Clinical History

A thorough clinical history is mandatory to begin the assessment of desquamative gingivitis.¹¹³ Data regarding the symptomatology associated with this condition as well as its historical aspects (i.e., when the lesion started, whether it has worsened, if there is a habit that exacerbates the condition) provide the foundation for a thorough examination. Information regarding previous therapy to alleviate the condition should also be documented.

Clinical Examination

Recognition of the pattern of distribution of the lesions (i.e., focal or multifocal, with or without confinement to the gingival tissues) provides leading information to begin the formulation of a differential diagnosis. In addition, a simple clinical maneuver such as Nikolsky’s sign offers insight into the plausibility of the presence of a vesiculobullous disorder.⁹⁷

Biopsy

Given the extent and number of lesions that may be present in an individual, an incisional biopsy is the best alternative to use to begin the microscopic and immunologic evaluation. An important consideration is the selection of the biopsy site. A perilesional incisional biopsy should avoid areas of ulceration, because necrosis and epithelial denudation severely hamper the diagnostic process. After the tissue is excised from the oral cavity, the specimen can be bisected and then submitted for microscopic examination. Buffered formalin (10%) should be used to fix the tissue for conventional hematoxylin-eosin (H&E) evaluation. Michel’s buffer (ammonium sulfate buffer, pH 7.0) is used as transport solution for immunofluorescence assessment. In general, an incisional biopsy of uninvolved (normal) mucosa will show the same immunofluorescent findings as the biopsy of the perilesional tissue. However, there are notable exceptions, such as lichen planus and chronic cutaneous lupus erythematosus, in which only the lesional tissue will exhibit the corresponding immunologic markers (Table 19-1).

Management

After the diagnosis is established, the dentist must choose the optimum management for the patient. This is accomplished in accordance with three factors: (1) the practitioner’s experience; (2) the systemic impact of the disease; and (3) the systemic complications of the medications. A detailed consideration of these three factors dictates three different scenarios.

In the first scenario, the dental practitioner takes direct and exclusive responsibility for the treatment of the patient; this occurs with conditions such as erosive lichen planus, which is responsive to topical steroids (Figure 19-3).

In the second scenario, the dentist collaborates with another health care provider to evaluate and treat a patient concurrently. The classic example is seen with cicatricial pemphigoid, in which dentists and ophthalmologists work together (Figure 19-4). Although the dentist addresses the oral lesions, the ophthalmologist monitors the integrity of the ocular conjunctiva.

In the third scenario, the patient is immediately referred to a dermatologist for further evaluation and treatment. This occurs with conditions in which the systemic impact of the disease transcends the boundaries of the oral cavity and results in significant morbidity and even mortality. Pemphigus vulgaris is a clear example of a condition that, after diagnosis by the dentist, requires immediate referral to a dermatologist (Figure 19-5). In addition, the complications of chronically administered systemic medications that are indicated for the management of diseases such as pemphigus vulgaris or nonresponsive mucous membrane pemphigoid (e.g., diabetes mellitus, osteoporosis, methemoglobinemia) warrant referral to a dermatologist or a specialist in internal medicine.

When oral treatment is provided, periodic evaluation is needed to monitor the response of the patient to the selected therapy. Initially, the patient should be evaluated at 2 to 4 weeks after beginning treatment to ensure that the condition is under control. This observation should continue until the patient is free of discomfort. Appointments every 3 to 6 months would then be appropriate. Doses of any medications are usually adjusted during this interval.

Table 19-2 summarizes suggested contemporary therapeutic approaches that can be used to treat select conditions that clinically present as desquamative gingivitis. Dentists clearly play an important role in the diagnosis and management of desquamative gingivitis. The importance of being able to recognize and properly diagnose this condition is accentuated by the fact that a serious and life-threatening disease (e.g., squamous cell carcinoma) may mimic desquamative gingivitis.¹²⁷

Oral Lesions.

Although there are several clinical forms of oral lichen planus (i.e., reticular, patch, atrophic, erosive, and bullous), the most common are the reticular and erosive subtypes. The typical reticular lesions are asymptomatic and bilateral, and they consist of interlacing white lines on the posterior region of the buccal mucosa. The lateral border and dorsum of the tongue, the hard palate, the alveolar ridge, and the gingiva may also be affected. In addition, the reticular lesions may have an erythematous background, which is a feature that is associated with coexisting candidiasis. Oral lichen planus lesions follow a chronic course and have alternating, unpredictable periods of quiescence and flare-ups.

The erosive subtype of lichen planus is often associated with pain. It clinically manifests as atrophic, erythematous, and often ulcerated areas. Fine white radiating striations are observed bordering the atrophic and ulcerated zones. These areas may be sensitive to heat, acid, and spicy foods (Figure 19-6).

Gingival Lesions.

Approximately 7% to 10% of patients with oral lichen planus have lesions restricted to the gingival tissue.99,136 These may occur as one or more types of the following four distinctive patterns:

1. Keratotic lesions. These raised white lesions may present as groups of individual papules, linear or reticular lesions, or plaquelike configurations.

2. Erosive or ulcerative lesions. These extensive erythematous areas with a patchy distribution may present as focal or diffuse hemorrhagic areas. These lesions are exacerbated by slight trauma (e.g., toothbrushing) (Figure 19-7).

3. Vesicular or bullous lesions. These raised, fluid-filled lesions are uncommon and short lived on the gingiva, quickly rupturing and leaving ulcerations.

4. Atrophic lesions. Atrophy of the gingival tissues with ensuing epithelial thinning results in erythema that is confined to the gingiva.

Histopathology.

Microscopically, the three main features that characterize oral lichen planus are as follows: (1) hyperkeratosis or parakeratosis; (2) hydropic degeneration of the basal layer; and (3) a dense, bandlike infiltrate, primarily of T lymphocytes, in the lamina propria (Figure 19-8). Classically, the epithelial rete ridges have a “sawtooth” configuration. Hydropic degeneration of the basal layer of the epithelium may be sufficiently extensive that the epithelium becomes thin and atrophic or detaches from the underlying connective tissue and produces either a subepithelial vesicle or an ulcer. Colloid bodies (Civatte bodies) are often seen at the epithelium–connective tissue interface. The microscopic diagnosis of oral lichen planus is straightforward in the keratotic lesions, and biopsy specimens should be obtained from these areas if possible. However, these classic histologic features may be obscured in areas of ulceration, thereby making a conclusive diagnosis of oral lichen planus difficult if it is based solely on conventional microscopy. Electron microscopy studies indicate that the separation of the basal lamina from the basal cell layer is an early manifestation of lichen planus.⁶¹

It is noteworthy that oral lesions of lichen planus may change in pattern, and, in certain unusual cases, a second or even a third biopsy may be necessary to arrive at a definitive diagnosis. More importantly, controversy exists regarding the malignant potential of oral lichen planus. In recent studies, it has been estimated that oral cancer emerges in up to 2% of patients with oral lichen planus.41,55,62,63,150 By contrast, other researchers reject or question the connection between oral lichen planus and oral cancer.^42,66,87,123 Despite this controversy, biopsy and close follow up are warranted in these patients.

Immunopathology.

Direct immunofluorescence of both lesional and perilesional oral lichen planus biopsy specimens reveals linear fibrillar (“shaggy”) deposits of fibrin in the basement membrane zone (Figure 19-9), along with scattered immunoglobulin-staining cytoid bodies in the upper areas of the lamina propria (Figure 19-10). Serum tests involving the use of indirect immunofluorescence are negative in patients with lichen planus (see Table 19-1).

Differential Diagnosis.

The classic clinical presentation of oral lichen planus can be simulated by other conditions and mainly by lichenoid mucositis. If oral lichen planus is confined to the gingival tissues (i.e., erosive oral lichen planus), then the identification of fine white radiating striations bordering the erosive areas support a clinical diagnosis of oral lichen planus. If the white striations are absent, the differential diagnosis should primarily include mucous membrane pemphigoid and pemphigus vulgaris. Other, less common possibilities include linear IgA disease (LAD) and chronic ulcerative stomatitis.

Treatment.

The keratotic lesions of oral lichen planus are asymptomatic and do not require treatment after the microscopic diagnosis has been established. However, evaluation of the patient every 6 to 12 months is warranted to monitor suspicious clinical changes and to look for the emergence of an erosive component.

By contrast, the erosive, bullous, or ulcerative lesions of oral lichen planus are treated with high-potency topical steroids, such as 0.05% fluocinonide gel (Lidex, three times daily). Lidex can also be mixed 1 : 1 with carboxymethylcellulose (Orabase) paste or another adhesive ointment. A gingival tray can also be used to deliver Lidex or 0.05% clobetasol propionate with 100,000 IU/ml of nystatin in Orabase. Three 5-minute applications of this mixture daily appear to be effective for controlling erosive lichen planus.⁵⁷ Intralesional injections of triamcinolone acetonide (10 mg to 20 mg) or short-term regimens of 40 mg of prednisone daily for 5 days, followed by 10 mg to 20 mg daily for an additional 2 weeks, have also been used in more severe cases.¹¹² Because of the potential side effects, the administration of systemic steroids should be prescribed and monitored by a dermatologist. Other treatment modalities (e.g., retinoids, hydroxychloroquine, cyclosporine, azathioprine, cyclophosphamide, free gingival grafts) have also been used.^112,119 A promising therapeutic agent, tacrolimus (0.1% Protopic ointment, twice daily), is an immunosuppressant that is effective for controlling the lesions of erosive lichen planus.^{72,91,104,144}

Because candidiasis is often associated with symptomatic oral lichen planus and because topical steroid therapy promotes fungal growth, treatment should also include a topical antifungal agent.16,52,67

Pemphigoid

The term pemphigoid applies to a number of cutaneous, immune-mediated, subepithelial bullous diseases that are characterized by a separation of the basement membrane zone, including bullous pemphigoid, mucous membrane pemphigoid, and pemphigoid (herpes) gestationis.118,140 Among these conditions, bullous pemphigoid and mucous membrane pemphigoid (also known as benign mucous membrane pemphigoid and cicatricial pemphigoid), have received considerable attention. Current molecular findings involving these two diseases clearly indicate that they are separate entities.¹⁴⁰ However, considerable histologic and immunopathologic overlap exists between the two diseases, so their differentiation may be impossible on the basis of these two criteria.¹¹⁸ In many cases, the clinical findings are probably the best cognitive element to use to discriminate between them. Accordingly, the term bullous pemphigoid is preferred when the disease is nonscarring and mainly affects the skin. The term cicatricial pemphigoid is favored when scarring occurs and the disease is mainly confined to mucous membranes, although scarring may be absent with some subtypes of mucous membrane pemphigoid.¹⁵⁸ Until more research allows for the better understanding of this family of diseases, bullous pemphigoid and mucous membrane pemphigoid are discussed separately.

Bullous Pemphigoid.

Bullous pemphigoid is a chronic, autoimmune, subepidermal bullous disease with tense cutaneous bullae that rupture and become flaccid (Figure 19-11). Oral involvement occurs in about a third of affected patients.¹⁴⁸

Although the skin lesions of bullous pemphigoid clinically resemble those of pemphigus, the microscopic picture is quite distinct.

Histopathology.

There is no evidence of acantholysis, and the developing vesicles are subepithelial rather than intraepithelial. The epithelium separates from the underlying connective tissue at the basement membrane zone. Electron microscopic studies show an actual horizontal splitting or replication of the basal lamina. The separating epithelium remains relatively intact, and the basal layer is present and appears to be regular. The two major antigenic determinants of bullous pemphigoid are the 230-kD protein plaque known as BP1 and the 180-kD collagen-like transmembrane protein BP2.105,121,129

Immunofluorescence.

Immunologically, bullous pemphigoid is characterized by immunoglobulin G (IgG) and complement 3 (C3) immune deposits along the epithelial basement membranes and circulating IgG antibodies to the epithelial basement membrane.71,109 Direct immunofluorescence is positive in 90% to 100% of these patients, whereas indirect immunofluorescence is positive in 40% to 70% of affected patients¹¹⁰ (see Table 19-1).

Oral Lesions.

Oral lesions have been reported to occur secondarily in up to 40% of cases. There is an erosive or desquamative gingivitis presentation and occasional vesicular or bullous lesions.¹⁴⁸

Treatment.

Because its etiologic factors are unknown, the treatment of bullous pemphigoid is designed to control its signs and symptoms.71,109 The primary treatment is a moderate dose of systemic prednisone. Steroid-sparing strategies (i.e., prednisone plus other immunomodulatory drugs) are used when high doses of steroids are needed or when the steroid alone fails to control the disease.³⁸ For localized lesions of bullous pemphigoid, high-potency topical steroids or tetracycline with or without nicotinamide can be effective.¹¹²

Mucous Membrane Pemphigoid (Cicatricial Pemphigoid).

Mucous membrane pemphigoid, which is also known as cicatricial pemphigoid, is a chronic vesiculobullous autoimmune disorder of unknown cause that predominantly affects women during the fifth decade of life. It has also rarely been reported in young children.22,106,140

Cicatricial pemphigoid involves the oral cavity, the conjunctiva, and the mucosa of the nose, vagina, rectum, esophagus, and urethra. In about 20% of patients, however, the skin may also be involved. Recent investigations suggest that cicatricial pemphigoid encompasses a group of heterogeneous conditions with distinct clinical and molecular features.33,101,133 An elaborate cascade of events is involved in the pathogenesis of cicatricial pemphigoid. Initially, antigen–antibody complexing occurs at the basement membrane zone, and this is followed by complement activation and subsequent leukocyte recruitment. Next, proteolytic enzymes are released and dissolve or cleave the basement membrane zone, usually at the level of the lamina lucida.⁴⁵ The two major antigenic determinants for cicatricial pemphigoid are bullous pemphigoid 1 and 2 (BP1 and BP2). Most cases of cicatricial pemphigoid are the result of an immune response directed against BP2; less often, this response is mounted against BP1, epiligrin (laminin-5, a lamina lucida protein in basement membrane of stratified epithelium), and β4 integrins.^8,20,33

Current research strongly suggests that there are at least five subtypes of cicatricial pemphigoid: oral pemphigoid, anti-epiligrin pemphigoid, anti-BP antigen mucosal pemphigoid, ocular pemphigoid, and multiple-antigens pemphigoid.¹⁴⁰ Recent studies have shown that the sera of ocular pemphigoid patients recognize the β4 integrin subunit, whereas the sera of patients with oral pemphigoid recognize the βα6 unit.¹²⁴

Ocular Lesions.

Among patients who first present to the dentist (mainly with desquamative gingivitis), the eyes are affected in approximately 25%.¹¹⁰ By contrast, among patients who first present to the dermatologist, 66% present with conjunctival lesions; in ophthalmic studies, 100% of patients have ocular involvement.^{51,81,102,103} The initial lesion is characterized by unilateral conjunctivitis that becomes bilateral within 2 years. Subsequently, there may be adhesions of eyelid to eyeball (symblepharon) (Figure 19-12). Adhesions at the edges of the eyelids (ankyloblepharon) may lead to a narrowing of the palpebral fissure. Small vesicular lesions may develop on the conjunctiva, which may eventually produce scarring, corneal damage, and blindness.

Oral Lesions.

The most characteristic feature of oral involvement is the presence of desquamative gingivitis, typically with areas of erythema, desquamation, ulceration, and vesiculation of the attached ging/>

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