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Gingival tissue may host a range of non-infectious mucous membrane diseases. Since the clinical manifestations of many of such diseases show significant similarities gingivitis and periodontal diseases, early diagnosis and prompt management of such diseases can be challenging to the clinicians. The objective of this chapter is to examine various and common non-infectious mucous membrane diseases of the gingiva ranging from idiopathic conditions to allergic and immunologic entities. This chapter will emphasize on the etiologic factors, key clinical features, diagnostic and histopathologic features, and most current treatment approaches for proper management of such conditions.
Oral and Maxillofacial Pathology, University of Nevada, Las Vegas School of Dental Medicine, Las Vegas, Nevada, United States of America
*Address all correspondence to: moni.ahmadian@unlv.edu
1. Introduction
Gingival tissue hosts an array of non-infectious mucous membrane diseases which may clinically resemble gingivitis and periodontal diseases. Appropriate diagnosis of such diseases is crucial for successful clinical management of the condition. This chapter examines several non-infectious entities affecting the gingival tissue with emphasis on etiology, clinical features, histopathology, and management recommendations.
Spongiotic gingival hyperplasia is an alteration of gingiva originally described in 2007 as juvenile spongiotic gingivitis [1]. Primarily affecting children and young adults and classically presenting as an isolated gingival lesion, the term localized juvenile spongiotic gingival hyperplasia (LJSGH) was subsequently recommended for this entity [2]. With later reports of occasional cases occurring in older adults and multifocal examples, modification of this terminology to spongiotic gingival hyperplasia was suggested to more accurately reflect its spectrum [3]. Although the exact pathogenesis of this condition remains uncertain, it is widely speculated that spongiotic gingival hyperplasia represents a patch of junctional epithelium that has been exteriorized [4]. Furthermore, a possible odontogenic origin has been speculated based on histopathologic and immunohistochemical studies [5]. Lack of association with plaque or calculus accumulation and failure of response to routine plaque-control measures suggests that this condition is unrelated to bacterial plaque deposition [1].
2.1 Clinical features
Although spongiotic gingival hyperplasia may be occasionally observed in adulthood, vast majority of the cases have been documented during the first two decades of life with a mean age less than 15 years [2]. Most recent literature suggests a balanced gender distribution in contrast to early reports of a female predilection [5]. The most typical presentation is a small isolated, painless, velvety bright red gingival patch that tends to bleed upon manipulation and may have an overall bosselated or papillary surface texture (Figure 1). The lesion is usually sessile-based, although occasional pedunculated examples have been reported [2]. Often present for years prior to excision, the condition does not exhibit an association or correlation with plaque or calculus deposition [1].
Figure 1.
Spongiotic gingival hyperplasia. Bright red velvety patchy of maxillary facial gingiva in an 11 year-old male.
Spongiotic gingival hyperplasia shows a strong predilection for the facial anterior maxillary gingiva [4]. However, occasional involvement of the posterior gingival tissue, interproximal papillae, and lingual gingiva may be seen [2]. Furthermore, multifocal examples of this condition and rare diffuse cases have been reported in the literature (Figure 2).
Figure 2.
Spongiotic gingival hyperplasia. Diffuse involvement of maxillary and mandibular facial gingiva in a 17 year-old male.
2.2 Histopathologic features
Microscopically, spongiotic gingival hyperplasia is characterized by variably hyperplastic, nonkeratinized stratified squamous epithelium that has a bosselated to papillary surface architecture [5]. The surface mucosa characteristically demonstrates prominent intercellular edema (spongiosis) and marked neutrophilic exocytosis (Figure 3a). This histopathologic appearance is reminiscent of gingival junctional epithelium. The lesional epithelium demonstrates a diffuse immunoreactivity with cytokeratin (CK) 8/18 and 19 [1, 4, 5]. In contrast, normal facial gingival tissue lacks expression of CK8/18 and only demonstrates CK19 reactivity confined to the basal cell layer [4]. If the excisional biopsy is representative of adjacent normal gingival epithelium, an abrupt transition in expression of CK19 is typically appreciated (Figure 3b).
Figure 3.
Spongiotic gingival hyperplasia. (a) Medium-power view showing transition of normal facial gingival mucosa to lesional tissue characterized by spongiosis and neutrophilic exocytosis. (b) Immunohistochemical staining shows diffuse expression of CK19 by junctional epithelial cells compared with the expression of CK19 confined to the basal epithelial cell layer in normal facial gingiva.
In spite of its overall papillary architecture, DNA polymerase chain reaction studies have revealed no association with the human papillomavirus (HPV) [4]. The underlying connective tissue stroma usually exhibits dilated and congested blood vessels [2]. A dense mixed acute and chronic inflammatory infiltrate is seen within the stroma [1, 2].
2.3 Treatment and prognosis
Since spongiotic gingival hyperplasia is rarely observed in adult population, it has been suggested that the condition may eventually undergo spontaneous resolution [1]. Localized cases spongiotic gingival hyperplasia are often treated conservatively with scalpel excision or laser ablation although achieving esthetic results in facial anterior maxillary gingiva may prove challenging [6]. There is a slight chance for recurrence of the lesion upon treatment [2]. Additionally, conservative treatment of multifocal and diffuse examples of spongiotic gingival hyperplasia may be difficult. Some reports have documented successful treatment of spongiotic gingival hyperplasia with cryotherapy or mild cauterization combined with topical clobetasol ointment with inconsistent success rates [7].
Plasma cell gingivitis is a rare and distinctive pattern of gingival inflammation characterized by a polyclonal proliferation of plasma cells within the submucosa [8]. Originally described in early 1970s, the exact etiopathogenesis of this condition remains elusive, although most cases have been linked to hypersensitivity reactions triggered by certain antigens including components of toothpaste, oral rinses, chewing gums, mint, and other spices [9]. Since the list of implicated allergens appears to be variable, diagnosis of plasma cell gingivitis can be challenging requiring a thorough investigation and evaluation of individual habits to establish possible cause and effect relationship [10]. Furthermore, often after thorough evaluation, in majority of the cases the cause remains unidentified and most of these cases are considered to be idiopathic [8, 11].
3.1 Clinical features
Plasma cell gingivitis may arise in any age group and involve both genders, however, some studies report a higher prevalence among females [8]. Clinically, the patients may be asymptomatic or may experience a rapid onset of oral soreness, pain, or burning sensation [12]. Most cases present as either localized or diffuse edematous erythema of the free and attached gingiva along with loss of gingival stippling (Figure 4). The affected gingival tissue may bleed easily [13]. Although ulcerative and erosive changes may be occasionally seen, unlike autoimmune vesiculobullous diseases, true desquamation and mucosal sloughing are typically absent in majority of cases. [8]. Nevertheless, rare reports of a bullous phenotype of plasma cell gingivitis warrants inclusion of the vesiculobullous disease processes in the differential diagnosis [12].
Figure 4.
Plasma cell gingivitis. Diffuse erythema and swelling of facial mandibular gingiva in a 39 year-old female associated with use of an herbal toothpaste.
Furthermore, in many instances, plasma cell gingivitis may present with involvement of extragingival sites such as the tongue and lips [10]. When involving the tongue, it typically presents with diffuse erythema and enlargement along with loss of the dorsal tongue coating. Often the enlarged tongue exhibits crenation along its lateral borders. Involvement of the lips typically present with general dryness, fissures, atrophic changes, and angular cheilitis. Many of these extragingival examples have been attributed to use of chewing gums.
3.2 Histopathologic features
Microscopically, the surface mucosa exhibits psorasiform hyperplasia characterized by elongated rete ridges, spongiosis, and neutrophilic exocytosis [8]. The underlying connective tissue stroma contains numerous dilated vascular channels and a dense chronic inflammatory infiltrate that is predominantly composed of plasma cells [14]. Investigation into the clonality of the plasma cells confirms a polyclonal proliferation which assists in ruling out neoplastic processes such as plasmacytoma and multiple myeloma.
It must be noted that plasma cell gingivitis can histologically mimic a wide range of entities such as conventional plaque-induced chronic gingivitis and periodontal disease, IgG4-related diseases, Castleman disease, among others [13, 15]. Therefore, the diagnosis of plasma cell gingivitis is established through correlation of the clinical features with histopathologic findings.
3.3 Treatment and prognosis
There is currently no international consensus in treatment of plasma cell gingivitis. Management of this condition can be challenging and often result in unsatisfactory outcome [13]. Plasma cell gingivitis is often treated symptomatically with systemic and topical immunosuppressive agents including dexamethasone rinse, fluocinonide gel, topical triamcinolone, and topical fusidic acid with variable response rates [12, 13, 14].
Additionally, the patients would benefit from maintaining a complete dietary history aimed to eliminate potential allergens [15]. If the potential allergen is not apparent extensive skin patch testing and elimination diet may be considered.
The term granulomatous gingivitis was formerly used to describe a pattern refractory gingival granulomatous inflammation that does not respond to improved oral hygiene and periodontal treatment [16]. Granulomatous gingivitis can result from a number of local and systemic causes listed in Table 1, however, when such alterations are elicited by impaction of foreign material in the gingival tissue the term foreign body gingivitis is more aptly used for this entity [17]. Energy-dispersive X-ray microanalysis (EDX) has demonstrated that foreign material eliciting such reactions are mostly of dental origin that can be introduced through professional dental hygiene and restorative procedures as well as routine household use of cosmetic and oral hygiene products [18]. A major component of toothpaste, pumice, and polishing paste, silicon is one of the most frequently identified foreign elements followed by aluminum and other dental restorative material [16, 18].
Local and systemic causes of orofacial granulomatosis.
4.1 Clinical features
Although foreign body gingivitis may arise across a broad age range, most cases occur during adulthood with a mean age of approximately 50 years and a female predilection [19]. The lesion shows a propensity for the posterior regions of maxillary and mandibular gingiva and anterior maxillary region [16, 19, 20]. Clinical presentation can be variable with most cases presenting as focal erythema of gingiva that may exhibit radiating peripheral white striations along with possible erosive changes closely mimicking those of lichenoid lesions (Figure 5). However, unlike lichen planus, the lesion fails to migrate or involve extragingival locations [16].
Figure 5.
Foreign body gingivitis. Plaque with lichenoid striations involving the facial marginal gingiva appearing after scaling and root planning in a 63 year-old female patient.
Some cases may present as gingival swelling or enlargement or simple discoloration of the gingival tissue [20]. Multifocal examples are fairly common (Figure 6). Furthermore, recently examples presenting as discrete leukoplakic lesions have been reported which may demonstrate verruciform surface texture [16].
Figure 6.
Foreign body gingivitis. Diffuse nodular swelling of facial anterior maxillary gingiva in a 25 year-old female.
4.2 Histopathologic features
Histopathologic features of foreign body gingivitis are variable. However, vast majority of the cases demonstrate chronic inflammatory reaction predominantly composed of lymphocytes, plasma cells admixed with occasional histiocytes and eosinophils [16]. Although the inflammatory infiltrate is typically noted in mid- or deep lamina propria, in some examples it may form a patchy band subjacent to the surface mucosa in a manner similar to lichen planus [20]. Furthermore, some examples may demonstrate a mixed acute and chronic inflammatory infiltrate while in some other cases true chronic granulomatous inflammation may be seen (granulomatous gingivitis) (Figure 7) [17, 18, 19]. When prominent granulomatous inflammation is present, investigation into other possible local or systemic causes of granulomas is warranted including special stain studies for microorganisms.
Figure 7.
Foreign body gingivitis. A granuloma characterized by aggregate of pale-staining epithelioid histiocytes and a multinucleated giant cell surrounded by lymphocytes.
The foreign particles may appear as minute opaque gray-black granules or translucent crystalline deposits [16]. When polarized, the crystalline structures may demonstrate birefringence. The granular particles show a tendency to aggregate and form small clusters and typically do not demonstrate birefringence when viewed with polarized light [20].
4.3 Treatment and prognosis
Surgical excision of localized lesion is the treatment of choice for symptomatic lesions or those cases presenting as leukoplakic plaques [16, 17, 20]. Although topical corticosteroids may improve sensitivity and symptoms, the effects are usually temporary and symptoms typically return after cessation of the medication. Additionally, to reduce risk for iatrogenic foreign body gingivitis, dental clinicians should use care during restorative and periodontal procedures [20].
Desquamative gingivitis is a clinical descriptive term that refers to patterns of painful erosion, ulceration, and peeling of the attached and free gingival tissue resulting from the rupture mucosal vesicles [21]. Although, it is unrelated to local dental plaque accumulation, desquamative gingivitis may be aggravated by plaque accumulation [21]. Rather than representing a distinctive diagnosis, desquamative gingivitis is a clinical manifestation one of several different vesiculobullous conditions listed in Table 2 [22, 23]. Classified under the category of autoimmune disorders, vesiculobullous conditions are characterized by formation of autoantibodies that target various components of the epithelial attachment apparatus depicted in Figure 8. In this chapter, three distinct vesiculobullous conditions are described including oral lichen planus, mucous membrane pemphigoid, and pemphigus vulgaris in which desquamative gingivitis may be a prominent clinical feature.
Vesiculoerosive or vesiculobullous diseases associated with desquamative gingivitis
Desquamative gingivitis as manifestation of vesiculobullous conditions.
Figure 8.
Epithelial attachment apparatus. Schematic diagram showing the molecular components of the stratified squamous epithelium attachment apparatus. Various components of this complex apparatus are targeted by autoimmune vesiculobullous diseases.
Lichen planus is chronic mucocutaneous disease [22]. While its exact pathogenesis still remains elusive, current evidence suggests that lichen planus is an immune-mediated condition characterized by T lymphocyte-mediated destruction of basal epithelial cell layer [24, 25]. Several potentially contributing risk factors have been implicated including genetic susceptibility factors, hepatitis C, hypothyroidism, autoimmune thyroid disease, and thyroid medications [24, 25, 26, 27]. Furthermore, controversial data suggests a possible association with anxiety or psychologic stress and many patients with a diagnosis of lichen planus often report aggravation of their oral symptoms in response to stress [28]. However, since most current studies rely on psychometric questionnaires and are subjective and lack appropriate controls, whether or not anxiety directly impact the pathogenesis of lichen planus remains a matter of debate [22].
6.1 Clinical features
Lichen planus is a relatively common disorder with worldwide prevalence estimated at 0.22–5% [29]. Most patients with lichen planus are middle-aged adults and although the condition can affect both genders, most studies indicate a female predominance [25, 30].
As a mucocutaneous condition, lichen planus may involve both skin, nails, and mucosa including oral, conjunctival, and vulvar mucosa [31, 32]. Up to 60% of patients with cutaneous lichen planus demonstrate oral lesions, however, only a minority of patients with oral lichen planus develop cutaneous expression of the disease [22, 30]. Skin lesions usually arise on the flexor surfaces of the extremities and classically present as pruritic, purple polygonal papules which may demonstrate characteristic lacelike white striations known as Wickham striae. While the oral lesions may arise in any mucosal site, the most common anatomic locations are bilateral posterior buccal mucosa, dorsal and lateral borders of the tongue, and gingiva [25]. Two distinctive patterns of oral lichen planus are recognized: reticular and erosive.
In reticular lichen planus, white papules enlarge and coalesce to form a plaque-like lesion that characteristically demonstrates fine, reticular Wickham striations (Figure 9). These striations are often arranged on a background of mild erythema [29]. Furthermore, in dark-complexioned individuals, background brown pigmentation may be seen known as post-inflammatory melanosis [24]. Reticular plaques most characteristically appear on posterior buccal mucosa in a bilateral fashion, however, lesions are not static and tend to migrate and involve other mucosal sites including dorsal surface and lateral borders of the tongue, labial mucosa, and gingiva [24]. As the patients are rarely symptomatic, reticular lichen planus is typically an incidental clinical finding [25]. When exhibiting the characteristic reticular striations and especially if the lesion involve the classic anatomic locations, a strong presumptive clinical diagnosis is possible.
Figure 9.
Reticular lichen planus. White plaque with fine lacelike striations arranged on a mildly erythematous background involving the left posterior mandibular vestibule in a 35 year-old male.
Erosive lichen planus is characterized by erosions that may exhibit active ulceration (Figure 10). Characteristically, at the periphery and the border of the erosive lesions, lacelike white striations may be present (Figure 11). Patients commonly complains of varying degree of pain, oral soreness, or burning sensation usually aggravated by spicy and hot foods [24, 25]. Lesions tend to follow periods of wax and wane and typically migrate and involve multiple mucosal sites including the gingiva tissue (desquamative gingivitis) [29]. However, generally unlike mucous membrane pemphigoid and pemphigus vulgaris, desquamative gingivitis in erosive lichen planus is not associated with significant sloughing or peeling of the mucosal epithelium (Figures 12 and 13). Rarely, if erosive component is extensive, the epithelium may separate from the underlying connective tissue resulting in a pattern known as bullous lichen planus [24, 29].
Figure 10.
Erosive lichen planus. Erosive lesion of right buccal mucosa surrounded by reticular striations in a 57 year-old female.
Figure 11.
Erosive lichen planus. Diffuse erosive lesion with peripheral white striations involving the buccal mucosa in 38 year-old female.
Figure 12.
Erosive lichen planus. Erosive lesions of the buccal marginal mandibular gingiva demonstrating peripheral striations in a 49 year-old female.
Figure 13.
Desquamative gingivitis involving the anterior facial maxillary gingiva in a 66 year-old female with erosive lichen planus.
Many conditions can clinically present with lichenoid appearance including chronic ulcerative stomatitis, cinnamon stomatitis, lichenoid drug reactions, lichenoid mucositis induced by dental restorative material, oral manifestations of systemic lupus erythematous, and oral manifestations of graft-versus-host disease [24, 25]. In cases, where the erosive lesion remains localized and fails to migrate, the possibility of contact allergic reactions should be suspected. Furthermore, given the significant clinical overlaps between erosive lichen planus and other vesiculoerosive conditions, tissue biopsies are warranted for both conventional light microscopic diagnosis and direct immunofluorescence studies to rule out mucous membrane pemphigoid and pemphigus vulgaris [24, 25, 29]. The clinician should obtain specimens from the perilesional intact and otherwise normal appearing mucosa as opposed to the ulcerative center.
6.2 Histopathologic features
Histologic features of lichen planus can vary depending on whether biopsy specimen is taken from reticular or erosive lichen planus. The epithelium may demonstrate hyperorthokeratosis, hyperparakeratosis, hyperplastic and atrophic changes [24]. However, classically, lichen planus is characterized by hydropic degeneration of the epithelial basal cell layer resulting in characteristic irregular “saw-toothed” or pointed rete ridges [33]. A dense band-like infiltrate of lymphocytes is present immediately subjacent to the surface epithelium at its interface with the underlying connective tissue (Figure 14). Additionally, at the interface of the epithelium and underlying connective tissue, apoptotic keratinocytes (colloid bodies or Civatte bodies) may be seen [24, 25, 33].
Figure 14.
Lichen planus. (a) Low-power view demonstrating an orthokeratotic stratified squamous epithelium with relative flat interface with the underlying connective tissue. A band-like dense lymphocytic infiltrate is seen immediately subjacent to the surface epithelium. (b) High-power view showing hydropic degeneration of the basal epithelial cells and occasional apoptotic basal keratinocytes (Civatte bodies, arrow).
Although these histopathologic features are often distinctive, direct immunofluorescence studies may assist in distinction between lichen planus and other vesiculobullous conditions when significant histologic overlaps are present [25]. The immunologic findings in lichen planus are not specific with most cases demonstrating a shaggy band of fibrinogen at the basement membrane [24].
6.3 Treatment and prognosis
As reticular lichen planus is typically asymptomatic, no treatment is indicated beyond periodic re-evaluation. Attention to maintenance of proper oral hygiene and periodic follow-up should be emphasized as occasionally reticular lichen planus may be superimposed with candidiasis necessitating topical antifungal therapy [32].
Wide variety of treatment approaches have been attempted for the management of erosive lichen planus including topical and systemic corticosteroid, direct intralesional steroid injection, systemic retinoids, doxycycline, and others. However, the validity of such approaches cannot be determined due to paucity of proper controlled double-blind studies [24]. In general, the first line of therapy is topical corticosteroids such as fluocinonide, clobetasol, and betamethasone gels applied in thin films to the affected areas several times a day [25, 32]. Recalcitrant cases may be treated with more potent corticosteroid regimens, direct intralesional steroid injection, tacrolimus ointment, or systemic medications. It must be emphasized that such therapies at best are palliative in nature and directed to reduce associated symptoms and improve quality of life [24]. Furthermore, the patient must be advised that due to the chronic nature of the disease, response to therapy can be delayed and often requires long-term maintenance, continuous dose adjustments with possible periods of flare-up and exacerbation of the condition. Patients should be continuously re-evaluated every 3–6 months.
Controversial studies have previously suggested that oral lichen planus has a potential to undergo malignant transformation [34]. A recent meta-analysis and systematic review of 16 studies cited an overall average malignant transformation rate of 1.09%. Many studies have investigated molecular mechanisms underlying this malignant transformation. As a result of such studies the World Health Organization designated lichen planus as a premalignant condition in 2005. However, in overall these results are not consistent and conclusive and the question of malignant potential of lichen planus still remains unresolved [24].
Mucous membrane pemphigoid is a chronic autoimmune blistering disease characterized by formation of autoantibodies that target several components of the basement membrane such as BP180, BP230, and laminin 332 (Figure 15) [22]. Mucous membrane pemphigoid was previously known by variety of other names such as cicatricial pemphigoid or benign mucous membrane pemphigoid. However, since 1999 this disease is widely classified as mucous membrane pemphigoid. While it is not as prevalent as lichen planus in general population, in many respects mucous membrane pemphigoid is a serious condition capable of inducing significant morbidity for the affected individuals.
Figure 15.
Mucous membrane pemphigoid. Schematic diagram demonstrating the targeted components of the epithelial attachment apparatus by autoantibodies in mucous membrane pemphigoid leading to subepithelial splitting at the level of the basement membrane.
7.1 Clinical features
Mucous membrane pemphigoid is more prevalent among adults in the fifth to sixth decades of life and shows a female predilection [35]. Typically, involving the mucosal tissues, mucous membrane pemphigoid may involve oral, conjunctival, nasal, esophageal, laryngeal, and vagina mucosa [22]. However, it rarely involves the skin which distinguishes this disease from pemphigus vulgaris [36, 37]. Cutaneous manifestations often appear in head and neck and upper body. Furthermore, in many instances the manifestations of mucous membrane pemphigoid remain confined to the oral mucosa [22, 36, 38].
Clinically, mucous membrane pemphigoid presents with variably-sized blisters that range from small vesicles to larger blood-filled bullae (Figure 16) [38]. Unlike those observed in pemphigus vulgaris, these blisters often last longer. However, eventually these blisters rupture and evolve in painful erosions and irregular ulcerations (Figures 17 and 18). These ulcerations and erosions are slow-healing and persist for weeks to months if left untreated. Although the manifestations of mucous membrane pemphigoid may involve any oral mucosal sites, in some instances the disease may remain fairly limited to the gingival tissue presenting as desquamative gingivitis (Figures 19 and 20) [35, 36, 38]. The erythema and desquamation of the gingival tissue do not correspond to plaque and tartar accumulation and will not resolve with routine plaque control measures [38]. The affected gingival tissue is fragile and friable and often readily peels off when applying lateral pressure.
Figure 16.
Mucous membrane pemphigoid. A blood-filled bulla in area of left pterygomandibular raphe in an 84 year-old male.
Figure 17.
Mucous membrane pemphigoid. Diffuse irregular shallow ulceration involving the right buccal mucosa in the same patient as Figure 16.
Figure 18.
Mucous membrane pemphigoid. Erosive and ulcerative lesion involving anterior buccal mucosa and desquamative gingivitis involving the anterior maxillary facial gingiva in an 82 year-old male.
Figure 19.
Mucous membrane pemphigoid. Localized desquamative gingivitis and associated mucosal sloughing in a 49 year-old female.
Figure 20.
Mucous membrane pemphigoid. Desquamative gingivitis localized to the right maxillary facial gingiva with no other mucosal lesions in a 40 year-old female.
The most serious complication of mucous membrane pemphigoid is involvement of the ocular and conjunctival mucosa [22]. Ocular involvement occurs in approximately 25% of patients and because its early manifestations can only be detected through slit-lamp microscopy, early referral to an ophthalmologist is critical in management of patients with mucous membrane pemphigoid [39]. Conjunctival manifestations begin with subconjunctival fibrosis and evolve to erosions that heal with formation of scar (cicatrix) [22, 36, 39]. With progression, it can lead to eyelid adhesions (symblepharons) and blindness [40, 41].
Since the clinical features of mucous membrane pemphigoid overlaps significantly with those of other similar autoimmune vesiculobullous disorders, the definitive diagnosis is established by combination of light microscopy and direct immunofluorescence studies [41]. The tissue biopsy must be obtained from the intact and normal-appearing mucosa adjacent to the lesional tissue as epithelium in the lesional tissue is often too loosely attach and readily strips off during surgical procedure leading to inadequate sampling [39].
7.2 Histopathologic features
Microscopically, mucous membrane pemphigoid is characterized by a complete separation and splitting of the surface epithelium from the underlying connective tissue (Figure 21a and b) [42]. This cleavage occurs at the level of the basement membrane below the basal cell layer and creates a subepithelial blister space with the entire thickness of the epithelium serving as the roof of the blister [39]. This microscopic finding explains the clinical persistence of the bulla in mucous membrane pemphigoid compared to those seen in pemphigus vulgaris. Unlike lichen planus, the basal cell layer appears intact. An inflammatory infiltrate consisting of lymphocytes, plasma cells, and often eosinophils is present within the blister space and superficial connective tissue [42]. Direct immunofluorescence studies performed on biopsy specimen obtained from perilesional mucosa reveals a continuous linear band of complement factor C3 and immunoglobulin IgG and sometimes IgA and IgM along the basement membrane [41]. While direct immunofluorescence findings are considered the gold standard for diagnosis of mucous membrane pemphigoid, indirect immunofluorescence studies detect circulating autoantibodies inconsistently and only in a minority of the cases [39, 43].
Figure 21.
Mucous membrane pemphigoid. (a) Low-power view demonstrating subepithelial cleavage of surface mucosa from the underlying connective tissue and a dense infiltrate of lymphocytes and plasma cells in the superficial connective tissue. (b) High-power view depicting the blister space and intact basal epithelial cells separated from the underlying connective tissue.
7.3 Treatment and prognosis
Although generally not an acute life-threatening condition, without proper treatment mucous membrane pemphigoid may demonstrate a progressive clinical course. Treatment with topical corticosteroids is typically sufficient for management of oral disease with systemic therapy usually indicated for ocular mucous membrane pemphigoid or refractory cases [38, 39, 40]. Topical regimens and dosing are tailored individually on the basis of severity of oral symptoms and may include mildly-potent corticosteroids such as fluocinonide gel to more-potent agents such as clobetasol [36, 40]. Similar to lichen planus, as a chronic condition, the treatment is often palliative and prolonged. This mandates regular adjustment of dosing and tapered-discontinuation of the agents when oral symptoms are improved [40]. However, discontinuation of immunosuppressive agents almost certainly ensures flare-up of the condition [39].
Although desquamative gingivitis in the setting of mucous membrane pemphigoid does not correlate with plaque and tartar accumulation, the inflammatory process associated with periodontal disease can trigger or prolong an autoimmune response [44]. Furthermore, gingival lesions often respond poorly to systemic immunosuppressive medications [40]. Maintaining optimal oral hygiene is therefore of paramount importance in management of gingival mucous membrane pemphigoid. For cases confined to the gingival tissue, a fabricated flexible night guard may be used as a direct medium of delivery of the topical agents to the affected tissue [39].
Patients with a confirmed diagnosis of mucous membrane pemphigoid should be promptly referred for ophthalmologic examination and continued regular re-evaluations even in the absence of clinical evidence of ocular manifestations. The dosing should be adjusted and tapered down gradually when symptoms improved. However, flare-up of the condition will certainly ensues upon discontinuation of regimens [39].
Pemphigus is a family of four serious autoimmune blistering conditions that include that pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, and pemphigus erythematosus [45].
Of these members, only pemphigus vulgaris and pemphigus vegetans have oral manifestations [46]. Furthermore, pemphigus vegetans is rare and probably represents a variation of pemphigus vulgaris [45]. Therefore, the following discussion is limited to pemphigus vulgaris.
Pemphigus vulgaris is characterized by formation of autoantibodies that target the components of epithelial intercellular bridges known as desmosomes (Figure 22). Desmoglein 3 and desmoglein 1 are molecular components of desmosomal cadherin proteins are the principal targets in pemphigus vulgaris [47, 48]. Formation of these autoantibodies disrupt the molecular adhesion between the epithelial cells resulting separation and splitting of epithelial cells (acantholysis).
Figure 22.
Pemphigus vulgaris. Schematic diagram demonstrating the targeted components of the epithelial attachment apparatus by autoantibodies in pemphigus vulgaris resulting in acantholysis and suprabasilar splitting of the keratinocytes.
8.1 Clinical features
Pemphigus vulgaris is a relatively rare condition with incidence of 1 in 100,000 people [49]. The disease is more prevalent among Jewish, South Asian, Middle-eastern, and Mediterranean populations highlighting its strong association with certain HLA-serotypes [49, 50, 51]. Usually presenting in adults, pemphigus vulgaris shows a slight female predilection [45]. Pemphigus vulgaris is a diffuse mucocutaneous condition with a progressive clinical course [49, 52]. Skin lesions may be localized or generalized showing a predisposition for trunk, groins, axilla, scalp, face and pressure points [49].
Skin lesions usually present as flaccid blisters that may coalesce [49]. These blisters typically rupture quickly leading to formation of painful and irregular shallow erosions and ulcerations (Figure 23). A characteristic finding in pemphigus vulgaris is the ability of the clinician to induce a bulla on otherwise normal skin by applying light lateral pressure [53]. Known as a positive Nikolsky sign, this finding is not specific for pemphigus vulgaris.
Figure 23.
Pemphigus vulgaris. Flaccid bulla and a ruptured blister involving the skin of the upper extremities in a 54 year-old male.
Mucosal involvement especially the oral mucosa usually precedes the cutaneous manifestations [49]. Like the skin lesions, oral manifestations begin with vesicles and bullae that quickly rupture and evolve into painful erosions and diffuse superficial ulcerations (Figures 24 and 25) [45, 49, 52]. These lesions typically are diffuse and involve virtually any and multiple oral mucosal sites simultaneously [45]. While desquamative gingivitis is a common clinical feature, unlike mucous membrane pemphigoid, pemphigus vulgaris seldom remains localized to the gingival tissue (Figure 26) [22, 54]. Another common oral feature of pemphigus vulgaris is appearance of hemorrhagic crusting lesions of the lip (Figure 27).
Figure 24.
Pemphigus vulgaris. Diffuse irregular ulcerations involving the lower labial mucosa in a 70 year-old female.
Figure 25.
Pemphigus vulgaris. Same patient in Figure 24 with diffuse erosive and ulcerative lesion of the right buccal mucosa.
Figure 26.
Pemphigus vulgaris. Erosive lesions of facial mandibular gingiva (desquamative gingivitis) in the same patient as Figures 24 and 25 at 3-month follow-up.
Figure 27.
Pemphigus vulgaris. Hemorrhagic crusting lesion of the lower lip vermillion in a 55 year-old male.
In addition to the oral mucosa, other mucosal sites such as nasal mucosa, oropharynx, esophagus, conjunctiva, larynx, urethra, vulva, and cervix may be involved [52]. However, unlike mucous membrane pemphigoid, ocular involvement is not as frequent and typically do not lead to scar formation [45]. Given the striking clinical similarities with other autoimmune blistering conditions, definitive diagnosis warrants correlation of the clinical features with histopathologic features and the findings with direct and indirect immunofluorescence studies [49, 53]. Solid tissue biopsies for routine light microscopic and direct immunofluorescence studies should be obtained from the perilesional tissue.
8.2 Histopathologic features
Microscopically, pemphigus vulgaris is characterized by loss of adhesion between the keratinocytes above the basal cell layer (acantholysis) resulting in formation of a blister space within the epithelium (Figure 28a). Within the intraepithelial blister space, acantholytic, free-floating epithelial cells are seen (Tzanck cells) (Figure 28b). The basal epithelial cells remain attached to the underlying connective tissue resembling a “row of tombstones.” An infiltrate of chronic inflammatory cells consisting of lymphocytes, plasma cells, and sometimes eosinophils is present in the underlying connective tissue.
Figure 28.
Pemphigus vulgaris. (a) Low-power photomicrograph depicting suprabasilar cleavage (acantholysis) and formation of an intraepithelial blister. The basal cell layer remain attached to the underlying connective tissue that exhibits a dense chronic inflammatory infiltrate. (b) High-power view of the intraepithelial blister space with free-floating acantholytic keratinocytes (Tzanck cells).
Although these histopathologic features are distinctive, diagnosis of pemphigus vulgaris should be confirmed with immunofluorescence studies [45]. Direct immunofluorescence studies reveal a diffuse deposition of immunoglobulins IgG or IgM and complement component C3 characteristically arranged in intercellular spaces in a “netlike” or “chicken wire” pattern [49]. Indirect immunofluorescence studies identifies circulating autoantibodies in vast majority of the cases [52, 55]. Furthermore, enzyme-linked immunosorbent assay (ELISA) has provided higher specificity and sensitivity in detection of these circulating serum autoantibodies [55].
8.3 Treatment and prognosis
Without proper treatment, pemphigus vulgaris can be a serious and potentially life-threatening condition signifying the importance of early diagnosis and management of this condition. As a widespread and systemic disease, treatment of pemphigus typically involves systemic immunosuppressive agents such as systemic steroids (e.g. prednisone or prednisolone) or steroid-sparing drugs (e.g. azathioprine or mycophenolate mofetil) [45, 46]. The traditional approach in management of these patients have been administration of high-dose immunosuppressive agents to clear the lesions followed by maintenance on lower-dose of the medications. Given the need for prolonged treatment and potential side effects associated with the prolonged use of these medication, the patient should be managed by a physician experienced in monitoring and adjusting the dose of medication accordingly. Furthermore, oral lesions of pemphigus tend be refractory to the systemic corticosteroid therapy warranting concurrent use of topical steroid regimens in management of these patients [46].
Recently, use of rituximab, a B-lymphocyte monoclonal antibodies, has provided an alternative approach in management of patients permitting a faster and prolonged remission of the disease [56]. With treatment, pemphigus vulgaris may undergo complete resolution. However, relapses and exacerbations of the condition are common during the course of treatment [49]. The disease activity can be monitored by evaluating the circulating autoantibodies.
The gingival tissue may be a host to variety of non-infectious mucous membrane diseases that can clinically mimic gingivitis and periodontal disease. Increased awareness of the clinical features and implications of such entities are crucial for early diagnosis and proper management of these conditions. While significant clinical overlapping may exist between various gingival conditions, lack of response to routine oral hygiene and plaque-control measure must raise the suspicion for these entities. Further clinical diagnostic workup including tissue biopsy may be necessary to explore such diagnostic considerations.
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Written By
Moni Ahmadian
Submitted: 01 January 2024Reviewed: 22 February 2024Published: 02 April 2024
Open access peer-reviewed chapter - ONLINE FIRST
