ORAL PEMPHIGUS VULGARIS PRECEDING CUTANEOUS LESIONS

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ARTICLE 2

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.; THOMAS P. SOLLECITO, D.M.D.

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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

Pemphigus vulgaris, or PV, is a mucocuta-

neous 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

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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.

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 fluidfilled 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 com-

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CLINICAL PRACTICE

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).

promised 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. 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

Figure 2. Hematoxylin-and-eosin–stained section revealing acantholysis, mononuclear infiltrate and suprabasilar separation.

intraepithelial clefts, or bullae; acantholysis, or separation of the epithelial cells; and a dense mononuclear lymphocytic infiltration (Figure 2). Direct im-

munofluorescent staining of specially preserved tissue reveals the characteristic “spiderweb” distribution of reaction product, or autoantibody, be-

TABLE

CHARACTERISTICS OF ORAL PEMPHIGUS VULGARIS LESIONS. CHARACTERISTIC

NUMBER (%) OF PATIENTS WITH CHARACTERISTIC

Location of Lesion Buccal mucosa

18 (43)

Gingiva

13 (31)

Multiple sites

6 (14)

Tongue

2 (5)

Palate

3 (7)

Floor of mouth

0

Skin

0

Color* White Red Mixed red and white

11 (26) 8 (19) 18 (43)

Appearance† Ulcer Raised lesion

29 (69) 2 (5)

* Five patients (12 percent) gave no response. † Eleven patients (26 percent) gave no response.

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CLINICAL PRACTICE

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diagnostic oral pathology service of the Temple University School of Dentistry, Philadelphia, to identify subjects for this retrospective study. We examined both C the biopsy request form subFigure 3. A variety of clinical presentations of oral pemphigus vulgaris, which generally appears in the mitted by the form of shallow, irregular nonspecific ulcers. A. The treating doctor palate. B. The buccal mucosa. C. The gingivae. and the corretween the epithelial cells (Figure sponding pathology report. From these records, we obtained 1). A simple smear taken from a patient demographic data and new lesion also can be used to information regarding the identify acantholytic cells, called appearance, location and diagTzanck cells, which are indicanostic impression, as well as the tive of PV. Tzanck cells, howevdefinitive diagnosis based on er, also can be found in diseases histopathologic findings. such as herpes simplex, carcinoThirty patients were female ma and transient acantholytic (71 percent) and 12 were male dermatosis; therefore, they are (ratio 2.5:1). The mean age not diagnostic. In the following summary of at time of diagnosis was biopsy specimens submitted to 56.1 ± standard deviation of 14.9 an oral pathology biopsy service years (the range was 27 to 68 by dentists, we describe clinical years). The preponderance (81 features of, diagnostic imprespercent) of the patients were sions of and histologic findings white; 11.9 percent were Asian, in 42 cases of oral PV. and 7.1 percent were black. The buccal mucosa and gingivae are SUBJECTS AND CASE the most common sites of oral DESCRIPTIONS PV; the table shows the distribuWe reviewed records from the tion of oral PV lesions among 1158

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. DISCUSSION

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 ero-

JADA, Vol. 131, August 2000 Copyright ©1998-2001 American Dental Association. All rights reserved.

CLINICAL PRACTICE ferred sample for biopsy is a perilesional sample, which contains normal epithelium, as well as tissue from the area of ulceration. Although Figure 4. A corneal erosion due to pemphigus the efficacy vulgaris. of H and E sive lichen planus. A history of staining alone (no immunofluorescence) in diagnosing PV trauma-induced bullae and a is probably greater than 90 positive Nikolsky’s sign will percent, direct immunofluohelp narrow the differential rescent staining is performed diagnosis. The presence of mulin most instances to detect tiple lesions is not typical in autoantibodies in the tissue malignancy, and the chronicity where the disease arises. When excludes more common causes this technique is used, special of intraoral ulceration such as preservative medium is essenherpes simplex, aphthous stomatitis and erythema multi- tial (Michel’s solution); fixation in formalin will destroy antiforme. However narrow the gen proteins and render direct differential diagnosis may be, immunofluorescent examinaa definitive diagnosis is possible only with microscopic tion useless. Indirect immunoexamination. fluorescence can be used to When the choice is made to detect circulating autoantibodperform a diagnostic biopsy for ies in the blood—which it does any of the bullous diseases, the in approximately 80 percent of specimen must contain epithepatients with PV. A negative lium; a sample solely from the result, however, does not ulcer or erosion center will be exclude a diagnosis of PV. of little diagnostic value. The While monitoring the circulatreason is simple: the target ing pemphigus autoantibody antigen, desmoglein 3, is found titers via indirect immunofluoin the intraepithelial, suprarescence is not an essential basilar tissue. Without the part of the diagnosis of PV, it epithelium, the antigen cannot is useful in assessing therapeube identified using direct tic response and predicting immunofluorescence techrelapse. niques (Figure 1). Even secMANAGEMENT OF tions that undergo routine PEMPHIGUS VULGARIS H and E staining must contain Any patient diagnosed with PV epithelium for the clinician to or pemphigoid should undergo identify areas of epithelial sepan ophthalmological examinaaration (acantholysis) and tion to determine if there is other cytopathologic features ocular disease. Both of these (Figure 2). Therefore, the pre-

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 steroidrelated 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 pa-

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CLINICAL PRACTICE tients who achieve complete remission often have detectable circulating pemphigus autoantibodies that require the use of low-dose or alternateday maintenance therapy to prevent relapse. SUMMARY

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 corti-

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costeroids 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. ■ 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. 1. Lever WF. Pemphigus and pemphigoid. Springfield, Ill.: Charles C. Thomas; 1965. 2. Fine JD. Management of acquired bullous skin diseases. N Engl J Med 1995; 333(22):1475-84. 3. Bastuji-Garin S, Souissi R, Blum L, et al. Comparative epidemiology of pemphigus in Tunisia and France: unusual incidence of pemphigus foliaceus in young Tunisian women. J Invest Dermatol 1995;104(2):302-5. 4. Kyriakis K, Tosca A, Lehou J, Hatzis J, Vareltzidis A, Sratigos J. A five-year retrospective study on pemphigus and pemphigoid. Australas J Dermatol 1989;30(1):33-6. 5. Shoda Y, Hashimoto K, Matsuoka Y, Yoshikawa K. A case of pemphigus in a sixyear-old girl. J Dermatol 1991;18(3):175-7. 6. Kanwar AJ, Kaur S. Pemphigus in children. Int J Dermatol 1991;30(5):343-6. 7. Simon DG, Krutchkoff D, Kaslow RA, Zarbo R. Pemphigus in Hartford County, Connecticut, from 1972 to 1977. Arch Dermatol 1980;116(9):1035-7. 8. Rosenberg FR, Sanders S, Nelson CT. Pemphigus: a 20-year review of 107 patients treated with corticosteroids. Arch Dermatol 1976;112(7):962-70. 9. Eversole LR, Kenney EB, Sabes WR. Oral lesions as the initial sign in pemphigus vulgaris. Oral Surg Oral Med Oral Pathol 1972;33(3):354-61. 10. Lamey PJ, Rees TD, Binnie WH, Wright JM, Rankin KV, Simpson NB. Oral presentation of pemphigus vulgaris and its response to systemic steroid therapy. Oral Surg Oral Med Oral Pathol 1992;74(1):54-7. 11. Robinson JC, Lozada-Nur F, Frieden I.

Oral pemphigus vulgaris: a review of the literature and a report on the management of 12 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84(4):349-55. 12. Pisanti S, Sharav Y, Kaufman E, Posner LN. Pemhigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion. Oral Surg Oral Med Oral Pathol 1974;38(3):382-7. 13. Sirois DA, Fatahzadeh M, Roth R, Ettlin D. Diagnostic patterns and delays in pemphigus vulgaris: experience from 99 patients. Arch Dermatol (in press). 14. Korman NJ. Pemphigus. Dermatol Clin 1990;8(4):689-700. 15. Eversole LR. Immunopathology of oral mucosal ulcerative, desquamative, and bullous diseases. Oral Surg Oral Med Oral Pathol 1994;77(6):555-71. 16. Calvanico NJ, Robledo MA, Diaz LA. Immunopathology of pemphigus. J Autoimmun 1991;4(1):3-16. 17. Fitzpatrick RE, Newcomer VD. The correlation of disease activity and antibody titers in pemphigus. Arch Dermatol 1980;116(3): 285-90. 18. Siegel MA, Balciunas BA, Kelly M, Serio FG. Diagnosis and management of commonly occurring oral vesiculoerosive disorders. Cutis 1991;47(1):39-43. 19. Nisengard RJ, Neiders M. Desquamative lesions of the gingiva. J Periodontol 1981;52(9):500-10. 20. Meurer M, Millns JL, Rogers RS 3d, Jordan RE. Oral pemphigus vulgaris: a report of ten cases. Arch Dermatol 1977;113(11): 1520-4. 21. Mourellou O, Chaidemenos CG, Koussidou T, Kapetis E. The treatment of pemphigus vulgaris: experience with 48 patients seen over an 11-year period. Br J Dermatol 1995;133(1):83-7. 22. Lamey PJ, Rees TD, Binnie WH, Wright JM, Rankin KV, Simpson NB. Oral presentation of pemphigus vulgaris and its response to systemic steroid therapy. Oral Surg Oral Med Oral Pathol 1992;74(1):54-7. 23. Mashkilleyson N, Mashkilleyson AL. Mucous membrane manifestations of pemphigus vulgaris: a 25-year survey of 185 patients treated with corticosteroids or with combination of corticosteroids with methotrexate or heparin. Acta Derm Venereol 1988;68(5): 413-21. 24. Bystryn JC. Adjuvant therapy of pemphigus. Arch Dermatol 1984;120(7):941-51. 25. Chryssomallis F, Dimitriades A, Chaidemenos GC, Panagiotides D, Karakatsanis G. Steroid-pulse therapy in pemphigus vulgaris: long term follow up. Int J Dermatol 1995;34(6):438-42. 26. Aberer W, Wolff-Schreiner EC, Stingl G, Wolff K. Azathioprine in the treatment of pemphigus vulgaris: a long-term follow-up. J Am Acad Dermatol 1987;16:527-33. 27. Pandya AG, Sontheimer RD. Treatment of pemphigus vulgaris with pulse intravenous cyclophosphamide. Arch Dermatol 1992; 128(12):1626-30. 28. Enk AH, Knop J. Mycophenolate is effective in the treatment of pemphigus vulgaris. Arch Dermatol 1999;135(1):54-61.

JADA, Vol. 131, August 2000 Copyright ©1998-2001 American Dental Association. All rights reserved.