Localized Juvenile Spongiotic Gingival Hyperplasia: A Report of Four Cases and Literature Review

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1 Localized Juvenile Spongiotic Gingival Hyperplasia: A Report of Four Cases and Literature Review Diego T. Fernandes, John M. Wright, Silvia Maria P. Lopes, Alan R. Santos-Silva, Pablo A. Vargas and Márcio A. Lopes Introduction: The aim of this case report is to present a distinct subtype of gingival inflammatory hyperplasia, providing information to avoid diagnostic mistakes and overtreatment. Also, an unexpected progression of the lesion is shown. Furthermore, a review of the literature to discuss the pathogenesis, diagnosis, treatment, and the need for new therapeutic approaches is presented. Case Series: The authors report four cases of localized juvenile spongiotic gingival hyperplasia involving the anterior maxillary gingiva with distinct clinical features. The patients were followed for a period of 1 to 9 years, and the evolution of the lesions was documented. Surgical excision or therapy by topical steroids was used to treat the lesions. Conclusions: The long-term follow-up provides important information for clinicians not to eliminate older patients for lesion diagnosis. Although surgical excision should not be recommended for all cases, considering the risk of esthetic problems, the treatment modality using topical steroids was not permanently effective in the authors cases. Investigations about new esthetic treatment modalities for lesions are needed. Clin Adv Periodontics 2018;8: Key Words: Gingiva; gingival diseases; gingival hyperplasia; periodontal diseases. Background Localized juvenile spongiotic gingival hyperplasia (LJSGH) is an unusual and distinct subtype of gingival inflammatory hyperplasia that usually affects the anterior facial gingiva in young patients, most commonly in the second decade of life. 1,2 There seems to be a female predilection of about 2:1. 1,3,4 Clinically, it is generally characterized as a solitary, small lesion, with a micropapillary or granular surface and a bright red gingival overgrowth. LJSGH is painless and may bleed easily during oral hygiene procedures. 3 5 The attached Oral Diagnosis Department, Piracicaba Dental School, University of Campinas University of Campinas, Piracicaba, São Paulo, Brazil Department of Diagnostic Sciences, Baylor College of Dentistry, Texas A&M University, Dallas, TX Received March 29, 2017; accepted July 20, 2017 doi: /cap gingiva of the anterior maxilla is the most common location, with variable marginal gingival involvement. 1 However, in some cases, the mandibular facial gingiva is affected. 1 The lesion is generally on the free gingival margin and attached gingiva centered over a tooth root, although the interdental papilla can be occasionally exclusively affected. 6 Histopathologically, LJSGH is characterized by epithelial hyperplasia, spongiosis of the spinous layer, and exuberant neutrophilic exocytosis mimicking inflamed junctional/sulcular epithelium. 1,2,6 The pathogenesis of these lesions has remained unclear. 2,6 Plaque-induced inflammation is apparently not the cause as there is a lack of response to oral hygiene 5 and the lesion does not regress after conventional periodontal treatment. 3 Herein, the authors report four new cases of LJSGH, aiming to avoid diagnostic mistakes and overtreatment. This study was conducted in accordance with the Helsinki Declaration and all the patients and patients parents provided oral informed consent to participate. Clinical Advances in Periodontics, Vol. 8, No. 1, March

2 FIGURE 1a A 9-year-old boy with an erythematous macule on the facial gingiva of his permanent maxillary right lateral incisor. 1b Histopathologic findings displaying inflammatory exocytosis and spongiosis of the spinous layer. (Hematoxylin and eosin stain; original magnification 200.) 1c Clinical aspect of the lesion after the incisional biopsy and use of clobetasol propionate 0.05%. A decreased reddish appearance was noticed. 1d Seven-year follow-up. The clinical features remained similar after stopping the topical treatment. FIGURE 2a A 17-year-old young woman presenting a localized and small erythematous red macule on the interdental papilla between her maxillary right central and lateral incisors. 2b Clinical aspect of the lesion after 4 years. The lesion was larger, involving the entire papilla and the marginal gingiva of the right lateral incisor. 2c Clinical view after 9 years of follow-up with similar features. Clinical Presentation, Management, and Outcomes Case 1 A healthy 9-year-old boy was referred for evaluation of an erythematous macule on the facial gingiva of his permanent maxillary right lateral incisor. The lesion was initially noted during orthodontic treatment and had been present for about 1 month. On clinical examination, there was a prominent reddish lesion on the marginal and attached gingiva with an irregular outline (Fig. 1a). The lesion was painless and bled when the patient brushed his teeth. Clinically, the diagnosis was compatible with LJSGH. However, particularly because of the lesion s size and the concern of the patient s mother, an incisional biopsy was performed, preserving the marginal gingiva to avoid gingival recession. The histologic features were consistent with a diagnosis of LJSGH (Fig. 1b). After 2 weeks, the lesion recurred, and a topical treatment with a gel of clobetasol propionate 0.05%, three times daily, was prescribed, resulting in a decreased reddish appearance (Fig. 1c). However, after 1 month, when clobetasol propionate was suspended, the initial clinical appearance of the lesion returned. The patient was lost to follow-up for 7 years, but when he returned, the lesion presented with a similar appearance (Fig. 1d). Nevertheless, the patient reported that the lesion stopped bleeding on brushing, and he did not report esthetic concerns. Case 2 A 17-year-old young woman with a history of Legg- Calvé-Perthes syndrome was referred for evaluation and treatment of a pyogenic granuloma localized on the marginal gingiva of her mandibular right first molar. Six months later, a localized and small erythematous red macule was noted on the interdental papilla between the maxillary right central and lateral incisor (Fig. 2a). The lesion was asymptomatic and did not appear to be plaqueor trauma-associated. The patient related bleeding on brushing or manipulation. Due to the characteristics of the lesion, it was decided to schedule a regular follow-up. However, the patient did not return for the following 4 years, at which time the lesion had increased and involved the entire papilla and a part of the marginal gingiva of the right lateral incisor (Fig. 2b). An incisional biopsy was performed, and the diagnosis of LJSGH was confirmed. Five years later (9 years after the first presentation), the lesion persisted with similar clinical features (Fig. 2c). Case 3 A 13-year-old girl presented with a focal erythematous lesion on the facial gingiva of her permanent maxillary left first premolar extending mesially to the interdental papilla. An intraoral clinical examination disclosed an asymptomatic pedunculated lesion with an irregular outline and a granular surface involving the marginal and attached gingiva (Figs. 3a and 3b). The lesion had been present for 3 months and did not bleed on brushing. The patient had good oral hygiene, and there was no calculus, enamel irregularities, or restorations. An excisional biopsy was performed, and histopathologic examination confirmed the diagnosis LJSGH (Fig. 3c). At the 1-year follow-up visit, the lesion had not recurred. 18 Clinical Advances in Periodontics, Vol. 8, No. 1, March 2018 Localized Juvenile Spongiotic Gingival Hyperplasia

3 FIGURE 3a and 3b A 13-year-old girl with a focal pedunculated erythematous lesion with a granular surface on the facial gingiva of the maxillary left first premolar extending mesially to the interdental papilla. 3c Clinical appearance 2 weeks after the excisional biopsy. FIGURE 4a A 10-year-old boy with an erythematous bright red macule on the free gingival margin involving the maxillary left central incisor. 4b Clinical aspect after the use of clobetasol propionate 0.05% three times daily, resulting in considerable improvement. 4c Clinical features after 1 year of follow-up. The lesion extended to the left lateral incisor with a similar appearance. Another very small lesion can be also noted on the right lateral incisor. Case 4 A 10-year-old boy was referred for evaluation of a localized reddish discoloration involving the facial gingiva of his maxillary left central incisor. The lesion had been present for 8 months, after the exfoliation of the involved primary tooth. On clinical examination, an erythematous bright red macule on the free gingival margin was noted (Fig. 4a). The lesion did not bleed on brushing, and there was a discreet bleeding on probing. However, the patient had excellent oral hygiene, and there was no calculus, enamel irregularities, or restorations. Due to the risk of gingival recession, a surgical approach was not considered. A clobetasol propionate 0.05% gel, three times daily, was prescribed, resulting in considerable improvement (Fig. 4b). However, when the clobetasol propionate was suspended, the lesion returned with its initial clinical appearance. After 1 year, the patient returned, and the lesion had extended to the left lateral incisor (Fig. 4c). Because the patient was asymptomatic and the lesion did not appear when he smiled, his mother opted for no treatment. Five months later, a new lesion appeared involving the free gingival margin on the maxillary right lateral incisor. Discussion LJSGH was originally described as juvenile spongiotic gingivitis (JSG) by Darling et al., 6 who presented a histopathologically unique condition that affected juvenile patients and was characterized by often multifocal, bright red, often slightly thickened lesions, preferentially on the attached gingiva. 1,6 Later, a study 2 emphasized the gingival overgrowth and proposed LJSGH as the most accurate term based on the analysis of clinical and histologic features of 52 cases. Currently LJSGH is the most widely used terminology to describe this condition. A recent case report 7 showed characteristics of both JSG and LJSGH. The authors speculated that JSG is likely the precursor for LJSGH, and the authors of this study concur. The authors further reported that a transition of JSG or LJSGH to generalized involvement has not been previously described, but they offered no documentation that their case began as an isolated lesion. Furthermore, although multifocal lesions have been documented, there is currently no evidence that localized involvement has any tendency to progress and involve multiple sites. Clinically, the authors reported cases generally corroborate the literature concerning the preferential involvement of the anterior maxillary facial gingiva. 1 6 With regard to the female sex predominance, 1 6 the authors report two cases in males and two in females, but the authors numbers are too small for this to be significant. The authors patients were within the affected age range reported where children and adolescents (average of 12 years old) are most affected, with only rare examples reported in young adults. 1 Darling et al. 6 originally speculated that JSG, and by extension LJSGH, was a self-limiting condition. They argued that only persistent lesions would be surgically excised and sent to a pathology laboratory, and if JSG was not self-limiting, the lesions would be found more frequently in older patients who simply did not have their lesions treated. Although this is conceptually logical, they offered no objective evidence that it was so. LJSGH is so characteristic clinically that a provisional diagnosis can often be made with confidence. LJSGH has been established for 10 years and, to date, no reports of Fernandes, Wright, Lopes, Santos-Silva, Vargas, Lopes Clinical Advances in Periodontics, Vol. 8, No. 1, March

4 spontaneous remission are documented. The authors case 2 showed a 26-year-old woman without remission of the lesion for 9 years. This finding is quite relevant because the presence of classic clinical features in the uncommon age range for LJSGH does not exclude the possible diagnosis of this lesion. The pathogenesis of LJSGH is not fully established. The lesion does not appear to be associated with plaque and calculus levels because the lesion does not regress after conventional periodontal treatment, 3,4 and many patients have acceptable oral hygiene at the time of diagnosis. The strong age predilection suggests a possible role for the sex hormones of puberty in the etiopathogenesis of LJSGH. However, immunohistochemical studies for the presence of estrogen and progesterone receptors have been negative. 4,6 Additionally, the papillary architecture of the lesion raises the possibility of human papillomavirus (HPV) as an etiologic factor. 3,4 However, LJSGH usually lacks the characteristic histopathologic features seen in HPV-related lesions, particularly koilocytosis. 2 Furthermore, the potential role of HPV in the pathogenesis of LJSGH was evaluated by p16ink4a (a tumor suppressor protein involved in regulation of the cell cycle) immunohistochemistry and HPV polymerase chain reaction (PCR). Most cases showed some degree of p16ink4a immunoreactivity, but most cases were negative for HPV PCR. Only one case showed definitive positivity (HPV 31). The authors concluded that the p16ink4a immunoreactivity was attributed to the intense inflammatory reaction and that HPV was not involved in the pathogenesis of LJSGH. 4 The age range of LJSGH also raises the possibility of a developmental etiology. Based on the histologic similarity of the LJSGH s epithelium to the junctional epithelium (JE) of the gingival sulcus, it was previously suggested that exteriorization of the JE could account for the development of this lesion. 1 3 Junctional and marginal gingiva are phenotypically distinct. Mackenzie et al. 8 showed that epithelium with the phenotypic expression of JE could be exteriorized developmentally onto the surface of the marginal gingiva. Previous studies have demonstrated that the immunohistochemical cytokeratin expression of LJSGH is similar to JE. 3,6 Exteriorized JE would be more predisposed to irritation from a variety of sources, resulting in inflammation and, ultimately, hyperplasia. 3 Although exteriorization of JE is an attractive explanation based on the age affected and histologic features, it does not explain the strong predilection for females, the maxilla, and the anterior segments. The authors speculate that the development of primary teeth favors developmental exteriorization over that of the permanent dentition. The ectopic tissue that constitutes the LJSGH may interrupt the layer of normal keratinized tissue, making it more prone to mechanical injury, resulting in cell damage, inflammation, hyperplasia, and then the clinical features of LJSGH. 6 Without the keratinized layer, the tissue will be more subject to environmental insults such as tooth eruption, lip incompetence, and minor local trauma (e.g., the placement of orthodontic appliances) that could contribute to the inflammatory changes observed in LJSGH. 3,5 Corroborating this theory, the authors case 4 showed initial alterations after the primary tooth exfoliated. The authors case 1 was undergoing orthodontic treatment that coincides roughly with 15% of the 52 patients reported by Chang et al. 2 with orthodontic brackets. The incidence of LJSGH is unknown. Prior to its initial description in 2007, 6 LJSGH may have been incorrectly diagnosed as several conditions, like puberty gingivitis, early-onset pyogenic granuloma, inflammatory gingival hyperplasia, hemangioma, squamous cell papilloma, foreign body gingivitis, peripheral ossifying fibroma, peripheral giant cell lesion, linear gingival erythema, plasma cell gingivitis, vesiculobullous disease, or a simple inflamed gingiva. 1 7,9 11 As previously described, 2,7 LJSGH does not regress after traditional periodontal treatment and usually shows a lack of response to any drug treatments such as corticosteroids. The demographics and clinical features are sufficiently characteristic that the diagnosis of LJSGH can usually be suspected clinically. Lack of response to periodontal therapy or topical steroid treatment would provide additional evidence for a diagnosis of LJSGH. After clinical and/or histopathologic diagnosis, there is no specific treatment for LJSGH except surgery. 7 Although it has been suggested that many cases of LJSGH undergo spontaneous resolution, no prospective study has been carried out to confirm this hypothesis. 6,9 Nor have spontaneously resolving cases been reported in the 10-year interval since the lesion s first description. Interestingly, most of the authors cases did not show any sign of remission of the lesion during follow-up. Case 2, with 9 years of follow-up (now aged 26 years), and case 1, with 7 years of follow-up, showed no significant alterations. The reporting of LJSGH in older patients argues against a spontaneous resolution natural history. 2,6,12 Thus, the authors cases provide some limited evidence against the theory of spontaneous regression, and the authors feel that a diagnosis of LJSGH can be made in older patients. Case 4 showed a considerable progression of the lesion after 1 year of follow-up. It is important to note, however, that although the lesion in patient 4 progressed from the central incisor and involved the lateral incisors, it did not show a more generalized progression as suggested by de Freitas Silva et al. 7 The majority of localized cases in the literature have been treated by surgical excision with a significant recurrence rate (6% to 16%). 1,2,5 7,9 There have been no consistent correlations with exclusive factors of each patient to suggest a reason for the recurrence. 1 Also, when considering surgical treatment, the risk of inappropriate esthetic results, such as a gingival recession, may compromise surgical excision. Thus, with the exception of case 3, the authors did not encourage the patients presented here to choose surgical intervention. 20 Clinical Advances in Periodontics, Vol. 8, No. 1, March 2018 Localized Juvenile Spongiotic Gingival Hyperplasia

5 Case 3 presented a focal and pedunculated lesion, which allowed an excisional biopsy without the risks of esthetic problems. Therefore, new therapeutic approaches to treat LJSGH are necessary. 2,6,9 Cryotherapy seems to be a potential option to treat LJSGH. Recently, the technique was positively applied in two cases reported. 9 The authors described the technique s particular advantages over surgery, and it is well accepted by pediatric patients. They cited the ease of application, the relative lack of discomfort, the absence of bleeding, and satisfactory esthetic outcomes as the main advantages of the treatment modality. Despite the complete remission with satisfying esthetic results and reduced risk of recurrence, the followup was relatively short. 9 Furthermore, other new esthetic treatment options, such as superficial laser ablation, could be potentially promising to treat LJSGH. However, further studies of new treatment modalities with a larger number of patients with longer follow-up are warranted to demonstrate their efficacy. Summary Why are these cases new information? These cases have long-term follow-up and provide prospective insight into the natural history of the lesion. What are the keys to successful management of these cases? Correct diagnosis and knowledge of the pathogenesis of the lesion is required for successful management. What are the primary limitations to success in these cases? The risk of esthetic problems limits the success of these cases. Acknowledgments The authors state that there are no funding sources that supported the current work. The authors report no conflicts of interest related to this case series. CORRESPONDENCE Prof. Márcio A. Lopes, Departamento de Diagnóstico Oral - Semiologia, Faculdade de Odontologia de Piracicaba - UNICAMP, Ave. Limeira, 901 CEP Piracicaba, São Paulo, Brazil. malopes@fop.unicamp.br References 1. Solomon LW, Trahan WR, Snow JE. Localized juvenile spongiotic gingival hyperplasia: A report of 3 cases. Pediatr Dent 2013;35: Chang JY, Kessler HP, Wright JM. Localized juvenile spongiotic gingival hyperplasia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106: Allon I, Lammert KM, Iwase R, Spears R, Wright JM, Naidu A. Localized juvenile spongiotic gingival hyperplasia possibly originates from the junctional gingival epithelium An immunohistochemical study. Histopathology 2016;68: Argyris PP, Nelson AC, Papanakou S, Merkourea S, Tosios KI, Koutlas IG. Localized juvenile spongiotic gingival hyperplasia featuring unusual p16ink4a labeling and negative human papillomavirus status by polymerase chain reaction. J Oral Pathol Med 2015;44: Flaitz CM, Longoria JM. Oral and maxillofacial pathology case of the month. Localized juvenile spongiotic gingival hyperplasia. Tex Dent J 2010;127: , Darling MR, Daley TD, Wilson A, Wysocki GP. Juvenile spongiotic gingivitis. J Periodontol 2007;78: de Freitas Silva BS, Silva Sant Ana SS, Watanabe S, Vêncio EF, Roriz VM, Yamamoto-Silva FP. Multifocal red bands of the marginal gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol 2015;119: Mackenzie IC, Rittman G, Gao Z, Leigh I, Lane EB. Patterns of cytokeratin expression in human gingival epithelia. J Periodontal Res 1991;26: Nogueira VK, Fernandes D, Navarro CM, et al. Cryotherapy for localized juvenile spongiotic gingival hyperplasia: Preliminary findings on two cases. Int J Paediatr Dent 2017;27: Damm DD. Gingival red patch. Juvenile spongiotic gingival hyperplasia. Gen Dent 2009;57:448, Noonan V, Lerman MA, Woo S-B, Kabani S, et al. Localized juvenile spongiotic gingival hyperplasia. JMassDentSoc2013;62: Vargo RJ, Bilodeau EA. Localized (juvenile) spongiotic gingival hyperplasia: A series of seventeen cases. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:e169. indicates key references. Fernandes, Wright, Lopes, Santos-Silva, Vargas, Lopes Clinical Advances in Periodontics, Vol. 8, No. 1, March