View larger version (85K): [in this window] [in a new window]   Figure 2. Ragged ulceration of the buccal mucosa is seen.

View larger version (108K): [in this window] [in a new window]   Figure 3. This low-power photomicrograph shows an intraepithelial separation at the level of the basal and parabasal cell layers. Scattered chronic inflammation is present in the underlying connective tissue (hematoxylin-eosin, original magnification x200).

View larger version (111K): [in this window] [in a new window]   Figure 4. The intraepithelial cleft exhibits numerous detached cells with a rounded shape (hematoxylin-eosin, original magnification x400).

1. benign mucous membrane pemphigoid
   
2. erythema multiforme
   
3. pemphigus vulgaris
   
4. erosive lichen planus
   
5. recurrent aphthous ulcers
   

	THE DIAGNOSIS

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C. pemphigus vulgaris Pemphigus is a group of autoimmune mucocutaneous diseases characterized by intraepithelial blister formation resulting from acantholysis, or the loss of cohesion between epithelial cells. The most common form of pemphigus is pemphigus vulgaris (PV), which accounts for approximately 80 percent of cases.¹ Current theories regarding the pathogenesis of PV center on autoantibodies directed against desmosomal components, particularly the transmembrane glycoproteins desmoglein 1 and 3, resulting in a loss of intercellular cohesion.^2,3 PV most commonly affects middle-aged to elderly adults, with a mean age at diagnosis of 50 years.⁴

The disease exhibits a predilection for people of Jewish or Mediterranean descent, and genetic factors are suggested by a strong association with particular human leukocyte antigen class II molecules.⁵ PV is a rare condition, with an incidence of approximately 0.1 to 0.5 per 100,000 population.⁶ Nevertheless, it is important for dental practitioners to be familiar with this disease, because in approximately 50 to 70 percent of patients, the oral lesions constitute the initial or sentinel finding and may precede the appearance of cutaneous lesions by one year or more.^1,4,7 Moreover, the oral lesions often are the most difficult aspect of this disease to treat.⁴

The oral lesions tend to be painful and may interfere with eating or other essential oral functions. The most common sites of oral involvement include the buccal mucosa, soft palate, labial mucosa and gingivae, although any oral site may be affected.^4,7 The earliest lesions appear as vesicles or bullae, which, because of their friability, tend to be short-lived and seldom are identified clinically.⁴ The blisters rupture easily to produce ragged, superficial ulcers or erosions, which typically heal slowly and only rarely cause scarring. Gingival involvement may appear as desquamative gingivitis.⁵ Cutaneous lesions appear as vesicles or bullae that rupture readily, leaving behind an erythematous, denuded surface.⁴

Biopsy. To make the diagnosis, the clinician needs to perform a biopsy of perilesional tissue, as opposed to tissue from the lesion center, which may exhibit nonspecific histopathologic features. Characteristic microscopic features include intraepithelial blister formation with suprabasilar acantholysis, resulting in loose, rounded cells (or Tzanck cells) within the epithelial cleft. If the roof of the blister is stripped away, all that may remain adherent to the lamina propria is the basal cell layer, which has been described as resembling a "row of tombstones."

To distinguish PV from other suprabasilar acantholytic processes, the clinician should submit biopsy tissue for direct immunofluorescence studies, which typically demonstrate intercellular deposition of autoantibodies (usually immunoglobulin G [IgG] or IgM) and the C3 component of complement (Figure 5).⁴ Additional advanced laboratory tests available include an enzyme-linked immunosorbent assay involving the use of recombinant human desmoglein 1 and 3, immunoblotting and immunoprecipitation.^6,8 An assay of circulating antibody titers via indirect immunofluorescence may help monitor disease severity and guide therapy.⁵

View larger version (92K): [in this window] [in a new window]   Figure 5. Direct immunofluorescence demonstrates bright green intercellular deposition of immunoglobulin G in the lower spinous cell layer.

Early diagnosis and treatment are essential; more extensive disease at the onset of treatment usually requires more intensive pharmacological regimens and higher doses of maintenance steroids, which result in a greater risk of developing secondary complications.⁷ Before the advent of modern corticosteroid therapy in the 1950s, PV typically was a fatal condition, with 60 to 80 percent of patients dying of infections or electrolyte imbalances. The mortality rate today is 5 to 10 percent and usually is related to complications of long-term corticosteroid therapy.⁴

	DIFFERENTIAL DIAGNOSIS

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In addition to PV, the differential diagnosis for chronic, multifocal oral ulcers commonly includes erosive lichen planus and benign mucous membrane pemphigoid. The ulcers of erosive lichen planus may exhibit peripheral radiating striae. In addition to oral mucosal involvement, skin, nail and scalp involvement are possible, although many patients with oral lichen planus do not exhibit extraoral manifestations.¹⁰ Oral lesions of benign mucous membrane pemphigoid can look similar to those of PV. In up to 25 percent of patients with oral benign mucous membrane pemphigoid, ocular disease develops, which can result in scarring and ultimately blindness.⁴ In contrast, ocular disease in association with PV and lichen planus is uncommon and typically mild. Desquamative gingivitis can be a common feature of all these conditions.

Establishing a diagnosis. A biopsy, a light microscopic examination and additional adjunctive tests, such as immunofluorescence studies, can be used to establish a diagnosis. In PV, the production of autoantibodies directed against desmosomal components results in separation of epithelial cells above the basal cell layer. In benign mucous membrane pemphigoid, however, the production of autoantibodies directed against basement membrane components results in a subepithelial separation. Erosive lichen planus can exhibit subepithelial separation as well. However, unlike the clean subepithelial separation typical of benign mucous membrane pemphigoid, a somewhat more "ragged" subepithelial separation is characteristic of erosive lichen planus, the result of hydropic degeneration of the basal cell layer with an associated superficial, bandlike lymphocytic infiltrate in the underlying connective tissue. Direct immunofluorescence studies characteristically demonstrate intercellular deposition of IgG and C3 in PV; linear basement membrane zone deposition of IgG, IgA and/or C3 in benign mucous membrane pemphigoid; and shaggy deposition of fibrinogen in lichen planus.^{4(pp669–73),11}

Less common conditions. Although the three conditions discussed above—erosive lichen planus, benign mucous membrane pemphigoid and PV—are the most common differential diagnostic considerations for chronic, multifocal oral ulcers, clinicians also may consider rare conditions such as linear IgA disease, epidermolysis bullosa acquisita and chronic ulcerative stomatitis.¹² Diagnostic confirmation of these less common conditions typically requires a light microscopic examination, immunofluorescence studies and possibly additional adjunctive tests.

In addition, we should note that acute, rather than chronic, onset of multiple oral ulcers can be associated with erythema multiforme and primary herpetic gingivostomatitis. Practitioners usually can exclude recurrent aphthous stomatitis on the basis of clinical history and appearance. Minor aphthae—the most common form of recurrent aphthous stomatitis—develop with recurrent episodes of ulcers that resolve in one or two weeks, are one to few in number, exhibit a pseudomembranous covering with an erythematous halo and are limited to nonkeratinizing mucosa.^{4(pp285–90)}

	CONCLUSION

TOP THE CHALLENGE THE DIAGNOSIS DIFFERENTIAL DIAGNOSIS CONCLUSION REFERENCES

 
PV is an uncommon yet serious autoimmune blistering disorder of the skin and mucosa. Because the oral cavity frequently is the first site of involvement, it is important for the dentist to recognize and diagnose this disease during its early stages.