The Bullous Desquamative Lesions of Oral Mucosa

The most common of the bullous/desquamative diseases that affect the mouth include the erosive form of lichen planus, erythema multiforme, pemphigoid, and pemphigus. This overview looks at the clinical features and diagnosis of these diseases. In addition, treatment options are discussed.

The blistering or bullous diseases comprise a group of mucocutaneous immunopathic inflammatory lesions that can affect mucosal surfaces and/or skin. With few exceptions, these conditions are not readily associated with any specific identifiable etiologic factors. As science progresses, the basic explanation will no doubt be associated with genetic chromosome deletions, transocations, or acquired mutations that alter epithelial-epidermal chemistry, which in turn attract immune cells (lymphocytes), resulting in cytokine release-induced reactions.¹ These reactions most often have clinical and microscopic characteristics that allow a specific diagnosis.^2-4

The most common of the bullous/desquamative diseases that affect the mouth include the erosive form of lichen planus, erythema multiforme, pemphigoid, and pemphigus. This overview will be limited to these entities.

Clinical Features

The cause of lichen planus is unknown. Lichen planus has three general forms: reticular (white lace-like keratotic pattern [Wickham’s striae]); atrophic (a red or erythematous component); and erosive (varying degrees of ulceration along with white and red changes) (Figures 1, 2 and 3). The main patient complaints are pain, discomfort, and irritation, with concerns for infectiousness and the potential risk of malignant transformation.⁵ There are oral conditions in which the clinical appearance resembles that of lichen planus as does the histology, yet the features are not classic (i.e., striae are absent, basal cell lysis is not evident microscopically). Such lesions are often referred to as "lichenoid" and may be indicative of a contact or delayed type hypersensitivity to an exogenous antigen such as cinnamon or mercury from dental restorations. Yet other lichenoid reactions are idiopathic.

Erythema multiforme can appear as a red, red-white, or red-white-ulcerative manifestation (Figures 4 and 5). Involvement of the lips is a typical feature, but it is not always seen. The outbreak can be chronic or cyclical and is usually associated with pain. Erythema multiforme represents a hypersensitivity reaction; but in oral erythema multiforme in contrast to skin presentations, a causative agent usually cannot be identified. Often the skin lesions present as "target" or "bull’s-eye" lesions.

Mucous membrane pemphigoid will usually occur as a red or red-erosive change

(Figure 6 and Figure 7). The gingiva is the most common site, accounting for the archaic term "desquamative gingivitis."⁶ Mucous membrane pemphigoid in a small number of cases can affect the eyes, causing a symblepharon (a fibrous scar between the lower eye lid and the conjunctiva). Bullous pemphigoid is the cutaneous counterpart to mucous membrane pemphigoid yet involves disparate immunologic targets and mechanisms.

Pemphigus vulgaris is most frequently manifested by bullae and cavernous-appearing ulcers. They can occur on any mucosal surface. While usually both skin and mucosa are involved, in many cases the first signs and symptoms occur in the mouth; and in some cases the skin is never involved (Figures 8 and 9). The vermilion borders of the lips are often involved, and this then helps in the clinical differentiation from mucous membrane pemphigoid.

Epidemiology

Adequate population studies have not been done to establish incidence rates or occurrence. Lichen planus is the most common of these diseases. The blistering diseases occur in all ethnic groups, and the initial onset is most often beyond the third and fourth decades of life, with an increasing incidence beyond the age of 50. Clinical reports reflect a moderate female predominance.

These diseases are almost always chronic and are often characterized by flares and mild remissions. While these lesions can occur on any mucosal surface, lichen planus most frequently presents on the buccal mucosa and mucous membrane pemphigoid on the gingiva. Occurrence is not related to either tobacco usage or alcohol. There is no evidence of a nutrition factor, although certain foods can cause flares, they are not the basic causative agent.

Diagnosis

Clinical features are used to determine a differential diagnosis, which is then confirmed by biopsy. In classical cases, there are cell-tissue patterns that are characteristic of each entity, reflecting inflammatory patterns in some and sites of antigen-antibody reactions in others. In some cases in which specific histopathologic patterns cannot be confirmed, immunofluorescence is helpful. This technique identifies sites of antigen-antibody reactions.

Since there is a slight increased risk of malignant transformation in lichen planus, these patients should be followed closely, and the diagnoses should be re-established when changes in signs and/or symptoms occur. The differential diagnosis and biopsy are very important, since these are chronic, lifelong conditions, and it must be made certain that the clinical red/white/erosive changes do not represent a dysplastic or malignant process.

Histologically, lichen planus is characterized by hyperkeratotic epithelium, which accounts for the white appearance; and in the subepithelial connective tissue an infiltrate of lymphocytes lies in juxtaposition to the epithelium. The basal layer is disrupted and when completely lysed; desquamation occurs with resulting areas of ulceration. Thus, in the so-called erosive form of the disease, the entire epithelial layer is lost. Erythema multiforme has a nonspecific histologic appearance. The epithelium shows a marked inflammatory infiltrate as polymorphonuclear neutrophil leukocytes and round cells emigrate out of vessels and transmigrate into the overlying epithelium. There is intense submucosal inflammation; and eventually the epithelium undergoes necrosis and sloughs, leaving an ulcerated pseudomembrane composed of fibrin. Mucous membrane pemphigoid shows a characteristic sub-basilar clefting that ensues subsequent to antibody and complement binding to basement membrane antigens. The submucosal connective tissue is variably infiltrated by mononuclear leukocytes, usually an admixture of plasma cells and lymphocytes. Biopsies of gingival lesions often demonstrate extensive desquamation of the epithelium with total detachment from the underlying connective tissue. In pemphigus vulgaris, a classic suprabasilar clefting occurs as antigens in the desmosomes are targeted by antibodies that cause a loss of adhesion between contiguous keratinocytes.

The immunofluorescent patterns seen in these bullous disease are indicative of the autoimmune targets within the basement membrane, desmosomes, or complexes in vessel walls. Direct immunofluorescent microscopy requires procurement of an oral biopsy from perilesional mucosa. A site should be selected adjacent to a clinical lesion and not directly in the zones of desquamation. Table 1 portrays the characteristic patterns of antigen:antibody deposition encountered in these lesions. Importantly, Michel’s transport medium is required to preserve tissue for immunofluorescent microscopy and of even greater import is the necessity of obtaining tissue for routine hematoxylin and eosin staining. Biopsies can be split, or two samples can be obtained.

Treatment

None of these condition is curable; therefore, treatment is based upon modifying patient discomfort and pain. The principle of treatment is directed toward the immunopathologic processes that are reacting with the epithelium and causing the symptoms. If mild over-the-counter medications are helpful, they should be the first line of control. However, the most effective and predictive approach is to modify immunologic activities. Corticosteroids are the agents of choice.^7,8 They can be administered topically or systemically (Figures 10a and b, 11a and b).

Topical corticosteroids must be potent forms, since prolonged exposure is required for drug-lymphocyte interaction. Table 2 lists the drugs and forms that are useful. Applications can vary from single daily applications (most effective before bedtime) to up to five times daily. Long-term studies have not shown any pathophysiologic adverse side effects. Occasionally, these topical agents might stimulate overgrowth of Candida sp., and the subsequent oral candidiasis must be treated with topical (clotrimazole) or systemic (fluconazole or ketoconazole) antifungal agents.

When systemic routes are utilized, the strategy is high-dose, short-course. In this manner, one can optimize efficacy and minimize side effects. In these situations, the treatment should be in conjunction with the patient’s primary care physician. In systemic routes, there should be caution in patients with diabetes, gastrointestinal ulcers, hypertension, and glaucoma.

Occasionally, when signs and symptoms are not responding adequately, a combination of azathioprine (Imuran), a synergistic cytotoxic drug, may be helpful. Care must be taken, since Imuran can cause bone marrow suppression and alter liver function.

Author

Sol Silverman, Jr., MA, DDS, is a professor of oral medicine at the University of California at San Francisco School of Dentistry

References

1. Delves PJ, Roitt IM, The immune system. N Engl J Med 343:37-49, 2000.

2. Weinberg MA, Insler MS, Campen RB, Mucocutaneous features of autoimmune blistering diseases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:517-34, 1997.

3. Eversole LP, Immunopathogenesis of oral lichen planus and recurrent aphthous stomatitis. Semin Cutan Med Surg 16:284-94, 1997.

4. Scully C, Carrozzo M, et al, Update on mucous membrane pemphigoid. A heterogeneous immune-mediated subepithelial blistering entity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88:56-68, 1999.

5. Silverman S Jr, Bahl S, Oral lichen planus update. Clinical characteristics, treatment responses, and malignant transformation in 95 patients. Am J Dent 10:259-63, 1997.

6. Dayan S, Simmons RK, Ahmed AR, Contemporary issues in the diagnosis of oral pemphigoid. A selective review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88:424-30, 1999.

7. Wood AJJ, Management of acquired bullous skin diseases. N Engl J Med 333:1475-84, 1995.

8. Lozada-Nur F, Miranda C, Oral lichen planus: topical and systemic therapy. Semin Cutan Med Surg 16:295-300, 1997.

To request a printed copy of this article, please contact/Sol Silverman, Jr., MA, DDS, UCSF School of Dentistry, 707 Parnassus Ave., Box 0422, San Francisco, CA 94143.

Table 1. Immune Targets and Immunofluorescent Patterns in Oral Bullous Diseases

Table 2. Corticosteorid Strategy

Systemic: high dose/short course

Prednisone 40-80 mg daily

Less than two weeks, no taper

Topical: potent corticosteroids (gel and ointment)*

Lidex (fluocinoide) 0.05 percent

Temovate (clobetasol) 0.05 percent

Ultravate (halobetasol) 0.05 percent

Mouth rinse: elixir dexamethasone 0.5 mg/5 ml

1 teaspoon three time daily, hold one minute, then spit out

* Paste: mix ointment with equal parts orabase

Legends

Figure 1. Reticular lichen planus, buccal mucosa.

Figure 2. Reticular lichen planus, tongue.

Figure 3. Atrophic lichen planus, gingiva and buccal mucosae.

Figure 4. Erythema multiforme, palate.

Figure 5. Erythema multiforme, lips.

Figure 6. Mucous membrane pemphigoid, gingiva.

Figure 7. Mucous membrane pemphigoid, palate.

Figure 8. Pemphigus vulgaris, gingiva.

Figure 9. Pemphigus vulgaris, buccal mucosa.

Figure 10a. Lichen planus. Painful buccal mucosa lesion present for six months.

Figure 10b. After 60 mg prednisone daily for one week. Patient was then maintained with topical fluocinonide-orabase with good control.

Figure 11a. Mucous membrane pemphigoid. Painful gingival lesions present for four years.

Figure 11b. After two weeks, daily topical corticosteroids lead to complete control of the symptoms and almost complete remission of signs.