Pemphigus Vulgaris: Clinicopathologic Review of 33 Cases in the Oral Cavity

Samantha Davenport, MD* Pemphigus vulgaris is an autoim- Sow-Yeh Chen, PhD** mune vesiculobullous disease that Arthur S. Miller, DMD** has potential systemic sequelae and morbidity if not properly man- A retrospective study was conducted on all cases of pemphigus vulgaris occur- aged.1,2 Although primarily recog- ring on oral mucosal surfaces in the files of the Oral Pathology Laboratory at nized as a skin disease, lesions also Temple University from 1974 to 1996. A total of 35 biopsies from 33 patients develop on the gingiva, oral mu- were reviewed, 25 female and eight male. Patient ages ranged from 27 to 79 cosa, and other mucosae, such as years; the mean age was 56.5. The most common clinical complaint was of conjunctival and vaginal.3 Oral painful ulcers that failed to resolve within several weeks. Thirty patients had no lesions have been reported as an known history of pemphigus, while in three patients a history of pemphigus was initial manifestation of the disease in known. The most common clinical impression was that of mucous membrane nearly 50% of cases.1 The clinical pemphigoid, but the differential diagnosis included other vesiculoerosive condi- presentation is similar to that of ero- tions. (Int J Periodontics Restorative Dent 2001;21:85–90.) sive lichen planus, benign mucous membrane pemphigoid (BMMP), erythema multiforme, major aph- thous ulcers, erythema migrans, and nonspecific or drug-induced oral ulcerations.1 It is reported to occur with equal frequency in males and females, and although earlier reported as more common in Jewish and Mediterranean populations, it affects all population groups. The diagnosis depends on biopsy con- **Pathology Resident, Temple University Hospital, Department of Pathology and Laboratory Medicine, Philadelphia. firmation of intraepithelial vesicle **Professor, Department of Pathology and Laboratory Medicine, Temple formation, acantholysis, and the University School of Medicine, Philadelphia. presence of Tzanck cells. Direct immunofluorescence examination **Reprint requests: Dr Sow-Yeh Chen, Temple University Hospital, Department of Pathology and Laboratory Medicine, 3401 North Broad of fresh lesional tissue will demon- Street, Philadelphia, Pennsylvania 19140. strate IgG or IgM and complement

COPYRIGHT © 2000 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING Volume 21, Number 1, 2001 OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NOPARTOF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITH- OUT WRITTEN PERMISSION FROM THE PUBLISHER. 2

Table 1 Clinical features of 33 cases of oral pemphigus

Age (y) Sex Race Site Color Pain Ulceration Miscellaneous 47 F Asian Mandibular vestibule Red Yes No 72 F White Tonsillar pillar Red Yes Yes 36 F Asian Mandibular vestibule Red Yes Yes 55 M White Mandibular vestibule White Yes Yes 44 M White Buccal mucosa Red Yes Yes 77 F White Buccal mucosa White and red Yes Yes 46 M White Entire oral mucosa White Yes Yes Other sites 32 F White Entire oral mucosa Not indicated Yes Yes 46 F Hispanic Entire oral mucosa Red Yes Yes Prior history 52 F African-American Buccal gingiva White and red No Yes Prior history 39 F White Buccal mucosa White and red Yes Yes Nikolsky sign 70 F White Buccal mucosa White No No 78 F White Maxillary ridge White and red Yes No 69 F White Buccal mucosa Red Yes Yes 64 F White Mandibular vestibule White No Yes 50 M White Entire oral mucosa White Yes Yes 41 F White Anterior alveolar ridge Red Yes Yes 66 F White Lateral tongue Red Yes Yes 72 F White Lateral tongue Red Yes Yes 56 F Hispanic Buccal gingiva Red Yes Yes 27 F White Soft palate Red No No 61 M White Mandibular vestibule Red No Yes 69 F Asian Entire oral mucosa Not indicated No Yes Nikolsky sign 58 F White Site not specified White and red No No 55 F White Hard palate White and red No No 64 M White Buccal mucosa White No No 66 F White Entire oral mucosa Not indicated Yes Yes 68 F White Buccal mucosa White and red Yes Yes 36 F White Mandibular vestibule White Yes Yes 69 M White Buccal mucosa White Yes No Prior history 42 F White Mandibular vestibule White and red Yes Yes 59 M White Mandibular ridge White Yes No Nikolsky sign 79 F White Ventral tongue White Yes No

components in the epithelial inter- Method and materials each case was reviewed, and data on cellular spaces.4,5 the age, sex, and clinical presenta- The purpose of this study was a All cases accessioned as pemphigus tion for each patient were recorded clinicopathologic review of cases vulgaris of the gingiva and oral (Table 1). Submitted clinical infor- accessioned in the Oral Pathology mucosa were identified and re- mation was carefully examined to Laboratory at Temple University as trieved from the files of the Oral determine those cases in which a pemphigus vulgaris between 1974 Pathology Laboratory, Temple prior diagnosis of pemphigus vul- and 1996 to assess the clinical para- University School of Medicine for the garis had been established. All slides meters of pemphigus that primarily period encompassing January 1974 were reviewed by the authors to con- involves the gingiva and oral mucosa. to May 1996. The clinical history of firm the diagnosis.

The International Journal of Periodontics & Restorative Dentistry COPYRIGHT © 2000 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NOPARTOF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITH- OUT WRITTEN PERMISSION FROM THE PUBLISHER. 3

Fig 1 Collapsed bulla of pemphigus vulgaris in the anterior Fig 2 Nonhealing ulcer of pemphigus vulgaris, maxillary mandibular vestibule. tuberosity–hard palate area.

Results started in the oropharynx and rapidly initial diagnosis of pemphigus was extended to the entire mouth. The made following an intraoral biopsy. Thirty-five specimens were identi- ulcers were so extensive in 4 weeks Microscopic examination of tis- fied from 33 patients. Most patients that the patient could not eat or sue samples revealed one of three were in the fifth and sixth decades of drink and was dehydrated and patterns: suprabasilar vesicle forma- life (Table 1). Their ages ranged from admitted to an emergency room. tion, a collapsed bulla, or an eroded 27 to 79 years, with a mean age of Two patients had vesicular skin lesion in which the basal cells re- 56.5. Twenty-five patients were lesions, one of whom had a known mained attached to the connective women and eight were men. The history of pemphigus. In three cases, tissue (Figs 3 and 4). In those lesions majority of the patients were Cau- presence of the Nikolsky sign on oral in which the epithelium remained casian, reflecting the population mucosa was reported by the clini- attached, acantholysis of squamous demographics in eastern Pennsyl- cian. The most common clinical im- cells was noted, along with occa- vania and southern New Jersey, but pression, as recorded by the dentist sional Tzanck cells (Fig 5). In two cases included a small percentage of or surgeon who was managing the cases, direct immunofluorescence African-Americans, Asians, and patient, was that of benign mucous had been performed on fresh tissue Hispanics as well. The most com- membrane pemphigoid followed by with positive results for IgG and IgM. mon clinical complaint was that of erosive lichen planus. In three None of the 33 patients were af- painful ulcers that failed to resolve in patients, a history of pemphigus vul- fected by lymphoma or leukemia, several weeks (Figs 1 and 2). In one garis was known, but, significantly, in which would suggest paraneoplastic patient, the vesiculoulcerative lesion 30 of the 33 patients in this study, the pemphigus.

Fig 3 (left) Photomicrograph of pemphigus vulgaris shows acantholysis and vesicle formation in oral epithelium. (Original magnification 40; hematoxylin-eosin stain.)

Fig 4 (below left) Photomicrograph of pemphigus vulgaris shows acantholytic epithelial cells within the vesicle. (Original magnification 100; hematoxylin-eosin stain.)

Fig 5 (below) Photomicrograph of pemphigus vulgaris in which the basal cells remain attached to the connective tissue. Single, enlarged acantholytic epithelial cells (Tzanck cells) are visible. (Original magnification 400; hematoxylin-eosin stain.)

Discussion may be indistinguishable from those Pemphigus is considered to be of lichen planus and pemphigoid. In primarily a dermatologic disorder. The age profile of the patients in this fact, the most common initial clinical However, in the series of our study, study coincides with data in the lit- impression of the pemphigus cases only one patient had a history of pre- erature; most patients were in the in this study was pemphigoid. Be- vious skin lesions and another one fifth and sixth decades of life.1,2 cause the clinical features are quite had skin involvement concurrent with Previous reports indicate that pem- similar for pemphigus, lichen planus, oral lesions. All 31 other cases had phigus vulgaris affects both men and and pemphigoid, the clinical differ- oral lesions alone. From this study, it women equally; however, results of ential diagnosis for vesiculoulcera- is clear that pemphigus can primar- this study revealed a 3:1 female:male tive lesions should include pemphi- ily involve the oral mucosa, and early ratio. There also is a female prepon- gus. If the diagnosis of pemphigus is detection of this disease condition derance in other oral vesiculoulcer- confirmed with laboratory proce- can be performed by the dentist. ative conditions such as lichen dures, the patient can be properly Pemphigus is an autoimmune planus and benign mucous mem- treated at an early stage of the dis- disease in which autoantibodies brane pemphigoid. Clinical features ease process and serious sequelae affect the intercellular bridges of the and the patient profile of pemphigus can be prevented. epithelium.4,5 Recent studies have

shown that these autoantibodies are that antigen-specific therapy for initial site of involvement.1,14 It may directed against the desmoglein pemphigus can be developed, thus remain localized in the mouth for subfamily of cell-adhesion molecules diminishing the need for long-term some months before progressing to in the desmosome.6–8 steroid therapy.6,7 Therefore, it is widespread skin and mucosal distri- Immunofluorescence demon- even more important to establish a bution, including the nose, pharynx, strates a unique pattern of deposi- definitive diagnosis of pemphigus larynx, esophagus, vulva, penis, and tion of immunoreactants in the inter- as early as possible so that early anus. If the condition is left un- cellular spaces of the epithelium. treatment can be instituted. treated, there is steady deteriora- The autoimmune reaction results in It has been shown that pemphi- tion with eventual death, with the destruction of desmosomes (inter- gus can be drug induced.9,10 In the average time being 14 months.14 cellular bridges) and dissociation of cases reviewed, a drug history had One case in the series of our study spinous cells, and hence blister (vesi- not been specifically elicited, and in showed serious sequelae after only cle) formation with floating epithelial no case was it included in the clini- several weeks. The initial lesion of cells, which are called Tzanck cells. cal differential diagnosis. However, it this case started in the oropharynx, Therefore, the blister is intraepithe- is important to consider a drug his- and the entire oral mucosa was so lial and suprabasal. In time, the blis- tory when evaluating the patient severely involved within a short ter will rupture and leave an ulcer- with oral ulcerations for pemphigus; period that the patient could not eat ated, raw surface. any drug possessing an active thiol or drink and became very dehy- The autoantibody-affected yet group in its molecule is considered drated. Therefore, it is important that still normal-appearing epithelium capable of inducing pemphigus.10 dental professionals keep pemphi- adjacent to a vesicle may be pulled Some known offenders include sul- gus in mind when they examine oral apart by minor traction force. This fonamides, penicillins, and anticon- vesiculoulcerative conditions so that phenomenon is called Nikolsky vulsants. It has also been suggested early diagnosis can be made and sign.1 However, Nikolsky sign may that members of the allium botani- proper treatment can be provided to not be a common manifestation in cal family, including onion, leek, and prevent serious sequelae and death. pemphigus, as only three cases garlic, may be contributory in the (10%) in the current study were induction of pemphigus lesions.11 A reported to have Nikolsky sign. careful drug and dietary history Furthermore, Nikolsky sign is also would be useful in the clinical differ- manifested by other vesiculoulcera- ential diagnosis of pemphigus and tive diseases, predominantly pem- other vesiculoulcerative lesions. phigoid. Therefore, the initial clinical Treatment for pemphigus is differential diagnosis of a vesicu- aimed at stopping production of the loulcerative condition with or with- offending autoantibodies.12 Usually, out Nikolsky sign in the oral cavity this is done through the administra- should include pemphigus along tion of moderate doses of oral with pemphigoid, and the final diag- steroids.13 A recent prospective nosis should rely on microscopic study showed that cyclosporine and examination and immunofluores- cyclophosphamide were no more cence procedures. effective than steroids in treating Because of recent development pemphigus, even when used in com- of recombinant proteins that are bination with steroids.12 capable of absorbing the desmo- Pemphigus is often localized in glein autoantibody, it is hoped the mouth, which is frequently the

Acknowledgments 7. Pignatelli M, Vessey CJ. Adhesion molecules: Novel molecular tools in tumor pathology. Hum Pathol 1994;25:849–856. Eleanora Satchell, HT (ASCP) and Joan Blakney provided technical support. Dorothy 8. Amagi M. Adhesion molecules. l:ker- McGahee was responsible for manuscript atinocyte-keratinocyte interactions; cad- processing. herins and pemphigus. Invest Dermatol 1995;104:146–152. 9. Eisenberg E, Ballow M, Wolfe SH, References Krutchkoff DJ, Tanzer JM. Pemphigus- like mucosal lesions: A side effect of peni- cillamine therapy. Oral Surg Oral Med 1. Neville BW, Damm DD, Allen CM, Oral Pathol 1981;51:409–414. Bouquot JE. Oral and Maxillofacial 10. Mutasim DF, Pelc NJ, Anhalt GJ. Drug- Pathology. Philadelphia: WB Saunders, induced pemphigus. Dermatol Clin 1995:559–561. 1993;11:463–471. 2. Barker LR. Principles of Ambulatory 11. Brennen S, Wolf R. Possible nutritional Medicine, ed 4. Baltimore: Williams and factors in induced pemphigus. Wilkins, 1995:1472–1475. Dermatology 1994;189:337–339. 3. Korman NJ. Pemphigus. J Am Acad 12. Chrysomallis F, Ioannides D, Teknetzis A, Dermatol 1998;18:1219–1238. Panagiotidou D, Minas A. Treatment of 4. Calvanico NJ, Robeldo MA, Diaz LA. oral pemphigus vulgaris. Int J Dermatol Immunopathology of pemphigus. J 1994;33:803–807. Autoimmunol 1991;4:3–16. 13. Fine J-D. Management of acquired bul- 5. Eversole LR. Immunopathology of oral lous skin diseases. New Engl J Med mucosal ulcerative, desquamative and 1995;333:1475–1481. bullous diseases. Oral Surg Oral Med Oral 14. Rose LF, Kay D. Internal Medicine for Pathol 1994;77:555–571. Dentistry. St Louis: Mosby, 1983:932–935. 6. Stanley JR. Cell adhesion molecules as targets of autoantibodies in pemphigus and pemphigoid, bullous lesions due to defective epidermal cell adhesion. Immunology 1993;53:291–325.