Brief communications Oral hairy leukoplakia unassociated with human immunodeficiency virus: Pseudo oral hairy leukoplakia David A. Fisher, MD,a Troy E. Daniels, DDS, MS,b and John S. Greenspan, BDS, PhD, FRCPath San Francisco, California Oral hairy leukoplakia (0 HL) was first reported in 1984 by Greenspan et aU Since then it has become widely recognized as a stigma of human immunodeficiency virus (HIV) infection. It most commonly affects the lateral tongue, but it has also been described on the buccal mucosa, floor of the mouth, soft palate, and oropharyruc 2,3 Examination by in situ hybridization and other techniques have identified the presence of EpsteinBarr virus (EBV) in the lesions, but the earlier reports of the presence of human papillomavirus have not been corroborated. 4 , 5 The response of OHL to acyclovir would appear to confirm that it is associated with EBV. 6,7 Green et al. 8 reported 11 patients with the clinical and microscopic features ofOHL who were HIV antibody-negative and whose lesional biopsy tissue was negative for EBV DNA. They named this disorder pseudo hairy leukoplakia. We report a patient with the clinical, microscopic, serologic, and virologic findings of pseudo hairy leukoplakia. CASE REPORT
A 30-year-old white woman had asymptomatic whitish plaques on the buccal and lower lip mucosae and lateral tongue margins for 2 months (Fig. 1). She related that this occurred after a course of cephalexin given in association with back surgery. She had no risk factors for HIV infection and no other medical problems. A potassium hydroxide preparation and a culture on Sabouraud's agar were negative. HIV antibody test was negative. An incisional biopsy specimen stained with hematoxylin and eosin showed many epithelial cells with an enlarged, pale-staining cytoplasm with pyknotic nuclei in vacuoles. There was mild hyperparakeratosis (Fig. 2). In situ hybridization for EBV with the probe for the IRI sequence revealed no signa1. 9 Treatment with oral acyclovir was ineffective. From the University of California Medical Center, San Francisco Department of Dermatology,' and School of Dentistry,b Reprint requests: David A. Fisher, MD, 3701 LoneTree Way, Suite 6, Antioch, CA 94509.
16/54/36085
Fig. 1. Left lateral side of tongue with whitish reticulate hyperkeratoses. Fig. 2. Low power view of labial mucosa biopsy specimen demonstrates epithelial cells with enlarged palestaining cytoplasm and pyknotic in nuclei vacuoles. DISCUSSION Because OHL is a predictor of clinical HIV development in more than 80% of patients within 2lh years, patients with these oral lesions should be tested for HIV antibody. 10 However, a subset of patients with OHL exists who do not have HIV risk factors, test negative for HIV antibody, and whose biopsy specimens are negative for EBV DNA. Ifthe lesions do not demonstrate Candida infection, EBV in situ hybridization studies should be performed.
257
258 Briefcommunications This is recommended because of a possible delay in the appearance of HIV antibody in the serum after infection. 1l In addition, EBV probe positivity may indicate a therapeutic trial of oral acyclovir. 5, 12 As would be anticipated, our patient, who tested negative for EBV, did not improve with acyclovir. Two reports describe 0 HL in HIV-negative renal transplant patients. 13. 14 Epstein et al. 15 described OHL in two patients and Birek et aI.'6 an additional patient after bone marrow transplantation. Reggiani and Pauluzzil? also reported HIV-seronegative liver transplant patients with OHL. These cases indicate that OHL may be a marker for immunosuppression from causes other than HIY. However, neither our patient nor those described by Green et al. 8 had evidence of immunosuppression. The most striking histopathologic feature ofOHL is tpe koilocyte-like epithelial cells described as balloon cells. 2 • 18, 19 This case, along with those presented by Green et al} indicates that these cells are not pathognomonic of HIV-related hairy leukoplakia. In addition, such cells may be observed at times in oral candidiasis and oral parakeratotic leukoplakias. 2 Whether koilocytic cells can occur in the normal mucosa of the lateral border of the tongue or elsewhere in the oral mucosa is unknown. 5 Langerhans cells are reportedly absent in OHL.20, 21 Their presence or absence in pseudo 0 HL was not studied in our patient or in the cases described by Green et al. 8 A negative HIV test and EBV in situ hybridization test in a patient presenting with a clinical and histopathologic finding seems to warrant, at present, designating the process as pseudo OHL and reassuring the patient and clinician that the person does not have HIV or a prodromal sign of HIV. Unfortunately, as of this date, no cause can be tendered, or effective therapy offered, for this mimic of HIVEBV-associated oral and lingual mucosal leukoplakia.
REFERENCES 1. Greenspan D. Greenspan JS, Conant MA, et at Oral "hairy" leukoplakia in male homosexuals: evidence of association with both papillomavirus and a herpes group virus. Lancet 1984;2:831-4. 2. Eversole LR, Jacobsen P, Stone CE, et al. Oral condyloma plana (hairy leukoplakia) among homosexual men: a clinicopathologic study of thirty-six cases. Oral Surg 1986; 61:249-55.
Journal of the American Academy of Dermatology
3. Kabani S, Greenspan D, De Souza Y, et aI. Oral hairy leukoplakia with extensive oral mucosal involvement. Oral Surg Oral Med Oral PathoI1989;67:41 1-5. 4. Lupton GP, James WD, Redfield RR, et aI. Oral hairy leukoplakia: a distinctive marker of human T cell Iymphotrophic virus type III HTLV-III/infection. Arch DermatoI1987;123:624-8. 5. De Souza YG, Greenspan D, Hammer M, et aI. Demonstration of Epstein-Barr virus DNA in the epithelial cells of oral hairy leukoplakia [Abstract]. J Dent Res 1986;65:765. 6. Resnick L. Herbst JS, Ablash DV, et aI. Regression of oral hairy leukoplakia after orally administered acyclovir therapy. JAMA 1988;259:384-8. 7. Greenspan D, De Souza YG, Conant MA, et aI. Efficacy of acyclovir in the treatment of Epstein-Barr virus infection of oral hairy leukoplakia. J Acquir Immune Defic Syndr 1990;3:571-8. 8. Green LL, Greenspan JS, DeSouza YG. Oral lesions mim· icking hairy leukoplakia: a diagnostic dilemma. Oral Surg Oral Med Oral Pathol 1989;67:422-6. 9. Greenspan JS, Greenspan D, Lennette ET, et a1. Replication of Epstein-Barr virus within the cells of oral "hairy" leukoplakia, an AIDS-associated lesion. N Engl J Med 1985;313:1564-71. 10. Greenspan D, Greenspan JS, Hearst NG, et a1. Relation of oral hairy leukoplakia to infection with the human immunodeficiencyvirus and the risk of developing AIDS. J Infect Dis 1987;155:475-81. 11. Horsburgh CR, Jason J, LonginiIM, et al. Duration ofhuman immunodeficiency virus infection before detection of antibody. Lancet 1989;2:637-40. 12. Shofer H, Oschsendorf FR, Helm EB, et al. Treatment of oral "hairy" leukoplakia in AIDS patients with vitamin acid (topically) or acyclovir (systemically). Dermatologica 1987;174:150-1. 13. Itin P, Rufli Th, Rudlinger R, et al. Oral hairy leukoplakia in a HIV-negative renal transplant patient: A marker for immunosuppression? Dermatologica 1988;177:126-8. 14. Greenspan D, Greenspan JS, De Souza YG, et aI. Oral hairy leukoplakia in an HIV-negative renal transplant recipient. J Oral Pathol Med 1989;18:32-4. 15. Epstein JB, Priddy R W, Sherlock CH. Hairy leukoplakialike lesions in immunosuppressed patients following bone marrow transplantation. Transplantation 1988;46:462-4. 16. Birek C, Patterson B, Maximiw WC, et aI. EBV and HSV infections in a patient who had undergone bone marrow transplantation: oral manifestations and diagnosis by in situ nucleic acid hybridization. Oral Surg Oral Moo Oral Pathol ]989;18:28-31. 17. Reggiani M, Pauluzzi P. Hairy leukoplakia in liver transplant patient. Acta Derm Venereal (Stockh) 1990;70:87-8. 18. Belton CM, Eversole LR. Oral hairy leukoplakia: ultrastructural features. J Oral PathoI1986;15:493-9. 19. Schilodt M, Greenspan D, Daniels TE, et aI. Clinical and histologic spectrum of oral hairy leukoplakia. Oral Surg 1987;64:716-20. 20. Daniels TE, Greenspan D, Greenspan JS, et aI. Absence of Langerhans cells in oral hairy leukoplakia, an AIDS-associated lesion. J Invest DermatoI1987;889:178-82. 21. Scuibba J, Brandsma J, Schwartz M, et a1. Hairy leukoplakia: an AIDS-associated opportunistic infection. Oral Surg Oral Moo Oral Pathol 1989;67:404-10.
A 30-year-old white woman had asymptomatic whitish plaques on the buccal and lower lip mucosae and lateral tongue margins for 2 months (Fig. 1). She related that this occurred after a course of cephalexin given in association with back surgery. She had no risk factors for HIV infection and no other medical problems. A potassium hydroxide preparation and a culture on Sabouraud's agar were negative. HIV antibody test was negative. An incisional biopsy specimen stained with hematoxylin and eosin showed many epithelial cells with an enlarged, pale-staining cytoplasm with pyknotic nuclei in vacuoles. There was mild hyperparakeratosis (Fig. 2). In situ hybridization for EBV with the probe for the IRI sequence revealed no signa1. 9 Treatment with oral acyclovir was ineffective. From the University of California Medical Center, San Francisco Department of Dermatology,' and School of Dentistry,b Reprint requests: David A. Fisher, MD, 3701 LoneTree Way, Suite 6, Antioch, CA 94509.
16/54/36085
Fig. 1. Left lateral side of tongue with whitish reticulate hyperkeratoses. Fig. 2. Low power view of labial mucosa biopsy specimen demonstrates epithelial cells with enlarged palestaining cytoplasm and pyknotic in nuclei vacuoles. DISCUSSION Because OHL is a predictor of clinical HIV development in more than 80% of patients within 2lh years, patients with these oral lesions should be tested for HIV antibody. 10 However, a subset of patients with OHL exists who do not have HIV risk factors, test negative for HIV antibody, and whose biopsy specimens are negative for EBV DNA. Ifthe lesions do not demonstrate Candida infection, EBV in situ hybridization studies should be performed.
257
258 Briefcommunications This is recommended because of a possible delay in the appearance of HIV antibody in the serum after infection. 1l In addition, EBV probe positivity may indicate a therapeutic trial of oral acyclovir. 5, 12 As would be anticipated, our patient, who tested negative for EBV, did not improve with acyclovir. Two reports describe 0 HL in HIV-negative renal transplant patients. 13. 14 Epstein et al. 15 described OHL in two patients and Birek et aI.'6 an additional patient after bone marrow transplantation. Reggiani and Pauluzzil? also reported HIV-seronegative liver transplant patients with OHL. These cases indicate that OHL may be a marker for immunosuppression from causes other than HIY. However, neither our patient nor those described by Green et al. 8 had evidence of immunosuppression. The most striking histopathologic feature ofOHL is tpe koilocyte-like epithelial cells described as balloon cells. 2 • 18, 19 This case, along with those presented by Green et al} indicates that these cells are not pathognomonic of HIV-related hairy leukoplakia. In addition, such cells may be observed at times in oral candidiasis and oral parakeratotic leukoplakias. 2 Whether koilocytic cells can occur in the normal mucosa of the lateral border of the tongue or elsewhere in the oral mucosa is unknown. 5 Langerhans cells are reportedly absent in OHL.20, 21 Their presence or absence in pseudo 0 HL was not studied in our patient or in the cases described by Green et al. 8 A negative HIV test and EBV in situ hybridization test in a patient presenting with a clinical and histopathologic finding seems to warrant, at present, designating the process as pseudo OHL and reassuring the patient and clinician that the person does not have HIV or a prodromal sign of HIV. Unfortunately, as of this date, no cause can be tendered, or effective therapy offered, for this mimic of HIVEBV-associated oral and lingual mucosal leukoplakia.
REFERENCES 1. Greenspan D. Greenspan JS, Conant MA, et at Oral "hairy" leukoplakia in male homosexuals: evidence of association with both papillomavirus and a herpes group virus. Lancet 1984;2:831-4. 2. Eversole LR, Jacobsen P, Stone CE, et al. Oral condyloma plana (hairy leukoplakia) among homosexual men: a clinicopathologic study of thirty-six cases. Oral Surg 1986; 61:249-55.
Journal of the American Academy of Dermatology
3. Kabani S, Greenspan D, De Souza Y, et aI. Oral hairy leukoplakia with extensive oral mucosal involvement. Oral Surg Oral Med Oral PathoI1989;67:41 1-5. 4. Lupton GP, James WD, Redfield RR, et aI. Oral hairy leukoplakia: a distinctive marker of human T cell Iymphotrophic virus type III HTLV-III/infection. Arch DermatoI1987;123:624-8. 5. De Souza YG, Greenspan D, Hammer M, et aI. Demonstration of Epstein-Barr virus DNA in the epithelial cells of oral hairy leukoplakia [Abstract]. J Dent Res 1986;65:765. 6. Resnick L. Herbst JS, Ablash DV, et aI. Regression of oral hairy leukoplakia after orally administered acyclovir therapy. JAMA 1988;259:384-8. 7. Greenspan D, De Souza YG, Conant MA, et aI. Efficacy of acyclovir in the treatment of Epstein-Barr virus infection of oral hairy leukoplakia. J Acquir Immune Defic Syndr 1990;3:571-8. 8. Green LL, Greenspan JS, DeSouza YG. Oral lesions mim· icking hairy leukoplakia: a diagnostic dilemma. Oral Surg Oral Med Oral Pathol 1989;67:422-6. 9. Greenspan JS, Greenspan D, Lennette ET, et a1. Replication of Epstein-Barr virus within the cells of oral "hairy" leukoplakia, an AIDS-associated lesion. N Engl J Med 1985;313:1564-71. 10. Greenspan D, Greenspan JS, Hearst NG, et a1. Relation of oral hairy leukoplakia to infection with the human immunodeficiencyvirus and the risk of developing AIDS. J Infect Dis 1987;155:475-81. 11. Horsburgh CR, Jason J, LonginiIM, et al. Duration ofhuman immunodeficiency virus infection before detection of antibody. Lancet 1989;2:637-40. 12. Shofer H, Oschsendorf FR, Helm EB, et al. Treatment of oral "hairy" leukoplakia in AIDS patients with vitamin acid (topically) or acyclovir (systemically). Dermatologica 1987;174:150-1. 13. Itin P, Rufli Th, Rudlinger R, et al. Oral hairy leukoplakia in a HIV-negative renal transplant patient: A marker for immunosuppression? Dermatologica 1988;177:126-8. 14. Greenspan D, Greenspan JS, De Souza YG, et aI. Oral hairy leukoplakia in an HIV-negative renal transplant recipient. J Oral Pathol Med 1989;18:32-4. 15. Epstein JB, Priddy R W, Sherlock CH. Hairy leukoplakialike lesions in immunosuppressed patients following bone marrow transplantation. Transplantation 1988;46:462-4. 16. Birek C, Patterson B, Maximiw WC, et aI. EBV and HSV infections in a patient who had undergone bone marrow transplantation: oral manifestations and diagnosis by in situ nucleic acid hybridization. Oral Surg Oral Moo Oral Pathol ]989;18:28-31. 17. Reggiani M, Pauluzzi P. Hairy leukoplakia in liver transplant patient. Acta Derm Venereal (Stockh) 1990;70:87-8. 18. Belton CM, Eversole LR. Oral hairy leukoplakia: ultrastructural features. J Oral PathoI1986;15:493-9. 19. Schilodt M, Greenspan D, Daniels TE, et aI. Clinical and histologic spectrum of oral hairy leukoplakia. Oral Surg 1987;64:716-20. 20. Daniels TE, Greenspan D, Greenspan JS, et aI. Absence of Langerhans cells in oral hairy leukoplakia, an AIDS-associated lesion. J Invest DermatoI1987;889:178-82. 21. Scuibba J, Brandsma J, Schwartz M, et a1. Hairy leukoplakia: an AIDS-associated opportunistic infection. Oral Surg Oral Moo Oral Pathol 1989;67:404-10.
