Major aphthous-like ulcers in patients with AIDS Joan A. Phelan, DDS,n Sidney Eisig, DDS,b Paul D. Freedman, DDS,c Nadine Newsome, DDS,d and Robert S. Klein, MD,e New York, Bronx, and Flushing, ALBERT EINSTEIN COLLEGE OF MEDICINE/MONTEFIORE MEMORIAL MEDICAL CENTER This report

describes

persistent,

painful

oral ulcers

that occurred

MEDICAL

N.Y.

CENTER, AND BOOTH

in nine patients

with the acquired

irnmunodeficiency syndrome (AIDS). These ulcers resembled major aphthous ulcers in clinical appearance and response to therapy. They occurred less frequently in patients with AIDS than those caused by herpes simplex and were found in 4 of 346 (1.1 O/O) patients with AIDS at one medical center. Lesions were typically painful. Identification and treatment with topical tetracycline and steroids led to resolution with relief of symptoms. Further study is necessary to understand the etiology and pathogenesis of these ulcers. (ORAL SURC ORAL MED ORAL PATHOL 1991;71:68-72)

M

ost oral ulcers that occur in patients with acquired immunodeficiency syndrome (AIDS) are due to herpes simplex virus infection.’ Oral ulcers caused by other microorganisms, including Mycobacterium avium-intracellulare, cytomegalovirus, Cryptococcus neoformans, Klebsiella pneumoniae, and Enterobacter cloacae, have also been reported in such patients. l-6 Lymphoma also may present as an ulcerating oral lesion6 Early in our experience with oral lesions in patients with AIDS, we noted the occasional occurrence of deep, persistent, painful ulcers from which we were unable to isolate any virus; they did not respond to acyclovir, and no cause was identifiable on biopsy and microscopic examination. The clinical appearance and persistence of these ulcers resembled major aphthous ulcers. Major aphthous ulcers have been described as large painful ulcers (> 1 cm in diameter), usually 1 to 10 in number, occurring on the labial and

aAssociate Professor, School of Dental and Oral Surgery, Columbia University College of Physicians and Surgeons, New York. bAssistant Professor, Department of Dentistry/Division of Oral and Maxillofacial Surgery, Albert Einstein College of Medicine/ Montefiore Medical Center, Bronx. CAttending, Department of Dentistry, Division of Oral Pathology, Booth Memorial Medical Center, Flushing. dAssistant Attending, Department of Dentistry, Montefiore Medical Center, Bronx. eAssociate Professor, Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx. 7/14/25500

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buccal mucosa, tongue, soft palate, and fauces. They may persist for up to 6 weeks and generally heal with scarring.’ The etiology of major aphthous ulcers has been unclear. Topical tetracycline has been used with some success in the treatment of major aphthous ulcers.‘, 8 Both topical and systemic steroids have also been recommended as treatment.8, 9 Major aphthous ulcers are rare. None of the reports of major aphthous ulcers include prevalence data. Prevalence studies of minor aphthous ulcers have been reported. The lowest rates (5% to 17%) have been reported in “indigent hospital patients” and in patients in a general medical practice.iO The highest rates (up to 60%) have been reported in professional school students.10-‘2 Aphthous ulcers have been reported in association with human immunodeficiency virus (HIV) infection and AIDS. Silverman et al.,r3 in their study of oral findings in homosexual men at risk for AIDS, grouped aphthae and erythema multiforme together. They reported a prevalence of 10% occurring in those who were healthy, 14% in those who were had AIDSrelated complex, and 7% in those in whom AIDS had been diagnosed. Barr et al.,i4 in their study of HIVassociated oral lesions, reported four aphthous ulcers occurring among 10 1 HIV-seropositive homosexual and bisexual men (4% prevalence) and no aphthous ulcers occurring among 34 HIV-seronegative homosexual and bisexual men. Bach et al.t5 described three patients with AIDS in whom large ulcers similar to aphthous ulcers developed in the oral cavity and responded to systemic steroid treatment; Gorin et al.16

Major aphthous ulcers in AIDS

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Fig. 1. Major cosa.

aphthous-like

ulcer on lower labial mu-

Fig. 2. Major tongue.

aphthous-like

ulcer on lateral

Fig.

Fig. border

3. Major

4. Major

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aphthous-like

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ulcer on buccal mucosa.

ulcer on soft palate.

of

also described in HIV-seropositive patients similar oral/pharyngeal ulcers, which were treated with and responded to thalidomide. We report an additional nine cases of AIDS with persistent oral ulcers, the characteristics of the patients, the prevalence of this finding among a group of patients with AIDS at one medical center, and our experience with the management of this condition. METHODS

Patients with AIDS who had oral ulcers persisting for more than a month, for which no infectious etiology was identified either by viral culture or by biopsy and histologic examination, were included in this study. All patients met the Centers for Disease Control surveillance definition for the diagnosis of AIDS.“, I8 Patients were either identified by the interdisciplinary AIDS team at Montefiore Medical Center or referred from physicians elsewhere for consultation. An oral soft tissue examination was done in all cases. The presence of minor aphthous ulcers was re-

corded together with other findings. Minor aphthous ulcers were defined as painful, round or oval, yellowish white ulcers surrounded by an erythematous halo, less than 1 cm in diameter, that occurred on nonkeratinized mucosa and were present for less than 10 days.6, ’ Viral culture was done in all cases, and biopsy and histopathologic examination in six patients. Electron microscopic examination of the biopsy specimen was done in two cases. Viral culture for seven of the nine patients was done at Montefiore Medical Center. For viral culture the specimen was collected by rubbing a sterile cotton-tipped applicator on the ulcer and inserting the applicator in 4 ml of Hanks balanced salt solution. The specimen was promptly inoculated into duplicate tubes of the following tissue culture host systems: primary African green monkey kidney cells, primary human embryonic kidney cells, human diploid fetal lung cells (Wi-38) and primary rabbit kidney cells. Cultures were incubated at 36.5 o C on roller drums and examined daily for cytopathogenic effect.19 In two cases viral culture had been done and therapy with acyclovir had been unsuccessful before the patients were referred to us. For biopsy and his-

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I. Diagnostic criteria for major aphthous-like ulcers in patients with AIDS

Table

Large (>l cm) painful oral ulcers that have persisted for >I0 days 0 Viral culture negative l No infectious etiology identified by biopsy and histologic examination l Improvement with topical tetracycline application and resolution with topical or systemic steroid treatment l

tologic examination, tissue was fixed in 10% formalin solution and initially stained with hematoxylin and eosin. Special stains for fungal organisms (periodic acid-Schiff or methenamine silver stains), bacteria (Brown-Brenn tissue Gram stain), and mycobacteria (acid-fast bacilli stain) were done subsequently. Tissue for electron microscopic examination was retrieved from paraffin-embedded tissue and examined for viral particles. The ulcers were treated with topical steroid application alone or in combination with topical tetracycline application. Tetracycline liquid, 5 ml (125 mg per 5 ml) four times a day, was administered either by rinsing as long as possible and then expectorating, or by soaking gauze with the liquid and placing it on the ulcers for 10 minutes.9 The topical steroid administered was either fluocinonide ointment mixed in equal parts with carboxymethyl cellulose sodium in plasticized hydrocarbon gel (Orabase) or triamcinolone acetonide (Kenalog) in Orabase. This was applied six times a day. An antifungal medication was usually taken concomitantly to control or prevent oral candidiasis. RESULTS

From among 346 patients with AIDS at Montefiore Medical Center from Nov. 1, 1985, to April 30, 1987, four patients (1.1%) were identified with this type of ulcer. These comprised outpatients and hospitalized patients. The additional five patients were referred for dental consultation from other sources. Of the nine patients, three were homosexual or bisexual men, and five were heterosexual (three male and one female intravenous drug users; one Haitian male). The risk behavior for one was not determined. Three patients had a single large ulcer, and six patients had multiple large ulcers. Four patients had concomitant minor aphthous ulcers. A total of 20 ulcers occurring in these nine patients met the criteria for major aphthous ulcers. Nine occurred on the buccal mucosa, seven on the tongue, two on the labial mucosa, one on the soft palate, and one on the lateral oropharynx (trigone area). Figs. 1 to 4 illustrate the ulcers in four different patients. All ulcers were deep and painful. When they occurred on the buccal mucosa, the ulcers were us-

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ually deeply penetrating and often stellate at the mucosal surface (Fig. 3). The ulcers had been present before the initial examination by one of us for 4 weeks in two patients, 5 to 14 weeks in six patients, and 4 months in one patient. The response of these ulcers to treatment was similar to that reported for major aphthae. Two ulcers (20%) completely resolved after biopsy without any treatment. Eight ulcers (40%) completely resolved with the application of a combination of topical tetracycline and topical steroid. Three ulcers had improved in patients who were subsequently lost to follow-up. In one patient who had three ulcers, two resolved and one on the lateral aspect of the tongue persisted after the two other ulcers resolved. This ulcer resolved shortly after the patient began taking diazepam before retiring to bed. In a single patient the lesions were treated by topical steroid alone. Two of the four ulcers in this patient completely resolved, and two became smaller and asymptomatic. The patient did not return for follow-up examination. One patient seen early in our experience had two ulcers. The ulcers, which were not treated, persisted until his death 6 months later. DISCUSSION

The pathogenesis of aphthous ulceration is not clear. It has been suggested that changes in cellmediated immunity, including autoimmunity, are involved in their development.20-26 However, most of the studies of the pathogenesis of aphthous ulcers have been of minor aphthae. Few studies of major aphthae have been reported, perhaps because these ulcers are uncommon. No studies of major aphthous ulceration have included prevalence data. Therefore it is not yet possible to compare the prevalence rates of major aphthous ulcers occurring in patients with AIDS and HIV infection with any previously reported data. The ulcers described in this study resemble major aphthous ulcers in clinical appearance and biologic behavior. We were unable to identify any etiologic agent. Rabeneck et a1.27 reported esophageal ulcers that contained enveloped viruslike particles morphologically consistent with retroviruses. We found no evidence of retrovirus on electron microscopic examination of tissue from the two ulcers studied. Because the pathogenesis of these ulcers is not understood, the mechanism of the action of drugs that appear to be effective in treatment is also poorly understood and treatment is empiric, based on reported successes.It should be noted that although most of the ulcers in our patients responded to medical therapy, two resolved spontaneously after biopsy. In the absence of a controlled trial, the response of the ulcers in this report to therapy must remain presumptive. It has been suggested that the antibacterial effect of

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tetracycline may be the reason for its effectiveness.28 However, in addition to the -antibacterial effect, the reported inhibition of collagenase activity by tetracycline may play some role in the apparent response of these ulcers to such treatment. The apparent effectiveness of topical and systemic steroids supports the possible importance of immune mechanisms in the pathogenesis of these ulcers. On the basis of our evaluation of the patients in this study, we propose diagnostic criteria for major aphthous-like ulcers in patients with AIDS (Table I). Although all patients included in this study met the surveillance criteria for the diagnosis of AIDS, we have also seen these ulcers in three additional patients who were HIV seropositive but in whom AIDS had not yet developed. In one patient major aphthous-like ulceration was the initial clinical problem recognized. Because these ulcers are so uncommon, their recognition in persons at risk for AIDS should prompt consideration of HIV infection. Further study will be necessary to determine whether these lesions may be suggestive of HIV infection to the degree seen with unexplained oral candidiasis29 or hairy leukoplakia.30 The management of ulcers in patients with HIV infection and AIDS should include viral culture for herpes simplex infection, and biopsy and histologic examination, including fungal, bacterial, and mycobacterial staining. Improvement of ulcers on administration of topical tetracycline is consistent with the behavior of major aphthous ulcers. Therefore if biopsy is not possible, initial treatment with topical tetracycline is recommended after herpes simplex infection as been excluded. In this study, although pain relief was obtained shortly after initiation of treatment with topical tetracycline alone, no ulcers completely resolved, suggesting that topical steroids should be used when improvement occurs. Treatment with topical steroids alone has been effective but should be avoided before other conditions are excluded. In addition, antifungal medication for oral candidiasis may be necessary. In conclusion, persistent, painful ulcers resembling major aphthous ulcers occur in a small proportion of patients with AIDS. These ulcers are painful and respond to treatment, and therefore identification and treatment will likely improve the quality of life for such patients. Further study is necessary to identify the etiology and pathogenesis of these ulcers. Whether these ulcers are unique to HIV infection or the same as major aphthous ulcers, which occur in patients who are not infected with HIV, remains to be determined. REFERENCES

1. Phelan JA, Saltzman BR, Friedland GH, Klein RS. Oral findings in patients with acquired immunodeficiency syndrome. ORAL SURG ORAL MED ORAL PATHOL 1987;64:50-6.

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2. Volpe F, Schwimmer A, Barr C. Oral manifestation of disseminated Mycobacterium avium intracellulare in a patients with AIDS. ORAL SURG ORAL MED ORAL PATHOL 1985;60:567-70.

3. Kanas RJ, Jensen JL, Abrams AM. Oral mucosal cytomegalovirus as a manifestation of the acquired immunodeficiency syndrome. ORAL SURG ORAL MED ORAL PATHOL 1987;64: 183-9.

4. Lynch DP, Naftolin LZ. Oral Cryptococcus neoformans infection in AIDS. ORAL SURG ORAL MED ORAL PATHOL 1987;64:449-53.

5. Glick M, Cohen SG, Cheney RT, Crooks GW, Greenberg MS. Oral manifestations of disseminated Cryprococcns neoformans in a patient with acquired immunodeficiency syndrome. ORAL SURG ORAL

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1987;64:454-9.

6. Greenspan D, Greenspan JS, Pindborg JJ, Schiodt M. AIDS and the dental team. Copenhagen: Munksgaard, 1986:35-75. 7. Shafer WG, Hine MK, Levy BM. A textbook of oral pathology. Philadelphia: WB Saunders, 1983:368-73. 8. Greenberg MS. Ulcerative, vesicular and bullous lesions. In: Lynch MA, Brightman VJ, Greenberg MS, eds. Burket’s oral medicine: diagnosis and treatment. Philadelphia: JB Lippincott, 1984:182-5. 9. Bottomley WK, Rosenberg SW, eds. Clinician’s guide to treatment of common oral conditions. American Academy of Oral Medicine, 1987:6-7. 10. Ship II. Epidemiologic aspects of recurrent aphthous ulcerations. ORAL SURG ORAL MED ORAL PATHOL 1972;33:400-6. 11. Miller MF, Ship II, Ram C. A retrospective study of the prevalence and incidence of recurrent aphthous ulcers in a professional population. ORAL SURG ORAL MED ORAL PATHOL 1977;43:532-7. 12. Eversole LR, Shopper TP, Chambers DW. Effects of suspected foodstuff challenging agents in the etiology of recurrent aphthous stomatitis. ORAL SURG ORAL MED ORAL PATHOL 1982;34:33-8. 13. Silverman S Jr, Migliorati CA, Lozada-Nur F, Greenspan D, Conant MA. Oral findings in neoole with or at hinh risk for AIDS: a study of 375 himosexuai males. J Am Dent Assoc 1986;112:187-92. 14. Barr C, Croxson T, Dobles A, Miller L, Anderson M, Khan M. HIV-associated oral lesions: immunologic and salivary parameters [Abstract 14431. J Dent Res 1990;69:289. - 15. Bach MC. Valente AJ. Howell DA. Smith TJ. Odvnonhania from aphthous ulcers of the pharynx and esophagusin ;he acquired immunodeticiency syndrome (AIDS). Ann Intern Med 1988;109:338-9. 16. Gorin I, Vilette B, Gehanno P, Escande JP. Thalidomide in hyperalgic pharyngeal ulceration of AIDS [Letter]. Lancet 1990;335:1343. 17. Centers for Disease Control. Update on acquired immune deficiencysyndrome (AIDS)-United States. MMWR 1982;31: 507-14. 18. Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR 1987;36(1S):3S9S. 19. Spigland I, Fox JP, Elveback LP, et al. The virus watch program: a continuing surveillance of viral infections in metropolitan New York families. II. Laboratory methods and preliminary report on infections revealed by virus isolation. Am J Epidemiol 1966;83:413-35. 20. Roitt IM, Lehner T. Immunology of oral disease. London: Blackwell Scientific Publications. 1980:368-73. 21. Greenspan JS, Gadol N, Olson JA, Talal N. Antibody-dependent cellular cytotoxicity in recurrent aphthous ulceration. Clin Exp Immunol 1981;44:603-10. 22. Malmstrom M, Salo OP, Fyhrquist F. Immunogenic markers and immune response in patients with recurrent oral ulceration. Int J Oral Surg 1983;12:23-30. 23. Greenspan JS, Shilitoe EJ. Microbial pathogenicity in oral soft tissue diseases. J Dent Res 1984;63:431-4. 24. Gadol N. Greenspan JS, Hoover CI, Olson JA. Leukocyte migration inhibition in recurrent aphthous ulceration. J Oral Path01 1985;14:121-32.

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January 199 1 25. Greenspan JS, Gadol N, Olson JA, et al. Lymphocyte function in recurrent aphthous ulceration. J Oral Path01 1985;14:592602. 26.

Graykowski EA, Kingman A. Double-blind trail of tetracycline in recurrent aphthous ulceration. J Oral Pathol 1978; 7~316-82.

Rabeneck L, Boyko WJ, McLean DM, McLeod WA, Wong K. Unusual esophageal ulcers containing enveloped virus-like particles in homosexual men. Gastroenterology 1989;90:1882-9. 28. Golub LM, Wolff M, Lee HM, et al. Further evidence that tetracycline inhibit collagenase activity in human crevicular fluid and from other mammalian sources. J Periodont Res 1985;20:12-23. 29. Klein RS, Harris CA, Small CB, Moll B, Lesser M, Friedland 27.

GH. Oral candidiasis in high-risk patients as the initial manifestation of the acquired immunodeficiency syndrome. N Engl J Med 1984;311:354-8. 30. Greenspan D, Greenspan JS, Hearst N, et al. Relation of oral hairy leukoplakia to infection with the human immunodeficiency virus and the risk of developing AIDS. J Infect Dis 1987;155:475-81. Reprint

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Joan A. Phelan, DDS Department of Oral Medicine and Pathology New York University College of Dentistry 345 E. 24th St. New York, NY 10010

Major aphthous-like ulcers in patients with AIDS.

This report describes persistent, painful oral ulcers that occurred in nine patients with the acquired immunodeficiency syndrome (AIDS). These ulcers ...
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