth in patients taking cyclosporine or nifedipine was 34%. Age, gingival inflammation, and attendance at periodontal maintenance visits were all significantly related to recurrence, and they suggest that regular remotivation and professional care at frequent recall appointments are of great importance in patients with a history of drug‐induced gingival overgrowth [20]. To prevent postsurgical recurrence, a chlorhexidine rinse twice daily is recommended [21].

Several medications have been shown to ameliorate gingival enlargement, such as systemic or topical folic acid [22] or a short course of metronidazole or azithromycin. The latter drugs work particularly well for significant resolution of cyclosporine‐induced gingival overgrowth [23]. The mechanism of action for these antibiotics is not clear, but it is suggested they may contribute to inhibition of collagen fiber proliferation in addition to their antimicrobial action.