Pemphigus Vulgaris
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Extensive, irregular blisters of the retromolar and buccal area broken but still retain their epithelial covers.

 

 

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Quick Review for Patients

Pemphigus vulgaris is an autoimmune or "self-allergy" disease in which a patient’s own circulating antibodies become altered so that they attack the points of adhesion of the epithelial cells, one to another, of the skin and mucous membranes. Women are more frequently affected than men and the disease is usually diagnosed between the ages of 50-70 years, often with oral blisters as the first sign. Children are rarely affected. The typical lesion is a small or large, clear-fluid blister which breaks rapidly in the mouth to leave a flat white, somewhat tender ulcer with a thin red line around it. Skin blisters may last for hours or days, and blisters may be caused by pressure on the skin or membranes of the mouth. There is no cure, but pemphigus is treated with heavy doses of corticosteroids and azathioprine, with frequent relapses after the therapy is stopped. Secondary infection is common because of the immune system suppression from these drugs. The overall mortality is less than 6%, usually from infection or loss of body fluid from a large number of blisters.

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Introduction

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The most serious of the bullous diseases affecting the oral mucosa is pemphigus vulgaris, a life-threatening autoimmune disorder of skin and mucous membranes. It is relatively rare but shows an increased frequency in Ashkenazi Jews. The mouth is the only site of involvement in half of all cases of pemphigus, and is the initial site of presentation in almost 3/4 of cases. An association between pemphigus vulgaris, myasthenia gravis and thymoma has been reported, and a variety of drugs have been implicated in its induction, especially penicillamine, phenylbutazone, rifampin and captopril, although most cases are idiopathic. It is also known to occur in association with a variety of internal malignancies (paraneoplastic pemphigus).

Patients with pemphigus vulgaris produce IgG autoantibodies to desmoglein 3 (the "PV antigen"), a transmembrane glycoprotein which mediates cell adhesion. Although the exact mechanism is unclear, autoantibodies theoretically produce an allosteric change in the desmoglein, impairing its adhesive abilities, and increase active plasmin in the area, producing cell degradation and acantholysis. Complement may be actively involved in this process.

Pemphigus vulgaris is a disease of older individuals, usually 50 years or older, but rare examples in children and adolescents have been reported. There is no gender predilection. The oral lesion is a fragile bulla, almost always ruptured by the time of diagnosis (Figure 1). There is little or no erythematous inflammatory halo and a fresh lesion may retain epithelial tags at its periphery. In contradistinction to traumatic ulcers and aphthous ulcers, the base of a pemphigus ulcer is not concave or saucerized and there is considerably less associated pain. The bullae tend not to become secondarily infected but may reach more than 4 cm. in diameter and may be so numerous as to represent most of the oral mucosa. Blisters can be created by pressure or friction upon a normal-appearing area of mucosa (Nikolsky sign).  With time skin blisters will usually occur and will become the major problem (Figure 2).

Bullae may present on any oral or oropharyngeal surface, but typically arise in the buccal, palatal and gingival regions (Table 1). Occasional patients have lesions restricted completely to the gingiva. Skin lesions are similar except that the more heavily keratinized epidermis allows blisters to remain intact much longer. Most patients have circulating autoantibodies which can be detected by indirect immunofluorescence using serum from other affected individuals. Titers are directly proportionate to the severity of the disease.

A special subset of patients demonstrates internal malignancy in addition to mucosal and skin erosions and bullae. Called paraneoplastic pemphigus, its oral manifestations may resemble erythema multiforme or bullous lichen planus and may be extremely severe and resistant to treatment. The associated autoantibodies are different from those of routine pemphigus vulgaris, and can be demonstrated by indirect immunofluorescence using rat bladder transitional epithelium as the substrate. Pemphigus vulgaris only shows positive indirect immunofluorescence on stratified squamous epithelium, such as monkey esophagus. Neoplasms most often associated with this form of pemphigus include lymphoma, leukemia, sarcoma and thymus tumors. Waldenstrom’s macroglobulinemia and Castleman’s disease have also been reported as associated.

Rare variants of pemphigus may affect the oral mucosa. Pemphigus vegetans presents with much smaller blisters than pemphigus vulgaris. The blisters are often filled with pus and coalesce to impart an appearance of vegetative growth. The vermilion border of the lips is especially prone to involvement. The oral disease most likely to clinically mimic this form of pemphigus is pyostomatitis vegetans, a rare oral manifestation of inflammatory bowel disease, particularly ulcerative colitis and Crohn’s disease. Oral lesions in this disease are characterized by yellow, partially ulcerated pustules arranged in serpentine strands or "snail tracks" on an erythematous background. Minimal discomfort is felt and the oral lesions may precede intestinal involvement.

Pemphigus foliaceus may affect perioral and other facial skin. The least severe form of pemphigus, pemphigus erythematosus, presents on the face and scalp with scaly dermal erythema reminiscent of seborrheic dermatitis. There may be a "butterfly" erythema of the nose and midface, mimicking lupus erythematosus. Oral and pharyngeal lesions are in these subtypes extremely rare.

The blistering or cleavage in this disease occurs above the basal layer of the epithelium, typically leaving a layer of basal cells with rounded tops, reminiscent of tombstones (Figure 3). The intact bulla is filled with serum and occasional sloughed, rounded, keratinocytes resembling fried eggs, with large, hyperchromatic nuclei and a rim of eosinophilic cytoplasm . The latter acantholytic cells, called Tzanck cells, are best seen in the smear sample of a fresh blister (Tzanck test). They are strongly suggestive of pemphigus vulgaris but may also be encountered in Darier’s disease and in regenerating thermally- or chemically-damaged epithelium. The suprabasal bulla frequently contains chronic and acute inflammatory cells, including eosinophils. The presence of eosinophils in oral vesiculoulcerative lesions is somewhat unique, but may also occur in pemphigoid, epidermolysis bullosa acquisita, eosinophilic granuloma, parasitic infection and traumatic eosinophilic ulcer.

When the bulla has ruptured, the associated ulcer bed slowly becomes covered with fibrinoid necrotic debris, with neovascularity and mixed inflammatory cells in the underlying stroma. The epithelium at the edge of a fresh ulcer will show intraepithelial cleavage.

Direct immunofluorescence of perilesional mucosa shows a lacy or chicken-wire pattern of deposits around individual spinous cells of the epithelium (Figure 4). IgG is almost always the deposited immunoglobulin, but IgM and IgA are seen in almost half of all cases. Some authorities have suggested direct immunofluorescence of cytologic smears as a reliable and noninvasive method of diagnostic confirmation. Direct immunofluorescence of paraneoplastic pemphigus mucosa demonstrates both intercellular and basement membrane IgG and complement deposits.

Differentiation from other oral and pharyngeal bullous diseases is easily made, because most of them produce subepithelial blisters (pemphigoid, epidermolysis bullosa, bullous lichen planus, linear IgA disease), but small lesions may be mistaken for intraepithelial viral vesicles and any lesion may be confused with the oral keratinized blisters of Darier’s disease. Clinical history or the presence of syncytial multinucleated epithelial cells will usually lead to a diagnosis of infection by a dermatotrophic virus capable of damaging oral mucosa, e.g. herpes simplex, herpes zoster and Coxsackie viruses, while the presence of excessive surface keratinization and cor ronds within intact bullae will help to differentiated Darier’s disease.

Finally, it is important to remember that mucosal lesions of erythema multiforme may demonstrate either intraepithelial or subepithelial blistering, or both. This unique allergic response, however, typically occurs in much younger patients, has a much more abrupt onset and has a limited duration, making it relatively easy to distinguish it from pemphigus.

Systemic corticosteroid therapy is effective in reducing or eliminating the clinical manifestations of pemphigus vulgaris, although doses of prednisone may have to be as high as 400 mg. daily for patients with severe involvement. Topical corticosteroids can be used as an adjunct therapy if the bullae are confined to oral mucosa. Oral or intravenous administration of cyclophosphamide, azathioprine, cyclosporine and methotrexate may have enough beneficial effect to allow reduced dosages of corticosteroids. Even with immunosuppressive therapy, however, almost 10% of patients will die from their disease, either from electrolyte loss, wound infection or treatment complications. Patients with paraneoplastic pemphigus may have to forgo treatment of their vesiculobullous disease until the underlying neoplasm is controlled, although supportive therapy can be instituted.

Table 1: Lesion locations for oral pemphigus vulgaris in patients 
who have not yet developed skin lesions, modified from Sirois et al, 2000.

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Pictures

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		Figure 1:  Extensive, irregular blisters of the retromolar and buccal area broken but still retain their epithelial covers.   [return to text]
		Figure 2: On the skin, even large blisters may remain intact for some time, because the keratin layer is thicker than that of the oral mucosa.   [return to text]
		Figure 3:  The classic microscopic appearance of pemphigus is one of epithelial cells literally falling away from each other and rounding out in the fluid of the blister. [return to text]
		Figure 4:  With immunofluorescence, the antibody attack is represented by apple green coloration of the area between or surrounding each epithelial cells.   [return to text]
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