Original articles Oral medicine

Peter A. Reichart\ Oral hairy leukoplakia: Angelika Langford\ Hans R. Gelderblom^ Hans-Dieter Pohle^ observations in 95 cases and Jijrgen Becker\ Hans Wolf ^Abteilung fur zahnarztliche Chirurgie/ Oralchirurgie - Word - Freie Universitat Bertin, review of the literature ^Robert Koch-lnstitut des Bundesgesundheitsamtes, ^11. Innere Abteilung, Universitats-Klinlkum Rudolf Virchow, Berlin and 'Max-von-Pettenkofer-institut, Munich, West Reichart PA, Langford A, Gelderblom HR, Pohle HD, Becker J, Wolf H; Oral Germany hairy leukoplakia; observations in 95 cases and review of the literature, J Oral Pathol Med 1989; 18; 410-415.

Oral hairy leukoplakia (HL) was observed in 25.4% of 373 HIV-seropositive patients (« = 95). 87 were men of an average age of 37.1 yr, 8 were women (30,3 yr). 71.6% of the patients were male homosexuals. At initial diagnosis of HL the majority of cases was elassified as CDC IVc, (45,3%) and CDC II Key words; HIV infection; Epstein-Barr virus; (22,1%), Average CD4/CD8 ratio {n = 19) was 0,24 with a range of 0,04-1,0, leukoplakia, hairy. Thirty biopsies of HL revealed some of the histologic features thought to be P. A. Reichart, Abteilung fur zahnarztliche characteristic. In only 20 of 30 biopsies EB-virus-specific-capsid antigen was Chlrurgie/Oralchirurgie (Nord), Freie Universitat detected. The problems of clinical and histological diagnosis of HL are Berlin, Fohrer Str. 15, D - 1000 Berlin 65, West discussed. Further strict criteria are necessary in order to define HL more ' Germany distinctly. Accepted for publication June 23, 1989.

Three years after the first patients with transfusion recipients (21) and female of 30 hemophiliac patients with factor acquired immunodeficiency syndrome partners of HIV-infected men (21). Re- VIII or IX deficiencies revealed HL (AIDS) were reported in 1981, oral cently, HL has been described in an (29), In contrast, 23 of 120 consecutive hairy leukoplakia (HL) was described HIV-negative patient with acute mye- patients belonging to the i.v, drug abus- (1). Ioblastic leukemia (22) and an HIV- ing risk group (19%) had developed negative renal transplant patient (23), HL (17), In a study on oral manifes- suggesting that HL is not a specific le- tations of AIDS in Tanzania 35% of 58 Clinical features and epidemiology sion associated to the HIV-infection, patients had developed HL, The male; but may be a sign of immunosuppres- female ratio in this cohort was 1,6 ; 1,0 Oral hairy leukoplakia is clinically sion in general. (20). characterized as a white lesion of the Prevalence rates of HL vary consid- The average age of HIV-infected pa- lateral border of the tongue, occasion- erably. Four out of 23 patients with tients with HL showed some variation. ally also occurring in the buccal mucosa antibodies against HIV revealed HL The average age of i.v, drug abusing with slightly raised, poorly demarcated (17.5%) (24), Among 115 HIV-sero- Italian patients was 25 yr (range 20 to and corrugated "hairy" surface. Le- positive patients 13% revealed HL 50 yr) (17), In contrast, the average age sions cannot be rubbed off and are re- (25). Among HIV-seronegative male of male homosexual patients (n = 50) ported to be usually symptomless. homosexuals {n = 492) 1% demon- was 38 yr (range from 25 to 53 yr) (13), Hairy leukoplakia has so far not been strated HL (25). Of a total of 375 ho- 36,6 yr (range 24 to 51 yr) (8) and 36 yr observed in other mucosal areas than mosexual men 28% had developed HL; (range 22 to 65 yr) (9), Duration of HL the oral (2), During recent years a it occurred in 23% of the AIDS cases, ranged from 1 to 64 months with a number of HL cases either as case re- in 9% of the ARC cases and 47% in mean of 13 months in a study of 50 ports or larger series have been re- high risk persons (9), In a study from cases with HL (13). ported from various areas of the USA, Berlin, 26% of ARC patients had HL The clinical features of HL vary con- Europe and Africa (3-20), (6). In Copenhagen, 32% of 69 sero- siderably. 70% of patients with HL had While HL was initially observed in positive asymptomatic patients, 36% bilateral lesions. The total area of HL male homo- or bisexual men, it has now and 46% of ARC and AIDS patients lesions ranged from 14 to 4200 mm- been shown to occur, though less often, revealed HL (26), Low prevalenee with a mean of 814 mm*. The degree of in all HIV risk groups; hemophiliacs (4, rates were reported from New York intensity of HL was mild in 40% of the 8, 21), drug abusers (6, 10, 17), blood (5%) and Frankfurt (4,8%) (28), None cases, moderate in 52 and severe in 8% Oral hairy leukoplakia 411 (13). While flat lesions were usually lo- these findings have also been observed cells of HL have recently been de- cated on the inferior surface of the in candidiasis and leukoplakias (8), In a scribed (37), tongue, the more corrugated hairy le- reeent study of histologic features of 40 sions were observed on its lateral bor- HL cases hyperparakeratosis was ob- der (13), There is no apparent associ- served in 100%, hyperplasia/acanthosis Treatment ation between the size and intensity of in 80%, hair-like projections in 80%, While most investigators do not con- HL and the relative risk for subsequent koilocytosis in 98% and lack of inflam- sider HL to be a clinical condition development of AIDS (30), While most matory infiltrate in 78%. The absence which requires therapy, some reports studies have stated that HL is rather of Langerhans cells in HL has been on the effect of treatment have been symptomless, burning sensation of considered to be an important factor in published. Thus, HL has been shown to tongues with HL even after antimycotic the pathogenesis of HL (38), Not all disappear during acyciovir therapy (7, therapy has been described (28), The lesions exhibit all mieroscopic charac- 19) and resolution has occurred follow- relation of HL to infection with HIV teristics as described in the first report ing therapy with DHPG (39), another and the risk of developing AIDS has (13), nucleoside analogue, topical vitamin A been studied. Of 155 patients examined The role of Candida infection in HL acid (28) and following azidothymidine 12 had AIDS at the time of diagnosis was of considerable interest beeause therapy (AZT) (4, 21)". After discontin- the syndrome developing in an addi- initially Candida infection was sup- uation of therapy recurrence was ob- tional 43 patients in 1 to 31 months. posed to be an underlying cause of HL served in all responders. Survival analysis showed that the prob- (1), Larger series of HL cases in which ability of AIDS developing in patients oral smears for Candida were taken with HL was 48% by 16 months and showed varying percentage of positive Material and methods 83% by 31 months. As such HL was smears; 70,3% (3), 58.8% (2), 50,7% During a period of 5 yr 373 HIV-sero- cotisidered to be a predictor of the de- (31), 26,1% (17), Demonstration of hy- positive patients (326 men, 47 women) velopment of AIDS (31), In this con- phae in PAS sections revealed presence of an average of 36,2 years were exam- text it is noteworthy that HL has been of Candida in; 100% (12), 66,7% (13), ined for the presence of HL (CDC II; included in the group of secondary in- 50% (18), 49,3% (3), 46.7% (1), 25%, CDC III; 9%, CDC IVa; 12%, fectious diseases (group IV, subgroup 46,2% (19), 43% (13), CDC IVb-e; 54%), Clinical diagnosis C, category C-2) of the CDC surveil- was based on the presence of white, lance case definition (32), non-removable patches on the lateral Immunohistochemistry border of the tongue in accordance Histopathoiogy DNA hybridization studies with Ep- with the original description of HL (1), stein-Barr virus (EBV) probes in In eases of oral candidiasis involving In their original description of HL Southern blots demonstrated EBV the HL lesion, either a topical (micona- GREENSPAN et al. (1) stated that the DNA in epithelial cells of HL (3), zote) or systemic antimycotic treatment histopathology of HL was similar to Other immunohistochemical studies us- (ketokonazole) was administered. The that of the flat wart of the skin. The ing in situ hybridization to detect EBV diagnosis of HL was made in those following criteria were proposed; 1; DNA confirmed the presence of this cases where a whitish lesion at the lat- keratin projections 2; some degree of virus in HL (16, 33, 34). However, it eral border of the tongue persisted af- parakeratosis and acanthosis. 3; char- must be stated that EBV DNA was also ter a minimum of 10 days in spite of this acteristic ballooning of cells in the found in an HIV-1-seronegative patient antimycotic regimen, A number of pa- prickle cell layer (pyknotic nuclei and (16). Using semithin cryosections in rameters were recorded; 1; sex. 2; age, perinuclear halos); these changes were conjunction with the APAAP staining 3; risk group, 4; period of observation, compared to koilocytosis as described teehnique, EBV capsid as well as nucle- 5; CDC-classification, 6; CD4/CD8-cell in dermal warts and uterine condylo- ar antigen of EBV was demonstrated in ratio, 7; regression in relation to ther- mata, 4: little or no inflammation, 5; cases of HL (35), While the presence of apy, 8: deaths occurring during obser- mild epithelial atypia in some cases. HPV was stated using immunohisto- vation. 9; smears for oral Candida in- Most researchers describing histo- chemical methods and electron-micros- fection. pathologic features of HL followed the copy in the first reports on HL (1, 3) it In addition, biopsies of HL were tak- proposed criteria. Koilocytosis, how- was not revealed in subsequent studies, en from 30 patients. Specimens were ever, has been used when describing HIV structural proteins were detected divided and one part was fixed in for- cells with pyknotic or crenated nuclei using immunohistochemistry (36), malin for routine histology (H & E, with voluminous cytoplasm with faint PAS), The other part was deep frozen eosinophilia (8), as koilocytoid cells Electron microscopy in liquid nitrogen. For the immunohis- (12), as large, pale staining cells similar tochemical detection of EBV-capsid to koilocytes as described in uterine Electron microscopic studies have re- antigen (EBV-VCA, BcLFl pl50) condylomata (15), as cells which had vealed the presence of herpes type vi- cryostat sections of 3-4 ^m were air- undergone cytopathic changes reveal- rus with clusters of nucleocapsids lo- dried for 2 h and fixed in acetone for 15 ing a ground glass nucleus with baso- cated in nuclei and enveloped complete min at room temperature. Sections philic nuclear inclusions, ballooning of particles occurring in the cytoplasm and were first incubated with primary cytoplasm and intracellular edema extracellular spaces (1, 11, 12, 15, 17, monoclonal antibody against EBV- (33), as well as vacuolated cells resem- 18, 35), In addition, tubuloreticular VCA (dilution 1 ; 2000), followed by bling koilocytes (13). It has been stated structures as well as membrane differ- the unlabelled goat-anti-mouse bridg- that parakeratosis and subcorneal koi- entiations were revealed in HL (12, ing antibody (dilution 1 ; 60; Jackson, locytosis are not specific for HL since 35), Cristalline inelusions in epithelial Avondale, USA) and finally with the

-^ Oral IS:7. 412 REICHART ET AL, et al. Table I. Risk groups for 95 patients with patients revealing an average of CD4/ Table 2, Initial CDC classification of 9,5 pa- HL, CD8: 0,24 with a range from 0,04-1,0, tients with HL, The absolute number of CD4 cells was : Risk factors Men: « = 87 Women: n = 8 CDC group n % 149 mm^ (range 10-470) (average IgA : 270 (134-380); average IgG : 1690 Homosexual 71 1 CDC II 21 22,1 i, v,/homosex. 3 (1100-2400), average IgM : 243 (149- CDC IV 12 12,6 i. V. drug user 9 7 374), A total of 13 patients with HL CDC IVa 2 2,1 Hemophiliac 2 received AZT, In seven patients HL CDC IVb 1 1,1 Transplant pat. 1 regressed clinically; two of these pa- CDC IVc, 43 45.3 Unknown 2 CDC IVcj 2 2.1 tients developed resolution of HL dur- CDC IVd 13 13.5 ing acyclovir therapy, one patient CDC IVe 1 1,1 showed regression under HOE/Bay 946 therapy and in one case the regression alkaline phosphatase-mouse-anti alka- did not coincide with a particular treat- line phosphatase (APAAP) immune ment. lar. In contrast, i,v, drug abusing HL complexes (dilution 1 : 50; Dianova, In 31 patients with HL without previ- patients (16) appear to be eonsiderably Hamburg, FRG) (35), ous antimycotic treatment smears for younger (27 years). Larger studies of Candida albieans were taken. Of these, cohorts of i,v, drug abusers with HL 14 smears were positive for C, albieans. compared to homosexual/bisexual When diagnosis of HL was stated 79% Results males are necessary in order to reveal of patients showed clinical symptoms of differences in the development and Of a total of 373 HIV-seropositive indi- oral C, albieans infection, 22% suffered course of HL, The short period of ob- viduals 95 patients revealed HL clin- from periodontal lesions of RPP and/or servation of HL (68 patients less than 4 ically (25,4%), In 75% HL was bilat- NUG, and 8% of oral Kaposi's sar- wk) does not allow to draw any conclu- eral, HL in extralingual sites was not coma. In 18% of patients HL was the sions on the development of HIV-in- seen. Clinically, HL varied in appear- only oral manifestation of HIV infec- fection in patients with HL, It must also ance, A corrugated pattern {n = 80) as tion, be stated that in this cohort the major- well as whitish plaque-like lesions (n = Histologic and immunohistochemical ity of patients were classified as CDC 15) (16%) extending on to the sublin- findings are summarized in Table 3, IVb, IVc, IVd or IVe (AIDS eases gual surface was observed. Hair-like Hyperparakeratosis (100%), acantho- 54%), Of considerable interest is the projections were rarely seen. In 17% of sis/hyperplasia (100%), relatively few CD4/CD8 ratio and the development of patients HL covered an area of up to 15 hair-like projections (33%) and koilo- HL, In HIV periodontitis a elear-eut mm in diameter. None of the patients cyte-like cells (90%) were found. Ab- relation between the decrease of the really complained about the lesion. sence of inflammatory changes was also number of CD4 cells as well as in CD4/ More than 75% of patients, especially observed (53%), In PAS-stained sec- CD8 ratio has been found (J, Winkler, homosexual men, were aware of their tions candidal hyphae in epithelium personal communication). It would be lesion, had heard about its significance were found in 47%, Immunohisto- of interest to see when and at which and usually were those who refused to chemically, EBV-capsid antigen CD4/CD8 ratio HL is first observed. have biopsy taken. Average age of the (VCA) was only detected in 20 out of Therapy of HL does not seem to be male patients was 37,1 yr (range 19 to 30 biopsies, A strong nuclear immuno- of major priority. In most cases HL was 82 yr), of the female patients 30,3 yr labelling was found in cells of the upper symptomless and exclusive treatment (range 26 to 46 yr), 87 patients were stratum spinosum and in the ballooned, of HL lesions was never necessary, men, 8 were women. The majority of koilocyte-like epithelial cells (Fig, 1), Acyclovir as well as AZT therapy re- the male patients were homosexual Staining was often not continuous over sulted in clinical disappearance of HL men (n = 68) (71,6%), Risk factors for the whole section and large areas, lesions, as has been observed in other 95 patients with HL are shown in Table whieh showed the same histologic char- studies (6, 28, 39), As could be sus- 1, 9 men and 7 women were i,v, drug acteristics as areas with an intense im- pected in cases of immunodeficiency, abusers (16,8%), 14 homosexual men munolabelling did, were essentially recurrences occurred. (average age 49,9 yr, range 39-82 yr) negative for VCA (Fig, 2), with HL had died after an average pe- Table 3. Histologic findings in 30 biopsies of riod of observation of 7,2 months HL, (range 1 to 27 months), 13 patients with Discussion HL have been observed more than 4 The largest group of individuals suf- wk with an average of 5,2 months fering from AIDS in the Federal Re- (range 1 to 13 months). In 68 patients public of Germany including West Ber- EBV-VCA+ 20 the period of observation was less than Hyperparakeratosis 30 lin are homosexual men (40), This is Hyperplasia/acanthosis 30 4 wk. Out of 95 patients with HL 18 the risk group with a high prevalence Hairlike projections 10 had no general symptoms, 17 presented rate of HL, as has been found in the Koilocyte-like cells 27 with ARC and 60 had developed present study. Although the prevalence Bacteria on surface 11 AIDS, The CDC classification at the PAS + ; (Candida) 14 rate showed significant differences Leukocytes in rel, to Catidida 0 initial diagnosis of HL in 95 patients is some centers (San Francisco, Copenh- Leukocytes in epithelium 10 shown in Table 2, agen) have recorded comparable prev- Inflammation absent 16 CD4/CD8 ratios at the time of initial alence rates (25,4%), Also the data for Superf, slight diffuse infl, 9 diagnosis of HL could be stated in 19 average age and range were very simi- Superf, small clusters 5 Orat hairv tettkoptakia 413 pears to be extremely difficult to make a diagnosis of HL in cases of HIV-sero- negative patients. Histologic criteria of HL may not always be present in all cases (12), In addition to this, some of the criteria are of doubtful value, par- ticularly in relation to: 1: hyperparak- eratosis, 2: hyperplasia/acanthosis, 3: keratin projections, 4: koilocytosis, 5: presence of EBV in biopsy material. To the present date we are not aware of any orthologic study of the macro- and microstructure of the lateral border of the tongue. Preliminary studies showed, however, that normal tongues reveal a eorrugated pattern at the lat- eral border which, however, is not white as in HL (Lis ANDERSEN et at., in preparation). In this context it is ques- tionable whether hyperparakeratosis as described for HL is an abnormal hist- ologic criterium for the microstructure of the lateral border of the tongue. This Fig. 1. Immunohistochemical detection of EBV-VCA in surface epithelium with even distri- is the area of the tongue which is in bution of positive epithelial cells (FITC, EBV-VCA; x 510), constant contact with the teeth and therefore, as a sign of increased epi- Although a considerable number of As in clinical diagnosis, the situation of thelial turnover due to microtrauma, cases with HL have been published, bias is also present for the oral patholo- some degree of hyperparakeratosis problems relating to clinical and hist- gist. The diagnosis of HL will readily be may normally occur. The same relates ologic diagnosis and of pathogenesis made if some of the criteria character- to hyperplasia and acanthosis. Studies have not been solved. istic for HL are present in a biopsy of of both the macro- and the microstruc- the lateral border of the tongue and if ture of the lateral border of the tongue the status of HIV infection of a patient in non-HlV-infected patients between Clinical diagnosis of orai hairy ieukoplakia is known. In most countries, biopsy the age of 20 and 45, preferably men, White lesions of the oral mucosa are specimens or smears have to be signed are utgently needed. Keratin projec- common and a number of differential out to be infectious or to contain HIV- tions have been observed in the major- diagnoses have been summarized as infected material. In contrast, it ap- ity of the cases (80%) (13), however. frictional keratosis, lichen planus, gal- vanic lesion, idiopathic leukoplakia, to- bacco-associated leukoplakia, tongue biting, severe leukedema and geo- graphic tongue (13), A most important issue in the diagnosis of HL is the ques- tion whether the diagnosis is based on information on HIV-seropositivity or -negativity. As soon as a clinician is informed about the HIV status of a pa- tient he is inclined to assess a lesion on the border of the tongue as HL, In addition to this bias the problem of oral candidiasis involving the lateral border of the tongue must be considered. Only alter antimycotic therapy should a diag- nosis of HL be made. The fact that HL also occurs in non-HIV-inlected indi- viduals (34) makes the diagnosis of HL even more complicated,

HIstopathoiogic diagnosis Although clear-cut histopathologic cri- teria have been proposed, a number of problems are still existent and have Fig. 2. Surface epithelium shows positive staining for EBV-VCA on left side of print. Boidcr been addressed recently (13, 18, 34), between positive and negative areas is abrupt (FITC, EBV-VCA; x 700). 414 REICHART ET AL, et al. they are missing in about 20% of diag- that comparative studies of the normal oral "hairy" leukoplakia, an AIDS-as- nosed HL cases. Clinically, as well as lateral border of the tongue are neees- sociated lesion, N Engt J Med 1985; 313: histologically, these keratin projections sary in order to reassess the various 1564-71, or hair-like formations have not been histological criteria used for the diag- 4, PINDBORG JJ, SCHIODT M, REIBEL J, observed in our material (33,3%) as nosis of HL, PRAETORIUS F, HANSEN HJ, GAUB J, Re- gression of oral "haret" leukoplaki hos frequently as it has been reported in patient med AIDS, Tandtaegebtadet other studies. Etioiogy, pathogenesis 1986; 90: 356-60, The concept of koilocytosis in HL 5, REICHART P, POHLE HD, GELDERBLOM has also been questioned recently (18, The detailed etiology of HL is un- H, STRUNZ V, AIDS - Orale Manifes- 34). Originally, this particular change solved. Several factors have been sug- tationen, Dtsch Zatinaerztt Z 1986; 4: has been described in uterine cervical gested to play a role in pathogenesis. 374-6, mucosa (41), Human papillomavirus Initially, Candida infection had been 6, REICHART P, GELDERBLOM H, POHLE (HPV) has been considered to be the considered to be the eause of HL (1), HD, PHILIPSEN HP, "Hairy leukopla- underlying eause of koilocytosis in cer- kia" (AIDS) - Klinik und Morphologie, In fact it must be stated that even after Dtscti Z Mund Kiefer Gesichtsdiir 1986; vical mucosa. In HL HPV, however, antimycotic therapy a high number of 10: 161-5, has to date not convincingly been dem- biopsy specimens (14 of 30) revealed 7, FRIEDMAN-KIEN AE, Viral origin of onstrated. The fact that some research- hyphae in PAS-stained sections. In EM hairy leukoplakia. Lancet 1986; 2: ers have used the term 'koilocyte-like studies the presence of both Candida 694-5, changes' is a hint towards a differen- and EBV particles in oral epithelium 8, EvERSOLE LR, JACOBSEN P, STONE CE, tiated understanding of the eoncept of has been demonstrated (35), The role FRECKLETON V, Oral condyloma planus these changes. EBV has undoubtedly of both Candida and EBV in producing (hairy leukoplakia) among homosexual been demonstrated in HL and has been a whitish lesion at the lateral border of men: a clinicopathologic study of thirty- discussed in the etiology of this lesion. the tongue has not been solved. In fact, six cases, Orat Surg 1986; 61: 249-55, According to SYRJANEN et al. (34) the our observation of HL-biopsies nega- 9, SILVERMAN S JR, MIGLIORATI CA, Lo- ZADA-NuR F, GREENSPAN D, CONANT vacuolized or ballooning epithelial cells tive for EBV antigen may hint to HL as MA, Oral findings in people with or at found in HL are not identical with the a condition for EBV expression rather high risk for AIDS: a study of 375 ho- true "koilocytes". The characterization than EBV as a cause of these lesions. mosexual males. JADA 1986; 112: of these large pale staining cells in the Although the absence of Langerhans 187-92. prickle cell layer of HL is even more cells at the lateral border of the tongue 10, WRAY D, MOODY GH, MCMILLAN A, complicated by the fact that such cells has been discussed in the pathogenesis Oral "hairy" leukoplakia associated may also be observed in oral mucosa of HL (38) it is not clear why HL pre- with human immtmodeficiency virus in- affected by candidiasis and in oral pa- fection: report of two cases, Br Dent J dominantly involves the lateral border 1986; 161: 338-9, rakeratotie leukoplakias (8), Enlarged of the tongue. It has recently been epithelial cells of the surface layers may 11, KiMMiG W, MENSING H, SEYFARTH K, shown that Langerhans cells represent ScHAEG G, JAENNER M, NASEMANN T, also occur in lesions such as tongue bit- a susceptible substratum for HIV-1 rep- Orale "hairy" Leukoplakie - Frubsymp- ing. It is unknown whether koilocyte- lication also serving as reservoir for tom bei HTLV-III/LAV-Infektion, like cells also occur in the normal oral HIV (42), Dtsch Med Wsehr 1986; 111: 1394-7, mucosa of the lateral border of the While HL appears to be a newly rec- 12, BELTON CM, EVERSOLE LR, Oral hairy tongue. ognized oral disease entity a number of leukoplakia: ultrastructural features, J Due to the insecurities which may problems are still unsolved. These re- Orat Pattiot 1986; 15: 493-9, occur in the histopathological diagnosis late to global epidemiology, clinical 13, SCHIODT M, GREENSPAN D, DANIELS TE, GREENSPAN JS, Clinical and hist- of HL SYRJANEN et al. (34) have sug- and histologic diagnosis, to etiology as ologic spectrutn of oral hairy leukopla- gested that in patients whose HIV anti- well as pathogenesis. In all these fields, kia, Orat Surg 1987; 64: 7K>-20. body status is unknown the presence of further studies are needed. 14, RiNDUM JL, SCHIODT M, PINDBORG JJ, EBV in lesions should be demonstrated ScHEiBEL E, Oral hairy leukoplakia in immunohistochemically or using DNA Acknowledgment - Supported by a grant three hemophiliacs with human immu- techniques. Although this procedure from Bundesministerium fur Forschung und nodeficiency virus infection, Orat Surg may help in clarifying the diagnosis of Technologie, No, 11-071-88, 1987; 63: 437-40, HL, it must be considered that EBV 15, LuPTON GP, JAMES WD, REDFIELD RR, has now also been demonstrated in oral References BROWN C, RODMAN OG, Oral hairy leu- koplakia, A distictivc marker of human mucosa other than that of the lateral T-cell lymphotropic virus type III border of the tongue (33), In particular 1, GREENSPAN D, GREENSPAN JS, CONANT M, PETERSEN V, SILVERMAN S JR, DH (HTLV-III) infection. Arch Dertnatot the demonstration of structural pro- SouzA Y, Oral "bairy" leukoplakia in 1987; 123: 624-8, teins of EBV (capsid antigen) in super- male homosexuals: evidence of associ- 16, GROSS G, WIEGAND H, ZENTGRAF H, ficial layers of oral epithelium would be ation with both papillomavirus and a Epstein Barr-Virus-Nachweis in oraler helpful in the histopathological diag- herpes-group virus. Lancet 1984; 2: haariger Leukoplakie bei AIDS-Patien- nosis of HL. However, due to the ten, in Leukoplakien und unauffiilligen spotty distribution of EBV expression 2. HOLLANDER H, GREENSPAN D, STRIN- Zungenepithelien HIV-1-negativer Pa- in oral epithelium, VCA may not be GARi S, GREENSPAN J, SCHIODT M. Hairy tienten. Z Hatttkr 1988; 63: 44-8. demonstrated if biopsies are too small leukoplakia and the acquired immuno- 17, FiCARRA G, BARONE R, GAGLIOTI D, et deficiency syndrome, Atin Interti Med at. Oral hairy leukoplakia among HIV- or non-representative as was found in 1986: 104: 892 (only), positive intravenous drug abusers: a the present study where EBV could on- 3, GREENSPAN JS, GREENSPAN D, LEN- clinicopathologic and ultrastructural ly be found in 20 out of 30 biopsies. It NEiTE ET, et al. Replication of Epstein- study. Orat Surg 1988; 65: 421-6. appears from the present knowledge Barr virus within the epithelial cells of 18, KANAS RJ, ABRAMS AM, RECHER L, JEN- Oral hairy leukoplakia 415 SEN JL, HANDLERS JP, WUERKER RB, GH, KLEIN RS. Oral findings in patients Ultrastruetural and immunohistoehem- Oral hairy leukoplakia: A light micro- with aequired immunodeficiency syn- ical findings in oral hairy leukoplakia, scopic and immunohistochemical study, drome, Orat Surg 1987; 64: 50-6, Virchows Arch A 1988; 412: 533-42, Orat Surg 1988; 66: 334-40, 28, SCHOEFER H, OCHSENDORF FR, HELM 36, BECKER J, ULRICH P, KUNZE R, GELDER- 19, RESNICK L, HERBST JS, ABLASHI DV, et EB, MiLBRADT R, Treatment of oral BLOM H, LANGFORD A, REICHART P, Im- al. Regression of oral hairy leukoplakia "hairy" leukoplakia in AIDS patients munohistochemical detection of HIV after orally administered acyelovir ther- with vitamin A aeid (topically) or acy- structural proteins and distribution of apy, JAMA 1988; 259: 384-8. clovir (systemically), Dermatotogica T-lymphocytes and Langerhans cells in 20, SCHIODT M, BYGBJERG I, BAKILANA P, et 1987; 174: 150-1, the oral mucosa of HIV infected pa- at. 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