J Cutan Pathol 2011: 38: 275279 Copyright 2010 John Wiley & Sons A/S

doi: 10.1111/j.1600-0560.2010.01649.x
John Wiley & Sons. Printed in Singapore Journal of
Cutaneous Pathology

Iatrogenic oral hairy leukoplakia:

report of two cases
Oral hairy leukoplakia (OHL) presents as a white, plaque-like lesion Erica C. Rushing1 , Aaron
typically occurring on the lateral border of the tongue. This condition is P. Hoschar1 , Jonnelle
caused by the EpsteinBarr virus, a human herpesvirus that often K. McDonnell2 and Steven
establishes lifelong, asymptomatic latent infection. OHL, initially D. Billings1,2
described in immunocompromised men infected with the human
1 Department of Anatomic Pathology,
immunodeficiency virus (HIV), has also been described in other
Cleveland Clinic, Cleveland, OH, USA, and
severely immunocompromised patients. Only rarely has OHL been 2
Department of Dermatology, Cleveland
reported in less profoundly immunocompromised patients primarily in Clinic, Cleveland, OH, USA
the setting of corticosteroid therapy. Here we report on two additional
Steven D. Billings,
cases of OHL attributable to immunosuppressive medications. Department of Anatomic Pathology,
Cleveland Clinic,
Keywords: EpsteinBarr virus, infectious diseases, in situ hybridization, 9500 Euclid Ave., L25,
oral hairy leukoplakia, pseudomalignancy Cleveland, OH 44195, USA
Tel: +1 216 444 2826
Rushing EC, Hoschar AP, McDonnell JK, Billings SD. Iatrogenic oral Fax: +216 445 6967
hairy leukoplakia: report of two cases. e-mail: billins@ccf.org
J Cutan Pathol 2011; 38: 275279. 2010 John Wiley & Sons A/S. Accepted for publication November 1, 2010

Case report keratosis, and morsicatio mucosae oris. As a result

Oral hairy leukoplakia (OHL) represents an
oral infection caused by EpsteinBarr virus
(EBV) infection. OHL was initially described in
1984 in a series of patients with the acquired
immune deficiency syndrome (AIDS).1 Since its
initial description, OHL has been described in
other severely immunocompromised individuals,
including transplant recipients, and patients with
leukemia or other malignancies. There have been
only rare reports of OHL in less profoundly
immunocompromised patients primarily in the
setting of corticosteroid therapy.
Clinically, OHL presents as leukoplakia. The
lesions present as unilateral or bilateral white, non-
removable, corrugated plaques on the lateral portion
of the tongue with thickened hair-like projections.2,3
In addition to the lateral tongue, OHL can also
affect the dorsal or ventral tongue, palate mucosa,
oropharynx, floor of the mouth, or the buccal
mucosa.3,4
OHL is often mistaken clinically for a variety
of entities that cause leukoplakia, including lichen
planus, candidiasis, benign alveolar ridge keratosis,
squamous cell carcinoma, smokeless tobacco
of OHL being confused with other entities, patients
may be treated with anti-fungal or topical steroid
agents for lengthy periods without response before
a biopsy is obtained. It is important to consider
OHL in the differential diagnosis of leukoplakia
in any patient, even if they are not profoundly
immunocompromised. Herein, we describe two cases
where the clinical diagnosis of OHL was not initially
suspected.
Methods
Clinical information was obtained through chart
review and direct communication with clinicians
and patients. Formalin-fixed and paraffin-embedded
tissue was stained with hematoxylin and eosin,
and the presence of EBV was confirmed using
chromogenic in situ hybridization (760-092, ISH
Iview Blue, Ventana Medical Systems, Tucson, AZ,
USA) with an EBER probe (780-2842, Inform EBER
probe, Ventana Medical Systems, Tucson, AZ,
USA). Periodic acid Schiff (PAS) (Dako, Denmark)
and Grocott Methenamine Silver (GMS) (Ventana
Medical Systems, Tucson, AZ, USA) stains were also
performed on case 2.
275
Rushing et al.
Fig. 1. Lesion characterized by a white, non-removable, reticulated
plaque of the right lateral tongue.
Case 1
The patient was a 65-year-old woman with a
history of type II diabetes and a 1-year history
of biopsy-proven erosive oral and vulvar lichen
planus. She was a widowed non-smoker with no
history of recreational drug use or risk factors for
A)
C)
Fig. 2. A) Low-power views showing parakeratosis, mild basal cell hyperplasia and ballooning keratinocytes. B) There were co-existing
features of morsicatio mucosae oris with prominent bacterial colonization of the epithelial surface. C) Examination on high-power showed the
characteristic eosinophilic intranuclear inclusions and beaded nuclear chromatin. D) EpsteinBarr virus RNA within keratinocyte nuclei as
shown by chromogenic in situ hybridization.
276
human immunodeficiency virus (HIV). Her lichen
planus treatment included fluconazole, dapsone, oral
prednisone sliding scale, dexamethasone swish, and
clobetasol ointment and gel for her oral lesions, as
well as clobetasol ointment, zinc oxide and nystatin
cream for her vulvar lesions. Subsequently, she
presented again to the clinic with white reticulated
plaques that would not scrape off involving the
right and left lateral tongue (Fig. 1). The lesions
were presumed to represent recurrent lichen planus,
but a biopsy was obtained. The biopsy showed
irregular parakeratosis, ballooning keratinocytes
and intranuclear eosinophilic inclusions (Fig. 2).
Chromogenic in situ hybridization for EBV (EBER)
was positive for EBV, thereby confirming the
diagnosis of OHL (Fig. 2D). Co-existing features of
morsicatio mucosae oris with prominent colonies of
bacteria on the mucosal surface were also present in
this case.
Case 2
The patient was a 77-year-old woman with a past
medical history significant for severe rheumatoid
B)
D)

A)
Fig. 3. A) Low-power magnification showing hyperkeratosis, ballooning keratinocytes and superficial papillary dermal inflammation without
superimposed features of morsicatio mucosae oris. B) High-power magnification demonstrating perinuclear clearing, eosinophilic intranuclear
inclusions and nuclear beading of chromatin.
arthritis who presented with a several week history
of a non-removable white plaque on the tongue
and floor of her mouth measuring approximately
2.5 cm 2.0 cm. The patient had a 40-year-long
history of methotrexate and prednisone therapy use
for treatment of rheumatoid arthritis. She was a
non-smoker without any history of recreational drug
use or risk factors for HIV. Despite being on long-
term steroid therapy, she had no history of recurrent
infections or hospitalizations. An initial biopsy of
her oral lesion was inconclusive. The patient was
initially treated for possible candidiasis with nystatin
and fluconazole without response. The clinical
diagnosis of oral lichen planus was entertained
and the patient was treated with fluticasone
propionate irrigation, again, without response. A
repeat biopsy 4 months later showed parakeratosis
with ballooning degeneration of keratinocytes
and intranuclear eosinophilic inclusions, without
evidence of dysplasia or carcinoma (Fig. 3).
Chromogenic in situ hybridization for EBV (EBER)
was performed and was strongly positive, confirming
the diagnosis of OHL. GMS and PAS stains were
negative for fungi.
Discussion
OHL was originally described in immunocompro-
mised homosexual men infected with HIV. It was
considered an early diagnostic and prognostic fac-
tor of immunosuppression and early progression
to AIDS and was found in up to 25% of that
patient population.2 The precise pathogenesis of
OHL is incompletely understood. It is well known
that EBV can remain in latent form in circulat-
ing B lymphocytes.2,5,6 Establishment of OHL in
HIV-positive patients may be the result of active
exchange of multiple EBV strains by B-cell transfer7,8
Iatrogenic oral hairy leukoplakia
B)
or via a direct entry of cell virions through basolateral
membranes with adjacent epithelial cell spread after
initial infection.9 OHL could be because of contin-
uous or repeated infection of the more superficial
epithelium by infected cells or alternatively might
stem from reactivation of latent lytic proteins in basal
cells.3,4,10 13 Differences in OHL pathogenesis may
also reflect differences in the immune status of the
affected patients.
OHL has also been documented in less
profoundly immunocompromised patients in the
settings of inhaled steroid therapy for asthma, steroid
therapy for chronic medical conditions and, in
rare instances, immunocompetent patients.2,14 18
Interestingly, there may be some pathogenetic
differences between OHL in HIV patients and OHL
in other patient groups. While EBV replication is
present in normal tongue epithelium in HIV-positive
patients, EBV replication is a rare occurrence in
immunocompetent patients.8,13,19,20 Therefore, a
latent reservoir in mucosal epithelium does not
appear to be an underlying mechanism for these
non-HIV patients, but rather OHL is probably the
result of new/persistent infection with EBV.
Our two cases highlight the fact that OHL
is less frequently considered in the clinical
differential diagnosis of leukoplakia in less profoundly
immunocompromised patients. They underscore the
importance of a biopsy to establish the diagnosis,
especially in the setting where patients do not respond
to medical therapy. OHL can be recognized by
its defining histopathological features: acanthosis,
parakeratosis, ballooning keratinocytes with small
pyknotic nuclei with intranuclear inclusions (Cowdry
type A) and clear perinuclear halos.3,4 The
vacuolated keratinocytes often show margination
of the nuclear chromatin giving it a nuclear
beading appearance.2,3 The cytoplasm can have a
277
Rushing et al.
ground glass appearance similar to other herpesvi-
ral infections and there may be a sparse associated
inflammatory infiltrate.3,4 Demonstration of EBV
within the mucosal epithelium is requisite for the
diagnosis.3,4 Chromogenic in situ hybridization for
EBV (EBER) is the most sensitive technique for
practical clinical use.4,21
The differential diagnosis of OHL includes other
causes of leukoplakia. As in our cases, lichen planus is
often the first clinical diagnosis considered in patients
with OHL. Patients with lichen planus can present
with features similar to OHL, with hyperkeratotic
white plaques involving the lateral tongue and buc-
cal mucosa, and clinical relapses and remissions can
ensue.22 However, OHL and lichen planus are read-
ily separable based on histopathological analysis.
In solitary lesions of OHL, squamous dyspla-
sia, squamous cell carcinoma or tobacco keratosis
could be considered. Although the acanthosis and
ballooning degeneration can cause confusion with
a neoplastic process, OHL lacks hyperchromasia,
pleomorphism, a disordered growth pattern or atyp-
ical mitotic figures, as can be seen with dysplasia
or carcinoma. Smokeless tobacco keratosis typically
presents in the mandibular sulcus, as opposed to the
lateral tongue. Microscopically, smokeless tobacco
keratosis also shows superficial pallor as a result of
ballooning keratinocytes, but the affected epithelium
typically has pyknotic nuclei without the intranu-
clear inclusions of OHL.23 Furthermore, smokeless
tobacco keratosis will show amyloid-like PAS-positive
material deposited around the minor salivary glands.
Candidiasis can bear a clinical resemblance to
OHL, but the plaques of candidiasis can usually
be scraped off on physical examination. Candidiasis
has less ballooning of the keratinocytes, but compli-
cating the pathological differential diagnosis is the
fact that patients with OHL may have co-existing
candidiasis.24 The recognition of the yeast may result
in underlying OHL being overlooked.
Morsicatio mucosae oris is perhaps the most diffi-
cult consideration in the histopathological differential
diagnosis. This entity represents frictional hyper-
keratosis that presents as leukoplakia clinically. It
represents a reactive alteration that is the result
of persistent chewing/biting of the mucosa. Most
commonly, it presents on the buccal mucosa (mor-
sicatio buccarum) but also may present on the
tongue (morsicatio linguarum) or lips (morsicatio
labiorum).25 Microscopically, morsicatio mucosae
oris bears a striking resemblance to OHL. Both
have acanthosis with ballooning degeneration of
keratinocytes and parakeratosis. Morsicatio charac-
teristically has prominent bacterial colonization of
the mucosal surface and lacks the EBV intranu-
clear inclusions of OHL.25 Like candidiasis, the
findings of morsicatio can coexist with OHL. This
was observed in our case 1 and can further com-
plicate interpretation. As the intranuclear inclu-
sions seen in OHL may be difficult to see in
individual cases, we recommend in situ hybridiza-
tion for EBER in immunocompromised patients
before rendering the diagnosis of morsicatio mucosae
oris.
Conclusion
OHL represents a benign oral infection that may be
misdiagnosed both clinically and histopathologically.
Our cases emphasize that OHL should be consid-
ered in the differential diagnosis of leukoplakia even
in patients who are not profoundly immunocompro-
mised. OHL should be considered in patients not
responding to medical treatment for other entities
such as lichen planus or candidiasis. Poor response
to medical therapy is always an indication for biopsy
in patients with leukoplakia.

References
1. Greenspan D, Greenspan JS, Conant M,
Petersen V, Silverman S, De Sousa Y. Oral
hairy leukoplakia in male homosexuals: evi-
dence of association with both papillomavirus
and a herpes-group virus. Lancet 1984; 2:
831.
2. Piperi E, Omlie J, Pambuccian S, Koutlas IG.
Oral hairy leukoplakia in HIV-negative
patients: report of 10 cases. Int J Surg Pathol
2008; 20: 1.
3. Triantos D, Porter SR, Scully C, Teo CG.
Oral hairy leukoplakia: clinicopathologic fea-
tures, pathogenesis, diagnosis, and clinical
significance. Clin Infect Dis 1997; 25: 1392.
4. Ikediobi N, Tyring S. Cutaneous manifesta-
tions of Epstein-Barr virus infection. Dermatol
Clin 2002; 20: 283.
5. Thomas JA, Felix DH, Wray D, et al.
Epstein-Barr virus gene expression and epithe-
lial cell differentiation in oral hairy leuko-
plakia. Am J Pathol 1991; 139: 1369.
6. Slots J, Saygun I, Sabeti M, Kubar A.
Epstein-Barr virus in oral diseases. J Periodont
Res 2006; 41: 235.
7. Palefsky JM, Berline J, Greenspan D,
Greenspan JS. Evidence for trafficking of
Epstein-Barr virus strains between hairy
leukoplakia and peripheral blood lympho-
cytes. J Gen Virol 2002; 83: 317.
8. Walling DM, Etienne W, Ray AJ, Flaitz CM,
Nichols, CM. Persistence and transition of
Epstein-Barr virus genotypes in the patho-
genesis of oral hairy leukoplakia. J Infect Dis
2004; 190: 387.
9. Tugizov SM, Berline JW, Palefsky JM.
Epstein-Barr virus infection of polarized
tongue and nasopharyngeal epithelial cells.
Nat Med 2003; 9: 307.
10. Itin PH. Oral hairy leukoplakia - 10 years on.
Dermatol 1993; 187: 159.
11. Niedobitek G, Young LS, Lau R, et al.
Epstein-Barr virus infection in oral hairy
leukoplakia: virus replication in the absence of
a detectable latent phase. J Gen Virol 1991;
72: 3035.
12. Walling DM, Ling PD, Gordadze AV,
Montes-Walters M, Flaitz CM, Nichols CM.
Expression of Epstein-Barr virus latent genes
in oral epithelium: determinants of the patho-
genesis of oral hairy leukoplakia. J Infect Dis
2004; 190: 396.

278

13. Walling DM, Flaitz CM, Nichols CM, Hud-
nall SD, Adler-Storthz K. Persistent produc-
tive Epstein-Barr virus replication in normal
epithelial cells in vivo. J Infect Dis 2001; 184:
1499.
14. Fluckiger R, Laifer G, Itin P, Meyer B,
Lang C. Oral hairy leukoplakia in a patient
with ulcerative colitis. Gastroenterology 1994;
106: 506.
15. Zakrzewska JM, Aly Z, Speight PM. Oral
hairy leukoplakia in a HIV-negative asthmatic
patient on systemic steroids. J Oral Pathol
Med 1995; 24: 282.
16. Lozada-Nur F, Robinson J, Regezi JA. Oral
hairy leukoplakia in non-immunosuppressed
patients. Oral Surg Oral Med Oral Pathol
1994; 78: 599.
17. Eisenberg E, Krutchkoff D, Yamase H. Inci-
dental oral hairy leukoplakia in immunocom-
petent persons. Oral Surg Oral Med Oral
Pathol 1992; 74: 332.
18. Felix DH, Watret K, Wray D, Southam JC.
Hairy leukoplakia in an HIV-negative nonim-
munosupressed patient. Oral Surg Oral Med
Oral Pathol 1992; 74: 563.
19. Herrmann K, Frangou P, Middeldorp J,
Niedobitek G. Epstein-Barr virus replication
in tongue epithelial cells. J Gen Virol 2002;
83: 2995.
20. Frangou P, Buettner M, Niedobitek G.
Epstein-Barr virus (EBV) infection in epithe-
lial cells in vivo: rare detection of EBV repli-
cation in tongue mucosa but not in salivary
glands. J Infect Dis 2005; 191: 238.
Iatrogenic oral hairy leukoplakia
21. Gully ML. Molecular diagnosis of Epstein-
Barr virus related diseases. J Mol Diagn 2001;
3: 1.
22. Epstein JB, Wan LS, Gorsky M, Zhang L.
Oral lichen planus: progress in understanding
its malignant potential and the implications
for clinical management. Oral Surg Oral Med
Oral Pathol 2003; 96: 32.
23. Pindborg JJ, Reibel J, Roed-Petersen B,
Mehta FS. Tobacco-induced changes in oral
leukoplakic epithelium. Cancer 1980; 45:
2330.
24. Sciubba JJ. Opportunistic oral infections in
the immnosuppressed patient: oral hairy
leukoplakia and oral candidiasis. Adv Dent
Res 1996; 10: 69.
25. Woo SB, Lin D. Morsicatio mucosae oris - a
chronic oral frictional keratosis, not a leuko-
plakia. J Oral Maxillofac Surg 2009; 67: 140.
279