Significance of’ oral hairy leukoplakia Deborah Greenspan, BDS, DSc, ScD(hc),a and John S. Greenspan, BDS, PhD, FRCPath, ScD(hc),b San Francisco, Calif. DEPARTMENT
OF STOMATOLOGY,
UNIVERSITY
OF CALIFORNIA,
SAN FRANCISCO
Since the original description of oral hairy leukoplakia among homosexual men in San Francisco in 1984, this white Lesion of the tongue has been seen in the mouths of persons infected with the human immunodeficiency virus (HIV) worldwide. Its presence in HIV-positive persons usually but not always indicates fairly rapid progression to acquired lmmunodeficiency syndrome in the absence of antiretroviral therapy. Although the lesion appears to be common in HIV-positive persons, it is also, albeit rarely, seen in other conditions associated with immunosuppression. Epstein-Barr virus is associated with and presumably causes hairy leukoplakia, and the lesion offers insights into the biology of this ubiquitous DNA-oncogenic virus.
(ORALSURCORALMEDORAL FATHOL1992;73:151-4)
0
ral lhairy leukoplakia (HL) is a white lesion of the tongue, and occasionally of other parts of the mouth and pharynx, that is due to epithelial hyperplasia. HL is found almost exclusively in persons with human immunodeficiency virus (HIV) infection. The lesion presents as a white patch that is often corrugated or even hairy. It may be very small, consist of several patches that run together, or be extensive, even covering the dorsal surface of the tongue. Since our original description in 1984, t, 2 when we found HL in homosexual men, this lesion has been seen in HIVinfected persons in all risk groups worldwide.3F” Its prevalence and incidence are not yet fully documented, but reports give a range of from 20% point prevalence in those with otherwise asymptomatic HIV infection in the United Statesi to 36% in patients in Tanzania with full-blown acquired immunodeficiency syndrome (AIDS).13 In one study in Africa the clinical presence of HL was found to have a predictive value for the presence of AIDS or HIV infection of 100% and 95%, respectively.i3 Similar findings have been reported from the United States and Europe. 14:l5 HL is also found, albeit rarely, in heart, kidney, and bone marrow transplant recipients.“jM20HL is occasionally seen on parts of the oral
Supported by National Institutes of Health grant POl-DE07946. %linical Professor of Oral Medicine, Department of Stomatology. bProfessor and Chair, Department of Stomatology. 7/12/31465
mucosa other than the tongue2’ but not in the anal mucosa. 22 The lesion may be noticed by the patient, physician, or dentist because of its appearance; it only rarely produces symptoms of mild discomfort or roughness.23 A significant proportion of patients with HL and without AIDS subsequently progress to AIDS fairly rapidly.24 In our latest analysis of 198 cases of HL the median time to AIDS was 24 months and the median time to death was 41 months.25 However, some patients in this group do not progress as rapidly to AIDS. Using a nested case-control study design, we showed that rapid progression is predicted by skin test anergy to Candida at the time of the original diagnosis of HL. We int,erpret this as indicating profound immunodeficiency in those HL cases with a more sinister prognosis rather than as indicating a specific role for Candida. Although Candida can be identified in more than 50% of HL lesions by smear, culture, or histopathologic sludy, the lesion is not eliminated even when all traces of the fungus are removed by aggressive antifungal therapy.l% g,23 In our original description’, 23 we reported the unusual histologic features associated with HL, including superficial folds or corrugations, thickening and acanthosis with groups or horizontal bands of ballooning cells resembling koilocytes, absence of atypia, and the lack of a connective tissue inflammatory cell infiltrate. Although these histologic appearances are highly suggestive of the diagnosis of HL, and although they are rarely seen in other forms of leuko151
152
Greenspan and Greenspan
ORAL
.%RG
&&AL
?“v’fhD OR%.
?ATlitri
February
plakia, we no longer consider them ro be unique to HL. Similar clinical and histologic appearances are occasionally seen in the absence of epithelial EpsteinBarr virus (EBV) infection in nonimmunosuppressed patients (pseudo-HL).26 Furthermore, a recent report suggests that some of the histologic appearances hitherto associated with HL can be seen in autopsy specimens of apparently normal tongue.27 For these reasons we require evidence of the presence of EBV to establish the definitive diagnosis of HL.9 However, the presence of EBV is not required for the presumptive diagnosis of HL, which can be made on clinical grounds. EBV is present in the epithelial cells of HL as a fully replicating infection with copious viral particles demonstrable by electron microscopy, viral antigen readily detected by immunocytochemistry, and EBV DNA in high copy number as the complete genome in !inear virion form and demonstrable by Southern blot or in situ hybridization. ‘. 28-33The latter technique forms the basis for some fairly straightforward noninvasive approaches to the detection of EBV and hence to the diagnosis of HL.9 One report gives preliminary evidence for the presence of unusual forms of EBV in HL and even EBV mutants.34 Whether these unusual and possibly new EBV types, if confirmed, are associated with viral oncogenesis remains to be determined. To date, neither severe dysplasia nor carcinoma has been seen in association with HL. However, with the lengthening of life expectancy of HIV-infected persons through the use of antiretroviral agents such as zidovudine, 2’,3 ‘-dideoxyinosine, and 2’,3’-dideoxycytidine, as well as the treatment and prevention of Pneumocystis carinii pneumonia, the malignant potential of HL ultimately will be determined. We and our colleagues35 recently showed that the keratin phenotype profile of HL resembles that of benign epithelial hyperplasias and differs from that seen in epithelial premalignant lesions. It is not clear why EBV infects the tongue epithehum and occasionally other parts of the oral mucosa in persons with HIV-induced immunosuppression. A role for a Langerhans cell defect is suggested by the observation that Langerhans cells are sparse or absent in the HL lesion. 36 Perhaps Langerhans cells in this location are damaged, directly or indirectly, by HIV infection, opening the way to epithelial cell EBV infection or reactivation. Support for the idea of reactivation of latent EBV infection comes from the observation that HL usually recurs after its elimination by acyclovir or desciclovir.3’. 37,38On the other hand, no convincing evidence has been published in support of the presence of EBV or components of EBV in the
1902
epithelial basal cell and adjoining iayers. It has been suggested that the epithelial cells of the lateral aspect of the tongue preferentially bear the EBV receptor.j9 However, reports on this issue are conflicting.“0 An intriguing approach to the study of the role of EBV in the pathogenesis of HL and other human diseases comes from recent reports on transgenic mice incorporating the BNLF-1 oncogene of EBV. These mice show epithelial proliferation of the skin and tongue associated with the presence of keratin type 6.4’ The authors suggested that induction of this keratin type by EBV may explain the hyperplasia seen in HL. Another recent report suggesting the presence of salivary IgA antibodies to EBV in HL patients offers an interesting link to nasopharyngeal carcinoma.“’ In our original reports we described a high prevalence of staining for papillomavirus antigen in the ballooning cells of HL with a commercial antiserum.t, 28However, we and others have been unable to confirm the presence of papillomavirus with the use of monoclonal antibodies, Southern blot, and in situ hybridization.8,9, 32 On the other hand, using electron cytochemistry, we have confirmed the reactivity with the commercial papillomavirus antiserum and have localized the staining to the small fairly dense particles, which in our early articles were likened to papillomavirus particles. Our current hypothesis is that this staining represents cross-reactivity between components of EBV and of the human papillomavirus.“3 HL is usually asymptomatic, although slight discomfort and concern about appearance are occasionally reported by patients. HL responds dramatically but temporarily to high doses of acyclovir3’, 37,44and to desciclovir,38 an analogue of acyclovir. Single case reports of response to ganciclovir45 and tretinoin (Retin-A)46 have not yet been confirmed in prospective double-blind trials. HL has also been reported to disappear while patients are receiving zidovudine.47M49We have seen HL both occur and recur while patients are taking zidovudine. HL remains a lesion of great clinical significance, represents a diagnostic challenge, raises important questions about the biology of epithelial cell differentiation and hyperplasia, and offers a unique model for the study of the biology of EBV. REFERENCES I. Greenspan D, Greenspan JS: Conant M, Petersen V, Silverman S Jr, DeSouza Y. Oral ‘hairy’ leucoplakia in male homosexuals: evidence of association with both papillomavirus and a herpes-group virus. Lancet 1984;2:831-4. 2. Greenspan D, Greenspan JS, Goldman H. Oral viral lesion (hairy leukoplakia) associated with acquired immunodeficiency syndrome. MMWR 1985;34:549-50.
Oral hairy leukoplakia
Volume 73 Number 2 3. Greenspan D, Hollander H, Friedman-Kien A, Freese UK, Greenspan JS. O’ral hairy leukoplakia in two women, a hemophiliac and a transfusion recipient [Letter]. Lancet 1986;2: 978. 4. Rindum JL, Schigdt M, Pindborg JJ, Schiebel E. Oral hairy leukoplakia in three hemophiliacs with human immunodeficiency virus infesction. ORAL SURG ORAL MED ORAL PATHOL 1987;63:437-40.
5. Greenspan JS, Mastrucci T, Leggott P, Greenspan D, Scott GW, DeSouza Y. Hairy leukoplakia in a child. AIDS 1988:2:143. 6. Melbye M, Gros,sman RJ, Goedert JJ, Eyster ME, Biggar RJ. Risk of AIDS after herpes zoster. Lancet 1987;2:728-31. 7. Reichart PA, Langford A, Gelderblom HR, Pohle HD: Becker J, Wolf H. Oral hairy leukoplakia: observations in 95 cases and review of the literature. J Oral Path01 Med 1989;18: 410-5. 8. Sciubba J, Brandsma J, Schwartz M, Barrezueta N. Hairy ORAL leukoplakia: an AIDS-associated opportunisticinfection. SURG ORAL MED ORAL PATHOL
1989;67:404-10.
9. Greenspan JS, ‘Greenspan D. Diagnosis and management of oral hairv leukoulakia. ORAL SURG ORAL MED ORAL PATHOL 1989;67:+396-40;.
10. Ficarra G, Barone R, Gaglioti D, et al. Oral hairy leukoplakia among HIV-positive intravenous drug abusers: a clinical, pathological and ultrastructural study. ORAL SURG ORAL MED ORAL PATHOL
1988;65:421-6.
11. Barone R, Ficarra G, Gaglioti D, Orsi A, Mazzotta F. Prevalence of oral lesions among HIV-infected intravenous drug abusers and othler risk groups. ORAL SURG ORAL MED ORAL PATHOL
1990;69:169-73.
12. Feigal DW, Overby GL, Greenspan D, Greenspan JS, UCSF Oral AIDS Epidemiology Group. Early oral lesions found in community cohorts: is hairy leukoplakia more common than candidiasis? Presented at Fourth International Conference on AIDS; Stockholm. 13. Schi$dt M, Bakilana PB, Hiza JF, et al. Oral candidiasis and hairy leukoplakia correlate with HIV infection in Tanzania. ORAL SURG ORAL MED ORAL PATHOL
1990;69:591-6.
14. Melnick SL, Engel D, Truelove E, et al. Oral mucosal lesions: association with the presence of antibodies to the human immunodeficiency virus. ORAL SURG ORAL MED ORAL PATHOL 1989;68:37-43.
15. Schulten EAJM, ten Cate RW, van der Waal I. The impact of oral examination on the Centers for Disease Control classification of subjects with immunodeficiency virus infection. Arch Intern Med 1990;150:1259-61. 16. Itin P, RuRi T, Rudlinger R, et al. Oral hairy leukoplakia in a HIV-negative renal transplant patient: a marker for immunosuppression? Dermatologica 1988;177:126-8. 17. Greensoan D, Greensoan JS. DeSouza Y. Levv JA. Unrrer AM. Oral hairy leukoplakia in an HIV-negative renal traisplant recipient. J Oral Path01 Med 1989;18:32-4. 18. Syrjanen S, Laine P, Niemela M, Happonen RP. Oral hairy leukoplakia is not a specific sign of HIV-infection but related to immunosuppression in general. J Oral Path01 Med 1987;18:23-31. 19. Schmidt Westhausen A, Gelderblom HR, Reichart PA. Oral hairy leukoplakia in an HIV-seronegative heart transplant patient. J Oral Pathol Med 1990;19:192-4. 20. Epstein JB, Priddy RW, Sherlock CH. Hairy leukoplakia-like lesions in immunosuppressed patients following bone marrow transplantation. Transplantation 1988;46:462-4. 21. Kabani ST Greenspan D, DeSouza Y, Greenspan JS, Cataldo E. Oral hairy leukoplakia with extensive oral mucosal involvement: report of two cases. ORAL SURG ORAL MED ORAL PATHOL
1989;67:411-5.
22. Hollander H, Schi$dt M, Greenspan D, Stringari S, Greenspan JS. Hairy leukoplakia and the acquired immunodeficiency syndrome [Letter]. Ann Intern Med 1986;104:892.
153
23. Schi$dt M, Greenspan D, Daniels TE, Greenspan JS. Clinical and histologic spectrum of oral hairy leukoplakia. ORAL SURG ORAL MED ORAL PATHOL
1987;64:716-20.
24. Greenspan D, Greenspan JS, Hearst NG, et al. Oral hairy leukoplakia; human immunodeficiency virus status and risk for development of AIDS. J Infect Dis 1987:155:475-81. 25. Greenspan D, Greenspan JS, Overby G, Hollander H, Abrams DI. Risk factors for rapid progression from hairy leukoplakia to AIDS: a rested case control study. J AIDS 1991;4:652-8. 26. Green TL, Greenspan JS, Greenspan D, DeSouza Y. Oral lesions mimicking oral hairy leukoplakia: a diagnostic dilemma. ORAL SURG ORAL MED ORAL PATHOL 1989;67: 422-6. 27. Andersen L, Philipsen HP, Reichart PA. Macro- and microanatomy of the lateral border of the tongue with special reference to oral hairy leukoplakia. J Oral Path01 Med 1990;19:77-80. 28. Greenspan JS, Greenspan D, Lennette ET, et al. Replication of Epstein-Barr virus within the eoithelial cells of oral hairv leukoplakia, an AIDS-associated lesion. N Engl J Med 1985;313:1564-71. 29. DeSouza YG, Greenspan D, Felton JR, Hartzog GA, Hammer M, Greenspan JS. Localization of Epstein-Barr virus DNA in the epithelial cells of oral hairy leukoplakia by in situ hybridization of tissue sections [Letter]. N Engl J Med 1989; 320:1559-60. 30. Greenspan JS, Rabanus JP, Petersen V, Greenspan D. Fine structure of EBV-infected keratinocytes in oral hairy leukoplakia. J Oral Path01 Med 1989;18:565-72. 31. Resnick L, Herbst JS, Ablashi DV, et al. Regression of oral hairy leukoplakia after orally administered acyclovir therapy. JAMA 1988;259:384-8. 32 Eversole LR, Stone CE, Beckman AM. Detection of EBV and HPV DNA sequences in oral hairy leukoplakia by in-situ hybridization. J Med Virol 1988;26:271-7. 33. Reed KD, Fowler CB, Brannon RB. Ultrastructural detection of herpes-type virions by negative staining in oral hairy leukoplakia. Am J Clin Path01 1988;90:305-8. 34 Patton DF, Shirley P, Raab-Traub N, Resnick L, Sixbey JW. Defective viral DNA in Epstein-Barr virus-associated oral hairy leukoplakia: J Virol 1990;64:397-400. 35 Leigh IM, Williams DM, Greenspan D, Greenspan JS. Epithelial differentiation in oral hairy leukoplakia: alteration towardsincreasedmaturation. JOralPatholMed 1991;20:16771. 36 Daniels TE, Greenspan D, Greenspan JS, Lennette E, Petersen V, DeSouza Y. Absence of Langerhans’ cells in oral hairy leukoplakia, an AIDS-associated lesion. J Invest Dermatol 1987: 89-178-82. 37 Friedman-Kien AE. Viral origin of hairy leukoplakia [Letter]. Lancet 1986;2:694. 38. Greenspan D, DeSouza YG, Conant MA, et al. Efficacy of desciclovir in the treatment of Epstein-Barr virus infection in oral hairy leukoplakia. J AIDS 1990;3:571-83. 39. Corso B, Eversole LR, Hutt Fletcher L. Hairy leukoplakia: Epstein-Barr virus receptors on oral keratinocyte plasma membranes. ORAL SURG ORAL MED ORAL PATHOL 1989;67: 416-21,
40. DeSouza Y, Greenspan D, Greenspan JS, SchiQdt M, Worsaae N. Epstein-Barr receptors in hairy leukoplakia. San Francisco: American Association for Dental Research. 41. Wilson JB, Weinberg W, Johnson R, Yuspa S, Levine AJ. Expression of the BNLF- 1 oncogene of Epstein-Barr virus in the skin of transgenic mice induces hyperplasia and aberrant expression of keratin 6. Cell 1990;61:1315-27. 42. Resnick L, Herbst JS, Raab-Traub N. Oral hairy leukoplakia. J Am Acad Dermatol 1990;22:1278-82. 43. Rabanus JP, Greenspan D, Petersen V, Greenspan JS. Antiserum against papillomavirus antigen reacts with intranuclear particles in keratinocytes of oral hairy leukoplakia, an AIDS
I 54
44.
45.
46.
47.
Greenspan and Greenspan
associated lesion. Presented at Sixth International Conference on AIDS; San Francisco; 1990. Herbst JS, Morgan J, Raab-Traub N, et al. Comparison of the efficacy of surgery and acyclovir in the treatment of oral hairy leukoplakia. J Am Acad Dermatol 1989;21:753-6. Newman C, Polk BF. Resolution of oral hairy leukoplakia during therapy with 9-( 1,3-dihydroxy-2-propoxymethyl) guanine (DHPG). Ann Intern Med 1987;107:348-50. Schafer H, Ochsendorf FR, Helm EB, Milbracht R. Treatment of oral hairy leukoplakia in AIDS patients with vitamin A acid (topically) or acyclovir (systemically) [Letter]. Dermatologica 1987;174:150-1. Kessler HA, Benson CA, Urbanski P. Regression of oral hairy leukoplakia during treatment with hzidothymidine. Ann Intern Med 1988;148:2496-7.
ORAL Sui+o ORAL ?ij~~ ORAL PATH~L February 1992 48. Pheian J, Klein RS. Resolution of oral hairy ieukoplakia during treatment with azidothymidine. ORAL SURG ORAL MED ORAL PATHOL
1988;65:717-20.
49. Brockmeyer NH, Kreuzfelder E, Mertins L, Daecke C, Goos M. Zidovudine therapy of asymptomatic HIV-l-infected patients and combined zidovudine-acyclovir therapy of HIV-linfected patients with oral hairy leukoplakia [Letter]. J Invest Dermatol 1989;92:647. Reprint
requests:
Deborah Greenspan, BDS, ScD Box 05 12, Department of Stomatology University of California, San Francisco San Francisco, CA 94143-0512
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of ORAL SURGERY, ORAL MEDICINE, AND ORAL PATHOLOGY are available to subscribers (only) for the 1991 issues from the Publisher, at a cost of $45.00 for domestic, $60.15 for Canadian, and $57.00 for international, for Vol. 71 (January-June) and Vol. 72 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO 63146-3318. USA; phone (800)325-4177, ext. 4351, or (314)453-4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscrip-
OF STOMATOLOGY,
UNIVERSITY
OF CALIFORNIA,
SAN FRANCISCO
Since the original description of oral hairy leukoplakia among homosexual men in San Francisco in 1984, this white Lesion of the tongue has been seen in the mouths of persons infected with the human immunodeficiency virus (HIV) worldwide. Its presence in HIV-positive persons usually but not always indicates fairly rapid progression to acquired lmmunodeficiency syndrome in the absence of antiretroviral therapy. Although the lesion appears to be common in HIV-positive persons, it is also, albeit rarely, seen in other conditions associated with immunosuppression. Epstein-Barr virus is associated with and presumably causes hairy leukoplakia, and the lesion offers insights into the biology of this ubiquitous DNA-oncogenic virus.
(ORALSURCORALMEDORAL FATHOL1992;73:151-4)
0
ral lhairy leukoplakia (HL) is a white lesion of the tongue, and occasionally of other parts of the mouth and pharynx, that is due to epithelial hyperplasia. HL is found almost exclusively in persons with human immunodeficiency virus (HIV) infection. The lesion presents as a white patch that is often corrugated or even hairy. It may be very small, consist of several patches that run together, or be extensive, even covering the dorsal surface of the tongue. Since our original description in 1984, t, 2 when we found HL in homosexual men, this lesion has been seen in HIVinfected persons in all risk groups worldwide.3F” Its prevalence and incidence are not yet fully documented, but reports give a range of from 20% point prevalence in those with otherwise asymptomatic HIV infection in the United Statesi to 36% in patients in Tanzania with full-blown acquired immunodeficiency syndrome (AIDS).13 In one study in Africa the clinical presence of HL was found to have a predictive value for the presence of AIDS or HIV infection of 100% and 95%, respectively.i3 Similar findings have been reported from the United States and Europe. 14:l5 HL is also found, albeit rarely, in heart, kidney, and bone marrow transplant recipients.“jM20HL is occasionally seen on parts of the oral
Supported by National Institutes of Health grant POl-DE07946. %linical Professor of Oral Medicine, Department of Stomatology. bProfessor and Chair, Department of Stomatology. 7/12/31465
mucosa other than the tongue2’ but not in the anal mucosa. 22 The lesion may be noticed by the patient, physician, or dentist because of its appearance; it only rarely produces symptoms of mild discomfort or roughness.23 A significant proportion of patients with HL and without AIDS subsequently progress to AIDS fairly rapidly.24 In our latest analysis of 198 cases of HL the median time to AIDS was 24 months and the median time to death was 41 months.25 However, some patients in this group do not progress as rapidly to AIDS. Using a nested case-control study design, we showed that rapid progression is predicted by skin test anergy to Candida at the time of the original diagnosis of HL. We int,erpret this as indicating profound immunodeficiency in those HL cases with a more sinister prognosis rather than as indicating a specific role for Candida. Although Candida can be identified in more than 50% of HL lesions by smear, culture, or histopathologic sludy, the lesion is not eliminated even when all traces of the fungus are removed by aggressive antifungal therapy.l% g,23 In our original description’, 23 we reported the unusual histologic features associated with HL, including superficial folds or corrugations, thickening and acanthosis with groups or horizontal bands of ballooning cells resembling koilocytes, absence of atypia, and the lack of a connective tissue inflammatory cell infiltrate. Although these histologic appearances are highly suggestive of the diagnosis of HL, and although they are rarely seen in other forms of leuko151
152
Greenspan and Greenspan
ORAL
.%RG
&&AL
?“v’fhD OR%.
?ATlitri
February
plakia, we no longer consider them ro be unique to HL. Similar clinical and histologic appearances are occasionally seen in the absence of epithelial EpsteinBarr virus (EBV) infection in nonimmunosuppressed patients (pseudo-HL).26 Furthermore, a recent report suggests that some of the histologic appearances hitherto associated with HL can be seen in autopsy specimens of apparently normal tongue.27 For these reasons we require evidence of the presence of EBV to establish the definitive diagnosis of HL.9 However, the presence of EBV is not required for the presumptive diagnosis of HL, which can be made on clinical grounds. EBV is present in the epithelial cells of HL as a fully replicating infection with copious viral particles demonstrable by electron microscopy, viral antigen readily detected by immunocytochemistry, and EBV DNA in high copy number as the complete genome in !inear virion form and demonstrable by Southern blot or in situ hybridization. ‘. 28-33The latter technique forms the basis for some fairly straightforward noninvasive approaches to the detection of EBV and hence to the diagnosis of HL.9 One report gives preliminary evidence for the presence of unusual forms of EBV in HL and even EBV mutants.34 Whether these unusual and possibly new EBV types, if confirmed, are associated with viral oncogenesis remains to be determined. To date, neither severe dysplasia nor carcinoma has been seen in association with HL. However, with the lengthening of life expectancy of HIV-infected persons through the use of antiretroviral agents such as zidovudine, 2’,3 ‘-dideoxyinosine, and 2’,3’-dideoxycytidine, as well as the treatment and prevention of Pneumocystis carinii pneumonia, the malignant potential of HL ultimately will be determined. We and our colleagues35 recently showed that the keratin phenotype profile of HL resembles that of benign epithelial hyperplasias and differs from that seen in epithelial premalignant lesions. It is not clear why EBV infects the tongue epithehum and occasionally other parts of the oral mucosa in persons with HIV-induced immunosuppression. A role for a Langerhans cell defect is suggested by the observation that Langerhans cells are sparse or absent in the HL lesion. 36 Perhaps Langerhans cells in this location are damaged, directly or indirectly, by HIV infection, opening the way to epithelial cell EBV infection or reactivation. Support for the idea of reactivation of latent EBV infection comes from the observation that HL usually recurs after its elimination by acyclovir or desciclovir.3’. 37,38On the other hand, no convincing evidence has been published in support of the presence of EBV or components of EBV in the
1902
epithelial basal cell and adjoining iayers. It has been suggested that the epithelial cells of the lateral aspect of the tongue preferentially bear the EBV receptor.j9 However, reports on this issue are conflicting.“0 An intriguing approach to the study of the role of EBV in the pathogenesis of HL and other human diseases comes from recent reports on transgenic mice incorporating the BNLF-1 oncogene of EBV. These mice show epithelial proliferation of the skin and tongue associated with the presence of keratin type 6.4’ The authors suggested that induction of this keratin type by EBV may explain the hyperplasia seen in HL. Another recent report suggesting the presence of salivary IgA antibodies to EBV in HL patients offers an interesting link to nasopharyngeal carcinoma.“’ In our original reports we described a high prevalence of staining for papillomavirus antigen in the ballooning cells of HL with a commercial antiserum.t, 28However, we and others have been unable to confirm the presence of papillomavirus with the use of monoclonal antibodies, Southern blot, and in situ hybridization.8,9, 32 On the other hand, using electron cytochemistry, we have confirmed the reactivity with the commercial papillomavirus antiserum and have localized the staining to the small fairly dense particles, which in our early articles were likened to papillomavirus particles. Our current hypothesis is that this staining represents cross-reactivity between components of EBV and of the human papillomavirus.“3 HL is usually asymptomatic, although slight discomfort and concern about appearance are occasionally reported by patients. HL responds dramatically but temporarily to high doses of acyclovir3’, 37,44and to desciclovir,38 an analogue of acyclovir. Single case reports of response to ganciclovir45 and tretinoin (Retin-A)46 have not yet been confirmed in prospective double-blind trials. HL has also been reported to disappear while patients are receiving zidovudine.47M49We have seen HL both occur and recur while patients are taking zidovudine. HL remains a lesion of great clinical significance, represents a diagnostic challenge, raises important questions about the biology of epithelial cell differentiation and hyperplasia, and offers a unique model for the study of the biology of EBV. REFERENCES I. Greenspan D, Greenspan JS: Conant M, Petersen V, Silverman S Jr, DeSouza Y. Oral ‘hairy’ leucoplakia in male homosexuals: evidence of association with both papillomavirus and a herpes-group virus. Lancet 1984;2:831-4. 2. Greenspan D, Greenspan JS, Goldman H. Oral viral lesion (hairy leukoplakia) associated with acquired immunodeficiency syndrome. MMWR 1985;34:549-50.
Oral hairy leukoplakia
Volume 73 Number 2 3. Greenspan D, Hollander H, Friedman-Kien A, Freese UK, Greenspan JS. O’ral hairy leukoplakia in two women, a hemophiliac and a transfusion recipient [Letter]. Lancet 1986;2: 978. 4. Rindum JL, Schigdt M, Pindborg JJ, Schiebel E. Oral hairy leukoplakia in three hemophiliacs with human immunodeficiency virus infesction. ORAL SURG ORAL MED ORAL PATHOL 1987;63:437-40.
5. Greenspan JS, Mastrucci T, Leggott P, Greenspan D, Scott GW, DeSouza Y. Hairy leukoplakia in a child. AIDS 1988:2:143. 6. Melbye M, Gros,sman RJ, Goedert JJ, Eyster ME, Biggar RJ. Risk of AIDS after herpes zoster. Lancet 1987;2:728-31. 7. Reichart PA, Langford A, Gelderblom HR, Pohle HD: Becker J, Wolf H. Oral hairy leukoplakia: observations in 95 cases and review of the literature. J Oral Path01 Med 1989;18: 410-5. 8. Sciubba J, Brandsma J, Schwartz M, Barrezueta N. Hairy ORAL leukoplakia: an AIDS-associated opportunisticinfection. SURG ORAL MED ORAL PATHOL
1989;67:404-10.
9. Greenspan JS, ‘Greenspan D. Diagnosis and management of oral hairv leukoulakia. ORAL SURG ORAL MED ORAL PATHOL 1989;67:+396-40;.
10. Ficarra G, Barone R, Gaglioti D, et al. Oral hairy leukoplakia among HIV-positive intravenous drug abusers: a clinical, pathological and ultrastructural study. ORAL SURG ORAL MED ORAL PATHOL
1988;65:421-6.
11. Barone R, Ficarra G, Gaglioti D, Orsi A, Mazzotta F. Prevalence of oral lesions among HIV-infected intravenous drug abusers and othler risk groups. ORAL SURG ORAL MED ORAL PATHOL
1990;69:169-73.
12. Feigal DW, Overby GL, Greenspan D, Greenspan JS, UCSF Oral AIDS Epidemiology Group. Early oral lesions found in community cohorts: is hairy leukoplakia more common than candidiasis? Presented at Fourth International Conference on AIDS; Stockholm. 13. Schi$dt M, Bakilana PB, Hiza JF, et al. Oral candidiasis and hairy leukoplakia correlate with HIV infection in Tanzania. ORAL SURG ORAL MED ORAL PATHOL
1990;69:591-6.
14. Melnick SL, Engel D, Truelove E, et al. Oral mucosal lesions: association with the presence of antibodies to the human immunodeficiency virus. ORAL SURG ORAL MED ORAL PATHOL 1989;68:37-43.
15. Schulten EAJM, ten Cate RW, van der Waal I. The impact of oral examination on the Centers for Disease Control classification of subjects with immunodeficiency virus infection. Arch Intern Med 1990;150:1259-61. 16. Itin P, RuRi T, Rudlinger R, et al. Oral hairy leukoplakia in a HIV-negative renal transplant patient: a marker for immunosuppression? Dermatologica 1988;177:126-8. 17. Greensoan D, Greensoan JS. DeSouza Y. Levv JA. Unrrer AM. Oral hairy leukoplakia in an HIV-negative renal traisplant recipient. J Oral Path01 Med 1989;18:32-4. 18. Syrjanen S, Laine P, Niemela M, Happonen RP. Oral hairy leukoplakia is not a specific sign of HIV-infection but related to immunosuppression in general. J Oral Path01 Med 1987;18:23-31. 19. Schmidt Westhausen A, Gelderblom HR, Reichart PA. Oral hairy leukoplakia in an HIV-seronegative heart transplant patient. J Oral Pathol Med 1990;19:192-4. 20. Epstein JB, Priddy RW, Sherlock CH. Hairy leukoplakia-like lesions in immunosuppressed patients following bone marrow transplantation. Transplantation 1988;46:462-4. 21. Kabani ST Greenspan D, DeSouza Y, Greenspan JS, Cataldo E. Oral hairy leukoplakia with extensive oral mucosal involvement: report of two cases. ORAL SURG ORAL MED ORAL PATHOL
1989;67:411-5.
22. Hollander H, Schi$dt M, Greenspan D, Stringari S, Greenspan JS. Hairy leukoplakia and the acquired immunodeficiency syndrome [Letter]. Ann Intern Med 1986;104:892.
153
23. Schi$dt M, Greenspan D, Daniels TE, Greenspan JS. Clinical and histologic spectrum of oral hairy leukoplakia. ORAL SURG ORAL MED ORAL PATHOL
1987;64:716-20.
24. Greenspan D, Greenspan JS, Hearst NG, et al. Oral hairy leukoplakia; human immunodeficiency virus status and risk for development of AIDS. J Infect Dis 1987:155:475-81. 25. Greenspan D, Greenspan JS, Overby G, Hollander H, Abrams DI. Risk factors for rapid progression from hairy leukoplakia to AIDS: a rested case control study. J AIDS 1991;4:652-8. 26. Green TL, Greenspan JS, Greenspan D, DeSouza Y. Oral lesions mimicking oral hairy leukoplakia: a diagnostic dilemma. ORAL SURG ORAL MED ORAL PATHOL 1989;67: 422-6. 27. Andersen L, Philipsen HP, Reichart PA. Macro- and microanatomy of the lateral border of the tongue with special reference to oral hairy leukoplakia. J Oral Path01 Med 1990;19:77-80. 28. Greenspan JS, Greenspan D, Lennette ET, et al. Replication of Epstein-Barr virus within the eoithelial cells of oral hairv leukoplakia, an AIDS-associated lesion. N Engl J Med 1985;313:1564-71. 29. DeSouza YG, Greenspan D, Felton JR, Hartzog GA, Hammer M, Greenspan JS. Localization of Epstein-Barr virus DNA in the epithelial cells of oral hairy leukoplakia by in situ hybridization of tissue sections [Letter]. N Engl J Med 1989; 320:1559-60. 30. Greenspan JS, Rabanus JP, Petersen V, Greenspan D. Fine structure of EBV-infected keratinocytes in oral hairy leukoplakia. J Oral Path01 Med 1989;18:565-72. 31. Resnick L, Herbst JS, Ablashi DV, et al. Regression of oral hairy leukoplakia after orally administered acyclovir therapy. JAMA 1988;259:384-8. 32 Eversole LR, Stone CE, Beckman AM. Detection of EBV and HPV DNA sequences in oral hairy leukoplakia by in-situ hybridization. J Med Virol 1988;26:271-7. 33. Reed KD, Fowler CB, Brannon RB. Ultrastructural detection of herpes-type virions by negative staining in oral hairy leukoplakia. Am J Clin Path01 1988;90:305-8. 34 Patton DF, Shirley P, Raab-Traub N, Resnick L, Sixbey JW. Defective viral DNA in Epstein-Barr virus-associated oral hairy leukoplakia: J Virol 1990;64:397-400. 35 Leigh IM, Williams DM, Greenspan D, Greenspan JS. Epithelial differentiation in oral hairy leukoplakia: alteration towardsincreasedmaturation. JOralPatholMed 1991;20:16771. 36 Daniels TE, Greenspan D, Greenspan JS, Lennette E, Petersen V, DeSouza Y. Absence of Langerhans’ cells in oral hairy leukoplakia, an AIDS-associated lesion. J Invest Dermatol 1987: 89-178-82. 37 Friedman-Kien AE. Viral origin of hairy leukoplakia [Letter]. Lancet 1986;2:694. 38. Greenspan D, DeSouza YG, Conant MA, et al. Efficacy of desciclovir in the treatment of Epstein-Barr virus infection in oral hairy leukoplakia. J AIDS 1990;3:571-83. 39. Corso B, Eversole LR, Hutt Fletcher L. Hairy leukoplakia: Epstein-Barr virus receptors on oral keratinocyte plasma membranes. ORAL SURG ORAL MED ORAL PATHOL 1989;67: 416-21,
40. DeSouza Y, Greenspan D, Greenspan JS, SchiQdt M, Worsaae N. Epstein-Barr receptors in hairy leukoplakia. San Francisco: American Association for Dental Research. 41. Wilson JB, Weinberg W, Johnson R, Yuspa S, Levine AJ. Expression of the BNLF- 1 oncogene of Epstein-Barr virus in the skin of transgenic mice induces hyperplasia and aberrant expression of keratin 6. Cell 1990;61:1315-27. 42. Resnick L, Herbst JS, Raab-Traub N. Oral hairy leukoplakia. J Am Acad Dermatol 1990;22:1278-82. 43. Rabanus JP, Greenspan D, Petersen V, Greenspan JS. Antiserum against papillomavirus antigen reacts with intranuclear particles in keratinocytes of oral hairy leukoplakia, an AIDS
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associated lesion. Presented at Sixth International Conference on AIDS; San Francisco; 1990. Herbst JS, Morgan J, Raab-Traub N, et al. Comparison of the efficacy of surgery and acyclovir in the treatment of oral hairy leukoplakia. J Am Acad Dermatol 1989;21:753-6. Newman C, Polk BF. Resolution of oral hairy leukoplakia during therapy with 9-( 1,3-dihydroxy-2-propoxymethyl) guanine (DHPG). Ann Intern Med 1987;107:348-50. Schafer H, Ochsendorf FR, Helm EB, Milbracht R. Treatment of oral hairy leukoplakia in AIDS patients with vitamin A acid (topically) or acyclovir (systemically) [Letter]. Dermatologica 1987;174:150-1. Kessler HA, Benson CA, Urbanski P. Regression of oral hairy leukoplakia during treatment with hzidothymidine. Ann Intern Med 1988;148:2496-7.
ORAL Sui+o ORAL ?ij~~ ORAL PATH~L February 1992 48. Pheian J, Klein RS. Resolution of oral hairy ieukoplakia during treatment with azidothymidine. ORAL SURG ORAL MED ORAL PATHOL
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49. Brockmeyer NH, Kreuzfelder E, Mertins L, Daecke C, Goos M. Zidovudine therapy of asymptomatic HIV-l-infected patients and combined zidovudine-acyclovir therapy of HIV-linfected patients with oral hairy leukoplakia [Letter]. J Invest Dermatol 1989;92:647. Reprint
requests:
Deborah Greenspan, BDS, ScD Box 05 12, Department of Stomatology University of California, San Francisco San Francisco, CA 94143-0512
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