JADA Continuing Education
ORAL PEMPHIGUS VULGARIS PRECEDING CUTANEOUS LESIONS: RECOGNITION AND DIAGNOSIS
DAVID SIROIS, D.M.D., PH.D.,
JANET E. LEIGH, B.D.S., D.M.D. and
THOMAS P. SOLLECITO, D.M.D.
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ABSTRACT
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Background. Pemphigus vulgaris, or PV, is a potentially life-threatening illness that manifests itself initially in the mouth in the majority of patients. Paradoxically, it is less commonly recognized when it involves lesions on the oral mucosa rather than on the skin.
Case Description. This article describes the clinical presentation of 42 cases of oral PV evaluated and diagnosed by dentists. Emphasis is placed on the common distribution and appearance of oral PV lesions and diagnosis of the disease.
Clinical Implications. The dentist has a unique opportunity to recognize the oral presentation of PV and contribute to an early diagnosis and, therefore, an improved treatment outcome.
Pemphigus vulgaris, or PV, is a mucocutaneous autoimmune bullous disease. While there are several types of pemphigus (such as vulgaris, foliaceus, vegetans and paraneoplastic), 80 percent of all patients with pemphigus have PV.1–4 PV affects both sexes equally and is more common among Jews, particularly Ashkenazic Jews, than among members of any other racial or ethnic group. Although rare pediatric cases have been reported, PV most commonly develops during the fifth to seventh decade of life.3–7
Although PV accounts for only 2 percent of intraoral ulcerative lesions, the serious nature of the disease justifies its consideration in nearly any situation in which multiple chronic oral ulcerations or desquamative gingivitis is present.
Before systemic steroids were available, the disease often was fatal. One study of 107 patients reported mortality rates of 46 and 24 percent, respectively, in the 10-year periods immediately before and after corticosteroids were introduced.8
PV affects the oral mucosa in nearly all cases and, more importantly, the oral mucosa is the site of the first lesion in the majority of cases.9–13 Pisanti and colleagues12 found that the oral cavity was the sole initial site of PV lesions in 56 percent of the cases, and that 88 percent of patients had primary lesions in the mouth alone or in combination with other sites. A recent survey completed by 99 patients with PV found that 81 percent had oral lesions first.13 Unfortunately, the high frequency of early oral involvement does not always lead to early diagnosis. In a recent study by Sirois and colleagues,13 nearly one-third of patients with oral PV did not receive an accurate diagnosis for more than six months, but 100 percent of patients who had cutaneous PV were correctly diagnosed within six months.
PV is characterized by autoantibodies directed against desmosome-associated protein antigens (desmoglein 3) found in epithelial and epidermal intercellular substance.2,14–16 Since the desmosome is the primary attachment mechanism between keratinocytes, the inflammatory destruction of that attachment leads to the characteristic fluid-filled bullae and subsequent ulceration. The autoantibodies can be detected in the epithelium using direct immunofluorescent staining techniques14–16 (Figure 1
). Circulating antibodies (immunoglobulin G, or IgG) are detectable in 80 to 90 percent of patients with PV, and the titer generally is correlated with the level of clinical disease.17 When the epithelial attachment is compromised or destroyed, even minor mucosal trauma may result in epithelial separation, or acantholysis, and bullae formation. Indeed, the formation of trauma-induced bullae is one diagnostic tool used in assessing the patient who has multiple, chronic oral ulcerations: a positive Nikolsky’s sign (blister or ulcer formation after gentle horizontal pressure is applied to the oral mucosa) is indicative of a mucocutaneous bullous disease such as PV or cicatricial pemphigoid. The bullae quickly rupture, leaving a relatively nonspecific, shallow ulceration with an irregular border.
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Figure 1. Direct immunofluorescent staining (immunoglobulin G) revealing pemphigus vulgaris antigen distribution in the oral epithelium. Note the "spider-web" distribution of reaction product in the spaces between squamous epithelial cells (obtained from perilesional biopsy specimen containing intact epithelium).
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The definitive diagnosis of PV cannot be based solely on clinical examination, as several other oral vesiculobullous and ulcerative lesions have a similar appearance (those in erosive lichen planus, pemphigoid and erythema multiforme).9–11,18–20 An incisional, perilesional biopsy containing intact epithelium is required for a definitive diagnosis. The characteristic histologic features of PV observed using a standard hematoxylin and eosin, or H and E, stain include intraepithelial clefts, or bullae; acantholysis, or separation of the epithelial cells; and a dense mononuclear lymphocytic infiltration (Figure 2). Direct immunofluorescent staining of specially preserved tissue reveals the characteristic "spider-web" distribution of reaction product, or autoantibody, between the epithelial cells (Figure 1
). A simple smear taken from a new lesion also can be used to identify acantholytic cells, called Tzanck cells, which are indicative of PV. Tzanck cells, however, also can be found in diseases such as herpes simplex, carcinoma and transient acantholytic dermatosis; therefore, they are not diagnostic.
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Figure 2. Hematoxylin-and-eosin–stained section revealing acantholysis, mononuclear infiltrate and suprabasilar separation.
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In the following summary of biopsy specimens submitted to an oral pathology biopsy service by dentists, we describe clinical features of, diagnostic impressions of and histologic findings in 42 cases of oral PV.
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SUBJECTS AND CASE DESCRIPTIONS
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We reviewed records from the diagnostic oral pathology service of the Temple University School of Dentistry, Philadelphia, to identify subjects for this retrospective study. We examined both the biopsy request form submitted by the treating doctor and the corresponding pathology report. From these records, we obtained patient demographic data and information regarding the appearance, location and diagnostic impression, as well as the definitive diagnosis based on histopathologic findings.
Thirty patients were female (71 percent) and 12 were male (ratio 2.5:1). The mean age at time of diagnosis was 56.1 ± standard deviation of 14.9 years (the range was 27 to 68 years). The preponderance (81 percent) of the patients were white; 11.9 percent were Asian, and 7.1 percent were black. The buccal mucosa and gingivae are the most common sites of oral PV; the table shows the distribution of oral PV lesions among the cases. The appearances were reported as white (26 percent), red (19 percent), and mixed red and white (43 percent); five reports did not specify the color of the lesion. Sixty-nine percent of the lesions were described as ulcers and 5 percent as raised lesions; 26 percent of the reports did not describe the appearance of the lesion. Remarkably, in no case were skin lesions described at the time of biopsy.
For 22 of the 42 specimens (52 percent), PV was included in the differential diagnosis. Pemphigoid was included in the differential diagnosis for 18 of 42 specimens (50 percent) and erosive lichen planus for 12 of 42 cases (28 percent). Figure 3 illustrates the typical clinical appearances of oral PV.
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Figure 3. A variety of clinical presentations of oral pemphigus vulgaris, which generally appears in the form of shallow, irregular nonspecific ulcers. A. The palate. B. The buccal mucosa. C. The gingivae.
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DISCUSSION
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As shown in the table, the most common clinical presentation of oral pemphigus is multiple, chronic ulcerations whose color is red, white or a mixture of both. These ulcerations most commonly involve the buccal mucosa or gingiva in a woman older than 45 years of age.
The presentation of multiple chronic ulcers should lead the clinician to consider only a few common disorders such as PV, cicatricial pemphigoid and erosive lichen planus. A history of trauma-induced bullae and a positive Nikolsky’s sign will help narrow the differential diagnosis. The presence of multiple lesions is not typical in malignancy, and the chronicity excludes more common causes of intraoral ulceration such as herpes simplex, aphthous stomatitis and erythema multiforme. However narrow the differential diagnosis may be, a definitive diagnosis is possible only with microscopic examination.
When the choice is made to perform a diagnostic biopsy for any of the bullous diseases, the specimen must contain epithelium; a sample solely from the ulcer or erosion center will be of little diagnostic value. The reason is simple: the target antigen, desmoglein 3, is found in the intraepithelial, supra-basilar tissue. Without the epithelium, the antigen cannot be identified using direct immunofluorescence techniques (Figure 1). Even sections that undergo routine H and E staining must contain epithelium for the clinician to identify areas of epithelial separation (acantholysis) and other cytopathologic features (Figure 2). Therefore, the preferred sample for biopsy is a perilesional sample, which contains normal epithelium, as well as tissue from the area of ulceration.
Although the efficacy of H and E staining alone (no immunofluorescence) in diagnosing PV is probably greater than 90 percent, direct immunofluorescent staining is performed in most instances to detect autoantibodies in the tissue where the disease arises. When this technique is used, special preservative medium is essential (Michel’s solution); fixation in formalin will destroy antigen proteins and render direct immunofluorescent examination useless. Indirect immunofluorescence can be used to detect circulating autoantibodies in the blood—which it does in approximately 80 percent of patients with PV. A negative result, however, does not exclude a diagnosis of PV. While monitoring the circulating pemphigus autoantibody titers via indirect immunofluorescence is not an essential part of the diagnosis of PV, it is useful in assessing therapeutic response and predicting relapse.
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MANAGEMENT OF PEMPHIGUS VULGARIS
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Any patient diagnosed with PV or pemphigoid should undergo an ophthalmological examination to determine if there is ocular disease. Both of these diseases can result in severe corneal desquamation and conjunctival adhesions, or symblepharon, between bulbar and palpebral conjunctivae, thus causing functional blindness (Figure 4). The patient also should be evaluated for the presence of skin lesions by a dermatologist.
Systemic corticosteroids are the first line of therapy for treatment of PV.2,21–23 When prednisone was introduced for the treatment of PV, doses often were excessive (more than 200 milligrams per day) and were associated with considerable morbidity. Lower doses (0.5 to 1 mg per kilogram of body weight) subsequently proved to be very effective and were associated with considerably less morbidity. Nonetheless, prednisone should be prescribed only by clinicians who have experience in monitoring and managing steroid-related complications. Most patients with PV receive a second immunosuppressant drug to achieve a complete remission.24–27 The most common drug combination is prednisone with either azathioprine or cyclophosphamide. These drugs not only provide additional immunoregulatory benefit, leading to complete remission, but also have steroid-sparing properties that allow the dose of prednisone to be reduced significantly. More recently, mycophenolate mofetil has been shown to allow significant prednisone dose reduction and complete remission with fewer side effects.28
With early diagnosis and aggressive treatment, between 50 and 80 percent of patients with PV achieve complete remission. However, even patients who achieve complete remission often have detectable circulating pemphigus autoantibodies that require the use of low-dose or alternate-day maintenance therapy to prevent relapse.
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SUMMARY
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This article illustrates the common oral presentation of PV and the vital role of the dentist in its early detection, which leads to earlier treatment and improved treatment outcome. PV usually is diagnosed in a patient’s fifth to seventh decade of life and most often affects the buccal mucosa and gingivae, though it can occur at any intraoral site. PV should be considered in the differential diagnosis whenever there is a history of multiple, chronic, nonhealing ulcerations that begin as a blister or bulla. Definitive diagnosis is achieved by histologic inspection of perilesional and lesional tissue, using both routine H and E stains (to detect suprabasilar clefting and epithelial acantholysis), as well as direct immunofluorescent stains directed against IgG.
High-dose topical corticosteroid ointments may control limited oral disease. In most cases, however, disease control or remission is achieved using systemic corticosteroid alone or in combination with immunomodulating medications. Several approaches are available to minimize the side effects of long-term corticosteroid use, including alternate-day dosing and combination therapy with steroid-sparing medications. Systemic corticosteroids should be prescribed only by clinicians trained in and familiar with their use.
The most important aspect of PV is its early recognition, diagnosis and treatment. The dentist has a unique opportunity to make the diagnosis and then refer the patient to a dental or medical specialist for treatment.
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FOOTNOTES
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Dr. Sirois is an associate professor and the chairman, Department of Oral Medicine, Division of Basic Sciences, Medicine and Surgery, College of Dentistry, New York University, 345 E. 24th St., New York, N.Y. 10010-4086. Address reprint requests to Dr. Sirois.
Dr. Leigh is an assistant professor, Department of General Dentistry, Louisiana State University, Dental School, New Orleans.
Dr. Sollecito is an assistant professor, Department of Oral Medicine, University of Pennsylvania, School of Dental Medicine, Philadelphia.
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ABSTRACT
SUBJECTS AND CASE DESCRIPTIONS
