Viral diseases of the oral mucosa

Bethany R. Hairston, MDa, Alison J. Bruce, MDb,c,*, Roy S. Rogers III, MDb,c

aDepartment of Dermatology, Mayo Graduate School of Medicine, Rochester, MN 55905, USAbDepartment of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

cDepartment of Dermatology, Mayo Medical School, Rochester, MN 55905, USA

The oral mucosa is often involved in diseases

caused by viral pathogens. Viruses isolated from the

oral cavity may be direct causative agents, adjuncts in

the disease process, or superinfection of a separate

primary process. Viruses have variable mucosal pro-

cesses and stages of evolution, and many viruses have

similar clinical presentations. Often, the investigator

must consider the oral lesions in the context of the

general clinical presentation and use laboratory tests

for diagnosis. Both DNA and RNAviral families have

been implicated in oral mucosal diseases.

DNA viruses

Human herpesvirus

Multiple human herpesvirus (HHV) serotypes are

associated with oral diseases (Table 1). All HHVs

consist of double-stranded DNA. The viruses replicate

in the host cell, causing both cytopathic and inflam-

matory-mediated cell damage.

Human herpesvirus 1 and human herpesvirus 2

( herpes simplex viruses)

Herpes simplex virus (HSV)-1 and HSV-2 are

associated with primary and recurrent mucocutaneous

disease. The location of the disease depends on the

site of inoculation. HSV-1 is responsible for more than

90% of the lesions caused by HSV in the oral mucosa

[1]. More than 85% of the worlds population has

serologic evidence of previous HSV-1 exposure [2].

Most persons are exposed to the virus during child-

hood by mucocutaneous contact with another infected

person. A primary infection is the first infection with

HSV in a seronegative patient; many people have

asymptomatic primary infections and are unaware that

they harbor the virus.

Primary exposure to HSV-1 and, less commonly,

HSV-2 results in the syndrome known as primary, or

acute, herpetic gingivostomatitis. The disease is most

common in children 1 to 5 years old or young adults,

and the onset is approximately 5 to 10 days after

intimate mucocutaneous exposure to HSV. The virus

must come into contact with the mucosa or abraded

skin for infection to occur [3]. Fever, sore throat, and

painful vesicles that progress to erosions and ulcer-

ations may be present. Most commonly, lesions are

located on the buccal and gingival mucosa, hence, the

term gingivostomatitis (Fig. 1). Both keratinized and

nonkeratinized oral mucosa may be involved [4]. In

severe cases, dysphagia and lymphadenopathy may be

present. The episode usually lasts 10 to 14 days.

Primary infections in adults are less likely to result

in gingivostomatitis; however, HSV-associated phar-

yngitis may be a component of a mononucleosis-like

syndrome (Fig. 2) [5].

Following primary infection, HSV migrates by

retrograde axonal flow to the sensory ganglion inner-

vating the primary lesion [6]. An eruption that occurs

after latency is known as reactivated or recurrent

infection and occurs in approximately 40% of those

harboring HSV-1 [7,8]. HSV-2 recurrences in the oral

mucosa are less common than HSV-1 recurrences [9].

Recurrences generally are milder and of shorter dura-

tion than primary episodes in immunocompetent hosts

0733-8635/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved.

PII: S0733 -8635 (02 )00056 -6

* Corresponding author. Department of Dermatology,

Mayo Clinic, 200 First Street Southwest, Rochester,

MN 55905.

E-mail address: bruce.alison@mayo.edu (A.J. Bruce).

Dermatol Clin 21 (2003) 1732

and typically occur three or four times per year.

Activation of the virus with subsequent anterograde

migration along the sensory nerve usually is heralded

by a tingling, itching, or burning sensation at the

vermilion border. Clustered lesions progress from

erythematous papules to vesicles and may ulcerate,

producing the characteristic lesions of herpes labialis

(Fig. 3). Recurrent intraoral HSV with vesicles and

ulcers on the gingivae and hard palate may occur

alone or in parallel with herpes labialis (Fig. 4).

Healing generally occurs in 8 to 10 days.

Recurrences may be spontaneous or associated

with multiple factors, including emotional stress,

fatigue, illness, dental trauma [10], neurosurgical

axonal injury [11], orofacial fracture [12], and ultra-

violet light [10,13,14]. Immune system compromise

from malignancy or immunosuppressive therapy

[15,16], radiation therapy [17], transplantation regi-

mens [1820], and HIV infection [21,22] may result

in more frequent and more severe recurrences, with

potential extension into the deep mucosal and cuta-

neous layers of the skin [23].

Recurrent erythema multiforme has been linked to

preceding HSV infection and is known as herpes-

associated erythema multiforme (Fig. 5) [24,25]. In a

British study that reviewed recurrent erythema multi-

forme, approximately 71% of cases had previous HSV

infection. Oral erosions or ulcerations were common

Table 1

Herpetic infections of the oral mucosa

Oral disease Etiology

Herpetic gingivostomatitis HSV-1, HSV-2

Herpes labialis HSV-1, HSV-2

Varicella HHV-3 (varicella-zoster virus)

Herpes zoster HHV-3 (varicella-zoster virus)

Mononucleosis HHV-4 (Epstein-Barr virus)

Oral hairy leukoplakia HHV-4 (Epstein-Barr virus)

Cytomegalovirus HHV-5

Exanthema subitum HHV-6

Kaposis sarcoma HHV-8

Abbreviations: HHV, human herpesvirus; HSV, herpes

simplex virus.

From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and

management of oral viral infections. Dermatologic Therapy

2002;15:27187: with permission.

Fig. 1. Primary herpetic gingivostomatitis. (A) Vesicles and erosions of palate. (B) Well-circumscribed erosions of tongue.

(C) Vesicles and erythema of gingivae and interdental papillae. (D) Labial mucosal vesicles and erosions. [(A) and (D) From

Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatol Ther 2002;15:27187. By

permission of Blackwell Publishing, Inc: with permission.]

B.R. Hairston et al / Dermatol Clin 21 (2003) 173218

(69%), especially of the buccal mucosa and palate

[24]; targetoid lesions of the lips have also been

described [25].

Diagnosis of primary and recurrent HSV is aided

by the location and configuration of the lesions and

associated clinical features. Differentiation of herpetic

lesions from the herpetiform variant of recurrent aph-

thosis may be difficult [26]. Typically, aphthous ulcer-

ations occur predominantly on the nonkeratinized

mucosa, whereas recurrent HSV generally is found

on keratinized mucosa overlying bony prominences

(ie, alveolar ridges and the hard palate) [26,27].

Multiple laboratory tests are available to assist in

the diagnosis of herpetic infection (Table 2). Under

ideal conditions, the Tzanck smear is positive in

approximately 50% of HSVinfections [28]. Histologic

examination demonstrates a combination of direct

cytopathic effect and inflammatory response [3]. Tra-

ditionally, the reference standard of diagnosis has been

culture, with sensitivity increased in early vesicular

lesions, primary disease, and immunosuppressed per-

sons [23]. The polymerase chain reaction (PCR)

detects specific DNA sequences in HSV infection

and herpes-associated erythema multiforme [25,29]

and is more sensitive than cell culture for detecting

HSV [3032]. Direct immunofluorescence [33] and in

situ hybridization (ISH) [34] demonstrate HSV in

cutaneous specimens. Serologic testing is useful in

identifying past infection but has little value in dia-

gnosing acute mucocutaneous HSV infection because

titers are slow to rise [23].

Mouth rinses containing topical anesthetic agents

(viscous lidocaine [Xylocaine]) or diphenhydramine

(Benadryl) plus coating agents (magnesium-contain-

ing antacids) are helpful in relieving oral discomfort in

severe herpetic gingivostomatitis [4]. Fluid and elec-

trolyte balance should be maintained in infants and

children. In a randomized, placebo-controlled clinical

trial, oral acyclovir was effective for herpetic gingivo-

stomatitis in children, but it has not been approved by

the US Food and Drug Administration (FDA) for this

indication [35].

Topical agents are often used to treat recurrent

herpes labialis. In a recent double-blind, placebo-

controlled study of recurrent herpes labialis, docosanol

10% cream, a 22-carbon, saturated, primary alcohol

available as an over-the-counter medication (Abreva),

was found to be clinically efficacious in decreasing the

mean time to healing and the duration of symptoms

[36]. Penciclovir (Denavir) is a topical nucleoside ana-

logue superior to both placebo [37] and acyclovir for

treatment of recurrent herpes labialis [38]; it has been

approved by the FDA for recurrent disease. Topical

Fig. 2. Herpes pharyngitis, with erythema and erosions of

posterior oropharynx.

Fig. 3. (A) Recurrent herpes labialis of lower lip. (B) Well-circumscribed erosions of lateral tongue in association with lip lesions.

[(A) From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy

2002;15:27187: with permission.]

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 19

acyclovir cream and ointment have been less effective

for the treatment and suppression of recurrent HSV,

likely because of poor absorption through perioral

skin [14]. These three topical agents were compared

recently in an animal model (guinea pig) of cutaneous

HSV, and the efficacy of penciclovir was greater than

that of acyclovir cream, which was greater than or

equal to that of acyclovir ointment; the efficacy of all

compared agents was superior to that of docosanol

cream [39]. Protection of the lips from ultraviolet

exposure with sunscreen is also beneficial [13].

Oral antiviral therapy has not been approved by the

FDA for either the treatment or suppression of herpes

labialis in immunocompetent persons; however, acy-

clovir has proved to be efficacious in decreasing

lesion size and healing time without decreasing the

number of lesions if treatment is started in the pro-

drome or erythema stage [14]. Famciclovir (Famvir),

the well-absorbed oral prodrug of penciclovir, has

been shown clinically to decrease lesion size and time

to healing in herpes labialis induced by ultraviolet

light [40]. Acyclovir prophylaxis against herpes labi-

alis has been demonstrated to decrease the frequency

of recurrent episodes [41,42]. The effects from the

therapy do not seem to be long-lasting, however,

because the pretreatment recurrence rate returns after

cessation of acyclovir treatment [41].

Acyclovir is the treatment of choice for immuno-

suppressed persons; oral, intravenous, and topical

ointment formulations have been approved by the

FDA [43]. Intravenous foscarnet (Foscavir) is recom-

mended for acyclovir-resistant disease [44]. Suppres-

sive therapy with acyclovir is commonly used in

transplantation and chemotherapeutic regimens [45].

Famciclovir is indicated for the treatment of recurrent

herpes labialis in HIV because it is as effective and

well-tolerated as high-dose acyclovir [46]. Famci-

clovir also has been shown to decrease the frequency,

duration, and severity of HSV recurrences in HIV-

infected persons, but it has not been approved by the

FDA for this indication [47].

Human herpesvirus 3 (varicella-zoster virus)

Primary infection with varicella-zoster virus

(VZV), resulting in varicella, occurs through direct

contact with lesions or inhalation of infective respi-

ratory droplets. Varicella is primarily a disease of

childhood, with 90% of cases occurring in children

younger than 10 years [48]. One study has demon-

strated a nearly 99% rate of serologic immunity

among adults [49]. The disease generally is more

severe and prolonged in older persons [50].

After a 14- to 16-day incubation period following

exposure to VZV, a generalized pruritic eruption with

crops of erythematous maculae, papules, vesicles,

pustules, and crusted lesions begins on the face and

spreads rapidly to the trunk, with relative sparing of

the extremities. Oral lesions may coincide in onset

with the cutaneous eruption. Painful vesicles that may

ulcerate are found most commonly on the palate or

buccal or pharyngeal mucosa (Fig. 6) [51].

Fig. 4. Recurrent intraoral herpes simplex virus in patient

with hairy cell leukemia.

Fig. 5. Herpes-associated erythema multiforme. (A) Hemorrhagic crusting of lower lip. (B) Targetoid papules of palm.

B.R. Hairston et al / Dermatol Clin 21 (2003) 173220

Similar to HSV, VZV establishes latency in sen-

sory ganglia. Recurrent disease occurs in the derma-

tome innervated by the affected sensory ganglion. A

recurrent episode is known as herpes zoster. Among

multiple predisposing factors for herpes zoster are

HIV [22,5254], malignancy [55,56], iatrogenic

immunosuppression with corticosteroids [57], trans-

plantation regimens [50,58], and senescence of the

cellular immune system related to aging [59].

The clinical features of herpes zoster include a

dermatomal eruption heralded by segmental neuralgia

and pruritus, followed by herpetiform vesicles and

erythema with progression to pustules and crusting in

7 to 10 days. Cephalic zoster involves the second and

third divisions of the trigeminal nerve and may present

with oral cavity vesicles on an erythematous base,

with erosions, ulceration, and crusting preceded by

odontalgia (Fig. 7) [60]. Tooth exfoliation and man-

dibular necrosis are reported complications [54,61].

Ramsay Hunt syndrome, with neuritic involvement

and inflammation of cranial nerves VII and VIII, may

result in tinnitus, vertigo, otalgia, ageusia, hearing

loss, and mucosal lesions on the palate and anterior

two thirds of the tongue [62]. Facial palsy and deaf-

ness are potential complications.

Table 2

Diagnostic tools for detection of herpetic infections

Test Method Medium Comments

Histopathology Hematoxylin and eosin stain Tissue Ballooning and reticular

epidermal degeneration with

multinucleated keratinocytes

in HSV, VZV [3]

Cytomegalic nuclear and

cytoplasmic inclusions in

CMV [94]

Direct

immunofluorescence

Epifluorescence microscopy

following monoclonal antibody

application [33]

Tissue Useful for HSV, VZV [33],

and EBV [84]

Culture Cell culture growth to detect

cytopathic change [28]

Tissue, vesicular fluid Reference standard of detection

for all herpesviruses

Polymerase

chain reaction

Identification of viral nucleic acid Tissue, vesicular fluid,

paraffin-embedded

Most sensitive means of detecting

HSV [3032] and VZV [28,64]

tissue [65] Effective for all herpesviruses

In situ hybridization

Serology

Tzancks smear

Fluorescein-labeled DNA probe

visualized with antifluorescein

antibody [66]

Detection of antibodies

Characteristic viral cytopathic changes

Tissue, paraffin-

embedded tissue

Serum

Vesicle base scraping

Demonstrates location of virus

in tissue

Useful for HSV [34], VZV [66],

EBV [75,83], and CMV [94]

Correlation with past infection

Rapid, inexpensive

Multinucleated keratinocytes in

HSV and VZV [28,63]

Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; VZV, varicella-zoster virus.

From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy

2002;15:27187: with permission.

Fig. 6. Varicella infection with vesicles and surrounding

palatal erythema. (From Bruce AJ, Hairston BR, Rogers RS

III. Diagnosis and management of oral viral infections.

Dermatologic Therapy 2002;15:27187: with permission.)

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 21

The diagnostic methods for VZV are similar to

those for HSV. The Tzanck smear is positive in ap-

proximately 75% to 80% of cases of herpes zoster and

viral cultures are positive in 44% to 60%, reflecting

the difficulty with culturing VZV [28,63]. PCR is

more sensitive than viral culture [28,64] and can detect

VZV in formalin-fixed tissue specimens, vesicle fluid

swabs, crusts, and Tzanck smear debris [65]. Neither

PCR nor culture reliably demonstrate VZV from oral

samples in primary varicella, however, because the

virus is not harbored in the oropharynx after the

incubation period [64]. Direct immunofluorescence

[33] and ISH [66] also distinguish VZV from HSV.

Positive serology correlates with immunity [67].

Acyclovir has been shown to decrease both the

duration and severity of varicella in children [68];

however, it has not been approved by the FDA nor

widely used in clinical practice because of the benign

course of the disorder in immunocompetent hosts,

financial considerations, and concern for emergence

of acyclovir resistance. Painful oral lesions may

respond to topical anesthetic mouth rinses [69]. Acy-

clovir is the drug of choice for adults and immunosup-

pressed persons. The live, attenuated OKA varicella

vaccine has been approved by the FDA and is given to

persons older than 12 months, those with chronic dis-

ease, and those who are immunosuppressed [48,70].

Intraoral herpes zoster generally is more severe

and painful than oral varicella; oral analgesics admin-

istered in combination with topical anesthetic prepa-

rations may be needed. Acyclovir, famciclovir, and

valacyclovir (Valtrex) have all received FDA approval

for treatment of herpes zoster because the three agents

have comparable efficacy and safety profiles [7173].

Corticosteroids generally are not necessary for ad-

junctive treatment in herpes zoster except in Ramsay

Hunt syndrome, for which the combination of acy-

clovir and prednisone has been shown to reduce facial

nerve degeneration [74].

Human herpesvirus 4 (Epstein-Barr virus)

Epstein-Barr virus (EBV)induced diseases with

oral manifestations include infectious mononucleosis,

oral hairy leukoplakia, and Burkitts and nasopha-

ryngeal lymphomas. EBV infects multiple cell lines,

including B and T lymphocytes and squamous epithe-

Fig. 7. Herpes zoster. (A) Unilateral erythema, erosions, and crusting of upper lip and cheek. (B) Erosion of palate. (C) Unilateral

erosion and fissuring of tongue (arrow). [(A) and (B) From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management

of oral viral infections. Dermatologic Therapy 2002;15:27187: with permission.]

B.R. Hairston et al / Dermatol Clin 21 (2003) 173222

lial cells of the oropharyngeal and nasopharyngeal

mucosa [75]. The virus establishes latency in B lym-

phocytes andmay be reactivated in immunodeficiency.

Infectious mononucleosis is associated with palatal

petechiae, pharyngeal erythema, and tonsillar hyper-

trophy. These are nonspecific findings that may be

seen in many infections of the upper respiratory tract.

Fever, cervical lymphadenopathy, and a morbilliform,

erythematous exanthem may be present. The cuta-

neous features are more common in childhood. In a

severe case, infectious mononucleosis may be associ-

ated with necrotic gingival tissue [69]. The diagnosis is

based on clinical symptoms, hematologic findings,

and the presence of heterophil antibodies. Detection

of EBV-specific antibody is confirmatory [76]. Be-

cause the disease is self-limited, treatment is usually

symptomatic. Acyclovir is not effective [77]. Coinfec-

tion with b-hemolytic streptococci should be ruled outand, if present, treated with antibiotics; however,

neither ampicillin (Omnipen, Principen) nor amoxicil-

lin (Amoxil, Augmentin) should be used because of

the potential for generalized morbilliform eruptions in

patients with mononucleosis treated with these medi-

cations [78,79].

Oral hairy leukoplakia is a benign, asymptomatic

white patch or plaque of hyperplasia most commonly

located on the lateral border of the tongue (Fig. 8).

Extension to the dorsal and ventral tongue, buccal

mucosa, palate, and tonsillar region has been described

[80]. It occurs most often in persons immunocompro-

mised from HIV infection, but it has been reported in

transplant recipients [81] and in patients with renal

failure associated with Fabrys disease [82]. Oral hairy

leukoplakia may be the first clinical sign of HIV

infection in more than 5% of cases [22]. Diagnosis is

aided by histopathologic examination; EBV may be

identified with ISH (Fig. 9) [75,83], Southern blot

hybridization, direct immunofluorescence, or electron

microscopy [84]. Treatment with acyclovir is success-

ful but has been associated with recurrence [85,86].

Other measures reported to improve the leukoplakia

during treatment include antiretroviral therapy for

HIV-associated disease [87], topical 0.1% vitamin A

acid [86], and topical podophyllum resin [88].

EBV has been identified as an etiologic factor in

Burkitts lymphoma by serologic tests [89] and ISH

[83]; this disease is divided into African endemic [83]

and nonendemic forms [89]. Nonendemic forms,

however, are less likely to be associated with EBV

[89,90]. Burkitts lymphoma is the most common

childhood cancer in tropical Africa [75]. The char-

acteristic features are palpable jaw masses, cervical

lymphadenopathy, sore throat, loosened teeth, and

odontalgia. The disease is responsive to chemother-

apy. EBV is also associated with nasopharyngeal

carcinoma, which most commonly presents with

metastatic disease-containing lymphadenopathy.

EBV-related nasopharyngeal carcinoma is the most

common cancer in parts of southern Asia; 75% of

nasopharyngeal carcinomas in the United States are

induced by EBV [75].

Human herpesvirus 5 (cytomegalovirus)

Primary infection with cytomegalovirus is usually

subclinical and asymptomatic, although patients

may have a mononucleosis-like syndrome with fever,

lymphadenopathy, pharyngitis, and inflamed salivary

glands. Cytomegalovirus persists in a latent phase,

but reactivation rarely affects the skin and mucous

membranes. Oropharyngeal ulcerations caused by

cytomegalovirus have been described in iatrogenic

Fig. 8. Oral hairy leukoplakia with typical corrugated

white plaque on lateral tongue. (From Bruce AJ, Hairston

BR, Rogers RS III. Diagnosis and management of oral

viral infections. Dermatologic Therapy 2002;15:27187:

with permission.)

Fig. 9. Epstein-Barr virus demonstrated with in situ hybrid-

ization in the epidermis of patient with oral hairy leukoplakia.

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 23

immunosuppression [91], HIV infection [22,92], and

bone marrow [93] and organ transplantation [92].

Cytomegalovirus may be cultured in fibroblast

media. Characteristic histopathologic features include

basophilic intranuclear inclusions and granular cy-

toplasmic inclusions, thus the name cytomegalic

inclusion disease. Serologic testing, ISH, or PCR

identifies the virus [94]. Ganciclovir has been effec-

tive in the treatment of cytomegalovirus-related oro-

pharyngeal disease [92].

Human herpesvirus 6

HHV-6 is responsible for exanthema subitum (ros-

eola infantum), the most common infectious exan-

them during the first 2 years of life [95,96]. The virus

remains latent in the salivary gland and can be

transmitted by oropharyngeal secretions. The enan-

them consists of erythematous maculae on the soft

palate. It may precede cutaneous exanthem of dis-

crete, 1- to 2-mm pink- to rose-colored maculae that

originate on the trunk following defervescence [97].

Serologic testing may detect antibody to HHV-6 [96].

Treatment is supportive.

Human herpesvirus 8

Kaposis sarcoma is a vascular neoplasm with

several clinical variants: classic, African endemic,

iatrogenic immunosuppression, and epidemic HIV-

associated. HHV-8 has been isolated from all subtypes

of Kaposis sarcoma, although its specific role in the

pathogenesis of the disease is unknown [98,99]. Oral

Kaposis sarcoma lesions are often the first indication

of HIV infection [22]. Erythematous to violaceous

maculae, patches, plaques, and nodules occur on the

palate, gingiva, and tongue (Figs. 10 and 11). Gen-

erally, Kaposis sarcoma of the oral cavity is asymp-

tomatic, although bleeding, pain, and ulceration may

occur. Because HHV-8 is not exclusive to Kaposis

sarcoma lesions, other pathogenic factors may con-

tribute to the development of the sarcoma [98].

In conjunction with histologic examination,

HHV-8 may be identified by PCR. Specific treatment

options for oral Kaposis sarcoma include local

excision [22], cryotherapy [100], injection of a scle-

rosing agent [101], intralesional interferon alfa-2b

[102], intralesional vinblastine [103], or site-directed

radiotherapy [104]. Radiotherapy must be used with

caution to avoid secondary mucositis [105]. Systemic

chemotherapy generally is reserved for patients with

rapidly progressive or disseminated disease or a high

tumor burden. Antiretroviral therapy in HIV-associ-

ated cases may interfere with immune deterioration

and prevent or reverse Kaposis sarcoma [106]. No

treatment has been approved specifically by the FDA

for Kaposis sarcoma of the oral cavity.

Human papillomavirus

Human papillomavirus (HPV) is a nonenveloped,

double-stranded DNA virus with at least 80 different

genotypes [107]. Diseases of the oral cavity induced

by HPV include squamous papilloma, oral verruca

vulgaris, condyloma acuminatum, and focal epithelial

hyperplasia (Table 3). Several subtypes of HPV have

been linked to the induction of malignancy [107,108]

but further study is needed to determine the role of

HPV in the etiology of oral squamous cell carcinoma.

Squamous papillomas and oral verrucae

Squamous papillomas and oral verrucae are com-

monly referred to as oral warts. Both lesions are

Fig. 10. Violaceous plaques with erosion on hard palate,

representing HIV-associated Kaposis sarcoma. (From Bruce

AJ, Hairston BR, Rogers RS III. Diagnosis and management

of oral viral infections. Dermatologic Therapy 2002;15:

27187: with permission.)

Fig. 11. Violaceous exophytic and fungating plaque on hard

palate, with violaceous macules and papules of lips in

person with classic Kaposis sarcoma.

B.R. Hairston et al / Dermatol Clin 21 (2003) 173224

typically exophytic, verrucous papules or plaques

located on any oral mucosal surface, including the

lips. A distinguishing feature between these two dis-

eases is that squamous papillomas tend to be small and

pedunculated, whereas the verrucae are more sessile

[4]. Koilocytes are more common in oral verrucae

than in squamous papillomas [108].

Condyloma acuminatum

Condyloma acuminatum is predominantly an ano-

genital disease; however, lesions of the palate and

tongue have been reported [109,110]. Oral lesions

likely are acquired by sexual transmission, hematog-

enous spread, or autoinoculation by the hands from

primary genital lesions. Oral condyloma acuminatum

typically consists of multiple, small, white- to flesh-

colored, soft exophytic papules that enlarge to plaques

with a pebbled surface.

Focal epithelial hyperplasia (Heck disease)

Focal epithelial hyperplasia occurs most com-

monly in Native Americans and Eskimos of Green-

land [111]. It also has been described in cases of HIV

infection [112]. Because the disease is relatively

isolated to these subgroups of the population, a

genetic predisposition and inheritance pattern are

likely factors. The disease usually is located on the

buccal mucosa or lips as asymptomatic solitary or

multiple whitish papules; HPV DNA has been iden-

tified with ISH [113] and PCR in lesions of the oral

mucosa [114]. Lesions often remit spontaneous-

ly. Mucosal involvement may be extensive and pain-

ful, however, and may be treated with surgical

excision, cryotherapy, or laser ablation [22]. Topical

interferon-b [115] and carbon dioxide laser [114]therapies have been described.

Poxvirus

Molluscum contagiosum

Poxvirus, responsible for molluscum contagiosum,

is a DNA virus that replicates in the cytoplasm of

infected cells. Oral molluscum contagiosum presents

as flesh-colored, dome-shaped, smooth-surfaced or

umbilicated papules and is most commonly found in

immunocompromised persons. Sites reported to be

Table 3

Benign HPV-associated oral diseases

Oral manifestation Predominant HPV genotype Lesion

Squamous papilloma HPV-6, HPV-11 [108,126] Pedunculated, pink papule on palatine,

buccal, labial mucosa

Verruca vulgaris HPV-2, HPV-4 [108,125] Sessile, papillomatous, pink papule of

lips, gingivae

Condyloma acuminatum HPV-6, HPV-11 [108,126] Multiple, soft, sessile, pink coalescing

papules of palate, tongue

Focal epithelial hyperplasia HPV-11, HPV-13, HPV-32 [108,113115] Multiple, soft, pink papules of lips,

buccal mucosa

Abbreviations: HPV, human papillomavirus.

Table 4

Oral infections caused by RNA viruses

Oral infection Etiology Transmission Lesion

Measles Paramyxovirus Infectious respiratory

droplets, saliva

Kopliks spots on buccal mucosa,

Herrman spots on tonsils

Mumps Paramyxovirus Infectious respiratory

droplets, saliva

Edema and erythema of salivary

gland orifices

Rubella Togavirus Infectious respiratory

droplets, saliva

Forschheimer sign of palate

Hand-foot-

and-mouth disease

Picornavirus Saliva, feces Vesicles, erosions, or ulcerations of

palate, buccal mucosa, tongue

Herpangina Picornavirus Saliva, feces Vesicle or ulcerations with surrounding

erythema of palate, tonsillar fauces, uvula

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 25

affected include the lips, buccal mucosa, and palate

[116]. Large intracytoplasmic inclusion bodies (Hen-

derson-Paterson bodies) are a characteristic histologic

feature [117]. ISH demonstrates the poxvirus in clin-

ical specimens [118]. Treatment of the oral lesions is

with cryotherapy or excision [22].

RNA viruses

All the RNA viruses that affect the oral mucosa

consist of a single-stranded nucleic acid molecule.

RNA viral enanthems may be associated with a

cutaneous exanthem except for the paramyxovirus

that causes mumps. Diseases caused by RNA viruses

are listed in Table 4.

Paramyxovirus

Measles

Paramyxoviridae-associated infections include

measles (rubeola) and mumps [95]. A prodrome of

fever, malaise, cough, coryza, and conjunctivitis may

occur in measles, followed by a generalized ery-

thematous morbilliform exanthem. Kopliks spots,

pathognomonic for measles, are discrete, bluish white

punctate mucosal maculae surrounded by a rim of

erythema; they represent foci of epithelial necrosis

(Fig. 12). The most common location of this enanthem

is the buccal mucosa, where the lesions may resemble

grains of salt sprinkled on an erythematous back-

ground [95]. Pharyngeal erythema and bluish gray to

Fig. 12. Measles infection with Kopliks spots having

progressed to extensive necrosis, erosions, and ulceration of

buccal mucosa. (FromBruce AJ, Hairston BR, Rogers RS III.

Diagnosis and management of oral viral infections. Dermato-

logic Therapy 2002;15:27187: with permission.)

Fig. 13. Hand-foot-and-mouth disease. (A) Pinpoint vesicle with surrounding erythema of buccal mucosa. (B) Discrete

erythematous papules with vesiculation on both palms. (C) Similar erythematous papules and vesicles on dorsum of both feet.

B.R. Hairston et al / Dermatol Clin 21 (2003) 173226

white maculae (Herrman spots) may be present on the

tonsils. Herrman spots are not specific for the measles

virus [119]. Oropharyngeal disease may present 24 to

48 hours before the cutaneous exanthem.

Measles is usually diagnosed clinically; serologic

test results confirm the disease. Treatment generally is

symptomatic, with analgesics, antipyretics, and main-

tenance of adequate hydration. Immune serum globu-

lin treatment may be necessary for disease in children

younger than 12 months, in pregnant women, and

in immunosuppressed persons; it is best given within

6 days after exposure. The disease may be prevented

with the measles-mumps-rubella (MMR) vaccine

according to guidelines recommended by the Centers

for Disease Control and Prevention [95,119].

Mumps

Mumps is characterized by salivary gland swelling

and tenderness, particularly of the parotid gland.

Sublingual orifices, Stensens duct on the buccal

mucosa, and Whartons duct at the base of the tongue

may be edematous and erythematous. Serologic tests

or culturing the orifice of Stensens duct confirms the

diagnosis. Mumps may be prevented with the MMR

vaccine [120].

Togavirus

Rubella

Togavirus is responsible for rubella, or German

measles. Infection with togavirus during pregnan-

cy may lead to serious fetal infection and congeni-

tal rubella syndrome. A prodrome is less common

than in measles, but symptoms may occur in older

children and adults. The fine, pale pink maculopap-

ular exanthem spreads in a cephalocaudad pattern

and may be followed by fine desquamation. The en-

anthem of erythematous, pinpoint, petechial-appear-

ing maculae occurs on the soft palate and uvula.

This nonpathognomonic enanthem is known as the

Forschheimer sign [95]. It occurs in the prodrome or

early rash in up to 20% of cases of rubella [69].

Marked lymphadenopathy, typically of the cervical

and postauricular nodes, is often an accompanying

feature. Diagnosis of rubella is more difficult than

measles because it has no pathognomonic features

and a low incidence with the widespread use of the

MMR vaccine. Serologic testing is especially impor-

tant in women of childbearing age and those who are

pregnant to determine the status of immunity. In most

persons, rubella is essentially benign, and treatment

is symptomatic.

Picornavirus

Hand-foot-and-mouth disease and herpangina are

picornavirus-associated diseases with characteristic

Fig. 14. Vesicles and erosions of hard palate and poste-

rior oropharynx in herpangina. (From Bruce AJ, Hairston

BR, Rogers RS III. Diagnosis and management of oral

viral infections. Dermatologic Therapy 2002;15:27187:

with permission.)

Fig. 15. Perioral and labial erosions and crusting of

recurrent herpes simplex labialis associated with chronic

lymphocytic leukemia.

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 27

features that allow a specific diagnosis. Type-specific

immunity is established in both herpangina and hand-

foot-and-mouth disease; however, recurrences of the

clinical syndromes are possible because both diseases

may be caused by various members of the Picorna-

virus family.

Hand-foot-and-mouth disease

Hand-foot-and-mouth disease is most commonly

caused by coxsackievirus serotype A16 or enterovirus

71 [121,122]. The disease usually occurs in small

epidemics among groups of children and is quite

contagious. Typical features include a short prodrome

of upper respiratory symptoms and low-grade fever,

followed by mucosal and cutaneous lesions. Shallow

erosions and ulcerations with surrounding erythema

are most common on the palate, tongue, and buccal

mucosa (Fig. 13A). Erythematous papules, vesicles,

or ulcers occur on the dorsal and palmoplantar sur-

faces of the hands and feet either concomitantly with

the mucosal lesions or shortly thereafter (Fig. 13B

and C). Picornaviridae may be cultured from the sa-

liva or feces. PCR detects viral DNA in vesicles and

defines the specific serotype [121]. Serologic testing

also detects antibodies to the specific coxsackie-

virus [122].

Symptomatic therapy for hand-foot-and-mouth

disease is usually sufficient. Oral analgesics and

anesthetic mouth rinses alleviate stomatodynia. Com-

plications of hand-foot-and-mouth disease are rare;

however, enterovirus 71 was associated with central

nervous system disease, including meningitis, enceph-

alitis, and flaccid monoparesis, in 24% and 8% of

afflicted patients in the 1973 and 1978 hand-foot-and-

mouth disease outbreaks, respectively, in Japan [122].

Herpangina

Herpangina is induced most commonly by cox-

sackievirus [123] and is characterized by the sudden

onset of fever without a prodrome. Pain and dysphagia

are associated with small erythematous papules,

vesicles, or ulcerations covered by a pseudomem-

brane. Typical locations of these lesions are the tonsils

and tonsillar fauces, palate, and uvula (Fig. 14) [4].

The virus may be isolated from vesicles of the throat

or fecal culture [123]. Because herpangina may be

associated with high fever, febrile seizure is a rare

potential complication. Otherwise, therapy is usually

supportive, with hydration, analgesics, antipyretics,

and topical oral anesthetics.

HIV

HIV is an RNA retrovirus with the reverse tran-

scriptase enzyme responsible for conversion of RNA

to DNA. Oral lesions often are the indication for initial

HIV testing, and oral diseases are more common as

the CD4 + count decreases [21]. The acute serocon-

version syndrome following HIV infection is associ-

ated with oral erythema and ulcerations in up to 30%

of patients [124]. Similar to the more severe and

frequent herpetic viral infections in malignancy and

during immunosuppressive therapy (Fig. 15) [3], viral

pathogens often display a more aggressive and pro-

tracted course in HIV-infected persons (Table 5).

Summary

A wide variety of both DNA and RNA viruses

affect the oral cavity. When considered in conjunction

with cutaneous features, careful examination of the

oral mucosa and oropharynx aids the clinician in

making a diagnosis. Examination of the oral cavity

should be incorporated as a regular component of the

dermatologic examination because diagnostic clues

are readily available to assist in the evaluation of

infectious processes.

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Viral diseases of the oral mucosa in HIV infection

Viral disease Etiology

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