Oral hairy leukoplakia

Lionel Resnick, MD,a Jay S. Herbst, MD,a and Nancy Raab-Traub, PhDb
Miami Beach, Florida, and Chapel Hill, North Carolina

Oral hairy leukoplakia occurs almost exclusively in human immunodeficiency virus (HIV)-
infected patients and is predictive for the development of acquired immunodeficiency
syndrome (AIDS). It presents as a white plaque with a rough surface, most commonly on
the sides of the tongue. The eruption is frequently overlooked, and, because it is commonly
mistaken for oral candidiasis, its true incidence is unknown. The leukoplakia is the result of
permissive infection of epithelial cells by the Epstein-Barr virus. Antiviral therapy that inhib-
its Epstein-Barr virus replication can result in clinical improvement. Oral hairy leukoplakia
provides a unique clinical model for investigations on the pathogenesis of Epstein-Barr virus
infection. (J AM ACAD DERMATOL 1990;22:1278-82.)

Oral hairy leukoplakia is a specific, viral-induced
eruption that has exhibited no malignant potential.
It occurs almost exclusively in human immunodefi-
ciency virus (HIV)-infected patients and is predic-
tive for the development of progressive immune
suppression and acquired immunodeficiency syn-
drome (AIDS).l-5 In one study, patients with oral
hairy leukoplakia hada 48% probability of develop-
ing AIDS within 16 months and 83% within 31
months. 6
In 1984, Greenspan and coworkers] described the
clinical, histopathologic, and virologic findings of
oral hairy leukoplakia in a cohort of homosexual
men. The leukoplakia has subsequently been identi-
fied in members of all HIV-associated risk groups
except infants. 7-9 Oral hairy leukoplakia appears as
white plaques with a rough surface, most commonly
on the sides of the tongue (Fig. 1). The plaques do
not rub off, and in the majority of patients they are
asymptomatic. Some patients complain of pain or
burning associated with the leukoplakia, not attrib-
uted to candidiasis or herpes simplex virus infec-
tion. 10, 11 The eruption is frequently overlooked, and
because it is commonly mistaken for oral candidia-
sis, the true incidence is unknown. In many cases,
From the Departments of Dermatology and Pathology, Mount Sinai
Medical Center of Greater Miami," and the Departments of Micro-
biology and I mmunology and Cancer Research Center, University of
North Carolina,b Chapel Hill.
Reprint requests: Lionel Resnick, MD, Departments of Dermatology
and Pathology, Mount Sinai Medical Center of Greater Miami, Mi-
ami Beach, FL 33140.
16/0/19118
1278
Candida alMeans can be demonstrated within the
leukoplakia. After the elimination of the yeast with
antifungal therapy, however, the plaques persist. 4
Although unexplained, spontaneous regression has
been reported. 1
The histopathology is unlike that of any previ-
ously described leukoplakia. Parakeratosis, acantho-
sis, and characteristic ballooning of the stratum
spinosum are seen (Fig. 2).1, J2 It resembles verrucae
and uterine condylomata. Previous studies sug-
gested the association of human papillomavirus with
the development of oral hairy leukoplakia.1, 13·15
Reports have been conflicting, and definitive evi-
dence is lacking, however.
Ultrastructural analysis with electron microscopy
revealed enveloped viral particles (175 nm in diam-
eter) that have the characteristic appearance of a
member ofthe herpes group (Fig. 3).1,16 This herpes
group virus within the cells of the leukoplakia was
shown to be Epstein-Barr virus. 17 Direct immuno-
fluorescence performed on biopsy specimens using
monoclonal antibodies directed against Epstein-
Barr virus viral capsid antigen and early antigen re-
vealed positive staining in the nuclei of the epithelial
cells (Fig. 4).4,17
Epstein-Barr virus IgA viral capsid antigen anti-
bodies have been detected in the saliva of patients
with oral hairy leukoplakia (personal observation)
(Table 1). These antibodies had previously been de-
scribed only in the saliva of patients with nasopha-
ryngeal carcinoma and may provide the basis for a
rapid diagnostic test. I8 Their presence suggests that
Epstein-Barr virus causes epithelial cell destruction,
Volume 22
Number 6, Part 2 Oral hairy leukoplakia 1279
June 1990

Fig. 1. Clinical appearance of oral hairy leukoplakia before (A) and after (B) surgical exci-
sion.
Fig. 2. Histopathology of oral hairy leukoplakia tissue. (X40.)

leading to a local mucosal IgA response. In situ Ep- Table 1. Epstein-Barr virus IgA viral capsid
stein-Barr virus DNA hybridization detected the antigen antibodies in saliva
presence of viral DNA at the koilocytotic cell layer Risk mv IgA
(Fig. 5).4, II A high copy number of linear Epstein- factor serostatus VeA titer
Barr virus genomes was demonstrated by Southern
Blot DNA hybridization, suggesting that Epstein- H + + 1:4
H + + 1:4
Barr virus is replicating and causing a lytic infection 1:2
H + +
of epithelial cells (Fig. 6),17 H + + 1:8
Oral hairy leukoplakia should be diagnosed by B + + 1:2
strict clinical, histologic, and virologic criteria. White H +
plaques on the sides of the tongue can be confused H +
IV +
with candidiasis, lichen planus, geographic tongue, H
or other conditions. 19 Virologic evidence of Epstein-
Barr virus within the epithelial cells should be nec- B, Bisexual; H. homosexual; IV, intravenous drug user; OHL, oral hairy
leukoplakia; VCA, viral capsid antigen; +, presence; -. absence. Sali-
essary to confirm the diagnosis of oral hairy leuko- vary Epstein-Barr virus IgA viral capsid antigen antibody tests were
plakia. Noninvasive techniques, such as in situ Ep- performed as previously described. IS
stein-Barr virus DNA hybridization ofcell scrapings
from the leukoplakia, allow for a simple, rapid (less Because oral hairy leukoplakia is not known to be
than 4 hours), and highly accurate method for the a premalignant condition, therapy is not indicated.
detection of Epstein-Barr virus that may eliminate If patients complain of pain or burning or the
the need for biopsy. I I appearance of their tongue, therapeutic options ex-
 Journal of the
American Academy of
1280 Resnick et al. Dermatology

Fig. 3. Electron microscopy of oral hairy leukoplakia tissue. (X60,OOO.)

Fig. 4. Direct immunofluorescence staining for Epstein-Barr virus viral capsid antigen
antibodies. A, Staining of nuclei in epithelial cells of hairy leukoplakia tissue. B, Normal
tongue control.

Fig. 5. In situ Epstein-Barr virus DNA hybridization. Photomicrographs of epithelial cells

of the tongue. A, Positive staining of nuclei from a biopsy specimen. B, Cell scrapings of oral
hairy leukoplakia. C, Negative staining of a biopsy specimen from uninvolved tongue mucosa.
(Immunoperoxidase stain; original magnification XlOOO.)
Volume 22
Number 6, Part 2
June 1990 Oral hairy leukoplakia 1281

ist. The antiviral agents acyclovir, 9-( 1,3-dihydroxy-

2-propoxymethyI) guanine (DHPG), desciclovir,
and zidovudine have been associated with regression
of the leukoplakia by inhibiting the replication of
Epstein-Barr virus. 2o-27 Epstein-Barr virus remains
latent within the epithelial cells and reactivates when
antiviral therapy is discontinued, resulting in recur-
rence. Replication of Epstein-Barr virus within the
epithelial cells is believed to be necessary for the de-
velopment of oral hairy leukoplakia. Oral hairy leu-
koplakia provides a clinical model for evaluation of
new antiviral agents with anti-Epstein-Barr virus
properties.
Another therapeutic modality is surgical excision.
Surgical excision of the leukoplakia is associated
with remissions and resolution of pain or burning
(Fig. 1).11 The long-lasting remissions despite the
presence of Epstein-Barr virus suggest that other
cofactors, altered by surgical excision, may be 095-8 HL1 HL2
Induced unlnduco<J
important in the development of oral hairy leuko-
plakia.
probe: Xhol 1.9
Many questions remain unanswered. Why is the
tongue the major target? What is the epithelial cell
receptor for Epstein-Barr virus? Is infection caused Fig. 6. Detection of Epstein-Barr virus DNA in hairy
by a lytic, nontransforming strain of Epstein-Barr leukoplakia tissue by Southern blot hybridization and
virus? Could a lytic, nontransforming strain of prepared with DNA extracted from two specimens of oral
hairy leukoplakia and the Epstein-Barr virus producer
Epstein-Barr virus cause other forms of clinical lymphoblastoid cell line, B95-8. The B95-8 cell line was
disease? Is Epstein-Barr virus replication in epit- either untreated or treated with phorbols to increase viral
helial cells associated with local or systemic im- replication. The right terminal BamHi fragments ofEp-
mune suppression, and what effects will antiviral stein-Barr virus were identified by hybridization with a
therapy produce? What is the role of human pap- probe, XhoI-1.9, representing unique DNA adjacent to
illomavirus or other cofactors in the develop- the terminal repeats at the right end of the linear genome.
In uninduced B95-8 DNA, abundant multiple fused
ment of oral hairy leukoplakia'? Understanding the fragments representing episomal DNA were detected.
Epstein-Barr virus/host cell interactions will lead After induction, a ladder array representing virion DNA
to effective prevention and therapy of Epstein-Barr was detected. In the oral hairy leukoplakia specimens,
virus-associated diseases. abundant ladder arrays representing linear DNA were
detected without evidence of fused terminal fragments.
We thank Jefferson Morgan, John Sixbey, and Beryn
Frank for technical assistance and helpful discussions.
REFERENCES
1. Greenspan D, Greenspan JS, Conant M, et al. Oral "hairy" cutaneous disease in patients with acquired immunodefi-
leukoplakia in male homosexuals: evidence of association ciency syndrome (AIDS) or AIDS-related complex. JAM
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Antiviral therapy against HIV infection

Hiroaki Mitsuya, MD, Robert Yarchoan, MD, Seiji Hayashi, MD, and Samuel Broder, MD
Bethesda, Maryland

The replication of human immunodeficiency virus (HIV) can be suppressed in vivo by drugs
chosen on the basis of their selective in vitro antiviral activity. Such suppression can confer
prolonged survival and improved quality oflife in patients with already established HIV in-
fection. The clinical benefits indicate that targeted therapy for acquired immunodeficiency
syndrome based on the emerging knowledge of replicative cycle of HIV is an attainable goal.
(J AM ACAD DERMATOL 1990;22:1282-94.)

The acquired immunodeficiency syndrome
(AIDS) is caused by human immunodeficiency vi-
rus (HIV), which hasthe capacity to replicate within
critical cells of the immune system, particularly in
monocytes/ macrophages and helper T cells). 1-4 The
From the Clinical Oncology Program, Division of Cancer Treatment,
National Cancer Institute, National Institutes of Health.
Reprint requests: Hiroaki Mitsuya, MD, The Clinical Oncology Pro-
gram, Building 10, Room 13N248, National Cancer Institute,
Bethesda MD 20892.
16/0/19115
1282
purpose of this article is to summarize possible ther-
apeutic interventions that are based on the emerging
knowledge of the life cycle of HIV and progress in
the development of drugs against AIDS.
The different stages in the life cycle of HIV
present a variety of targets for antiviral agents. 5
These are summarized in Table I. Reverse tran-
scriptase is one of the most attractive targets and
there have been notable clinical successes, especially
with 3'-azido-2',3'-dideoxythymidine, better known
as zidovudine or azidothymidine (AZT).6-9 The
testing of new antiretroviral agents depends on the