Management of White Lesions of the Oral Cavity

Many white lesions involving the oral mucosa are benign and do not require treatment. These
include congenital or developmental conditions such as white sponge nevus, keratosis
follicularis, hereditary benign intraepithelial dyskeratosis, pachyonychia congenita, and Fordyce
granules. Other benign conditions that do not require intervention include skin and mucosal
grafts, materia alba associated with the gingiva or tongue, and keratotic lesions such as hairy
tongue. In contrast, many diseases that may require dental intervention can cause whitening of
the oral mucosa, depending on symptoms and potential morbidity or mortality.

This article presents the most recent information related to the management of several types of
white lesions of the oral cavity.

See Clues in the Oral Cavity: Are You Missing the Diagnosis?, a Critical Images slideshow, to
help identify the causes of abnormalities of the oral cavity.

Candidiasis
Candidiasis has a variable presentation but can consist of slightly elevated, whitened plaques that
can be wiped away to leave a bleeding capillary bed. Candidiasis can result from a patient’s use
of broad-spectrum antibiotics or corticosteroids over a prolonged period, use of medications or
presence of disease that causes severe oral dryness (xerostomia), disease that causes
immunosuppression, poor oral hygiene, or poorly fitting prosthetics. [1]

The 2 types of candidiasis that cause white oral tissue include pseudomembranous candidiasis
and chronic/hyperplastic candidiasis. Tongue annular plaques have also been reported to be
associated with candidal infection. [2]

Given that this yeastlike fungal organism is opportunistic and proliferates in the presence of an
imbalance in normal oral flora, one of the approaches to reestablishing oral flora equilibrium and
eliminating infection is via the use of antifungal medication. Multiple studies have shown a
number of drugs to be efficacious. [3, 4] Topical antifungal agents include nystatin (Mycostatin,
Nilstat) oral suspension, nystatin ointment, ketoconazole (Nizoral) cream, nystatin topical
powder, clotrimazole (Mycelex) troches, and clotrimazole or miconazole nitrate vaginal creams.
Dosages and dispensing information is covered elsewhere (see topics below). These medications
should be applied to the oral mucosa and to any removable oral prostheses. The latter should be
soaked in an antifungal denture-soaking solution.

Consultation with the patient’s physician is warranted if the recurrent candidiasis is the result of
prolonged corticosteroid or other immunosuppressant use or from diabetes. In these cases,
treatment of the disease may need to include systemic antifungal agents, which can interfere or
interact with other prescribed medications (eg, ketoconazole, fluconazole, itraconazole) or
compromise liver function in patients with liver disease. Treatment of xerostomia and conditions
causing the problem (eg, diabetes) may also improve one of the underlying conditions
predisposing a patient to candidiasis.
A number of interesting but relatively untested therapeutic approaches may yet find their way
into the management of oral candidiasis. For example, there is limited in vitro evidence that
probiotic intervention with Streptococcus salivarius K12 might reduce growth of Candida. [5]
Other novel interventions being studied include the use of cranberry proanthocyanidins to inhibit
the adherence of Candida albicans to epithelial cells and as a means of reducing cytokine
secretion, [6] photodynamic therapy with photosensitizing dyes such as methylene blue or
toluidine blue, [7] and an aqueous extract of garlic mouthrinse to reduce denture stomatitis caused
by Candida. [8]

Also see Candidiasis, Candidiasis Empiric Therapy, Mucosal Candidiasis, Chronic

Mucocutaneous Candidiasis, and Noncandidal Fungal Infections of the Mouth.

Papilloma, Verruca Vulgaris, and Condyloma Acuminatum

A variety of genetic mutations in the human papillomavirus (HPV) causes conditions such as
papilloma, verruca vulgaris, and condyloma acuminatum. These conditions present clinically as
flat plaques, exophytic spiky projections, or pedunculated [9] exophytic cauliflowerlike growths
that are pinkish-white or white in appearance. One variant of the oral wart, oral florid
papillomatosis, can affect the skin as well as mucocutaneous tissues, including the oral mucosa.
This condition is characterized by multiple warty or verrucous lesions. Papilloma lesions can
develop anywhere in the mouth and pharynx/tonsillar region. All should be considered
precancerous in nature.

The reported prevalence of HPV-associated oral warts in the general population is approximately
5%, and the lesions reportedly are present in 5% of HIV-seropositive subjects but up to 23% of
HIV-seropositive subjects on highly active antiretroviral therapy. [10] Several studies suggest that
HPV type 16 (HPV-16) is a primary cause of oral squamous cell carcinoma in men (smoking and
alcohol use are also linked to the etiology of oral cancer in men). Research suggests that the
prevalence of HPV is approximately the same for men and women, but HPV-16 accounts for
28% of all HPV detected in the oral region. [11] While found throughout the mouth, HPV-16
lesions reportedly are most likely to occur at the base of the tongue and oropharynx (tonsils), and
it is in these areas that the prevalence of squamous cell carcinoma appears to be increasing
significantly. [12] This is in contrast to other non-HPV, alcohol- and smoking-related cancers,
which have declined over the same period.

In current practice, no medical treatment is effective for eliminating the HPV, but HPV
vaccination shows potential for preventing some oral lesions as it has demonstrated efficacy in
reducing HPV-16 at other sites. [13] Much more basic and clinical research, including prospective
randomized controlled trials, remain to be concluded before final conclusions can be made
regarding vaccination as a means of treating papilloma. The problem is complex. For example,
recent data appear to demonstrate that short-peptide vaccines may not be effective in therapeutic
vaccines against HPV-16–induced cancer, while long-peptide vaccines containing both CD4 and
CD8 T-cell epitopes that require dendritic-cell processing are very efficient. [14]

Nonetheless, given the potential for cervical cancer consequent to HPV-16 infection, the US
Centers for Disease Control and Prevention (CDC) has recommended vaccination for young
girls. [15] Further, given that HPV-16 has now been linked to neoplasms of the tongue and tonsils
in adult males, future recommendations may include vaccination for boys. At present, for the
vaccination to be effective, it must be provided before the subject becomes sexually active.

Treatment of oral warts is primarily surgical in nature. Therapy that is suggested in the literature
as intervention for intraoral lesions includes laser ablation, loop electrosurgical excision,
incisional and excisional biopsy, carbon dioxide laser treatment, interferon-alfa injection, and
surgery. Lesions on the lips reportedly can be removed using podofilox cream, [16] imiquimod
ointment, or fluorouracil 2% topical preparations. [17] Podofilox (Condylox) is an antimitotic
topical preparation that is typically used as an intervention for genital and anal condyloma.
However, it is not approved by the US Food and Drug Administration (FDA) for oral use at this
time.

It should be appreciated that most suggested treatments for oral warts are based not on
randomized controlled trials, or even comparative studies, but are based on anecdotal evidence or
uncontrolled case series. [18] One of the problems with basing treatment on uncontrolled case
studies is that oral warts may dissipate over time without treatment. In addition, interventions
deemed appropriate for the management of skin lesions have not been studied for oral lesions
(eg, oral zinc sulfate treatment). [19]

Finally, as would be expected, the use of antiretroviral therapy does not appear to reduce the
prevalence of HPV-16 in patients with HIV infection. In one study, [20] it was demonstrated that
while the prevalence of HPV-16 infection was significantly higher in HIV-infected patients than
in non–HIV-infected controls, the difference between those who were on and were not on
antiretroviral therapy was not significant with respect to the disease. Antiretroviral use did not
alter the prevalence of the virus. [21]

Leukoplakia, Oral Dysplasia, and Carcinoma in Situ

Leukoplakia is a term used to describe a noninfectious change in the mucosal epithelium
characterized by a white plaquelike lesion that cannot be rubbed off. [22] In most cases, lesions
defined by clinical examination as leukoplakia consist of epithelial hyperkeratosis,
hyperparakeratosis, hyperorthokeratosis, and combinations of these changes with acanthosis, and
they are benign. However, it has been reported that approximately 20% of leukoplakia lesions
develop dysplasia that involves a number of changes in epithelial cellular morphology, including
pleomorphism, hyperchromatism, and other cytologic changes. When leukoplakia is found in the
region of the floor of the mouth and lateral tongue, the percentage of dysplasia has been reported
at greater than 40%. [23] Hence, until proven otherwise, leukoplakia should be considered a
premalignant lesion.

It should also be appreciated that when leukoplakia is interspersed with areas of erythema, the
risk of dysplasia and malignant conversion is greater. [24] When cytologic changes are extensive
and extend from the basal cell layer through the epithelium, the condition is defined as
carcinoma in situ.
Oral keratotic (leukoplakia) lesions can vary considerably in size and surface configuration,
depending on their location. The condition can present as single or multifocal smooth plaques
and as extensive fissured or roughly corrugated lesions. The initial step in management,
regardless of size, is the acquisition of a tissue specimen via biopsy (or biopsies) to precisely
define the level of cellular atypia and potential for malignancy. It is not within the scope of this
article to describe the many different procedures that can be used to acquire mucosal tissue. For
further information, see Oral Tissue Biopsy and Oral Brush Biopsy With Computer-Assisted
Analysis.

For large lesions with varying surface characteristics, best practice is for the acquisition of
multiple tissue samples via incisional biopsy. Should subsequent pathology studies be positive
for severe dysplasia, carcinoma in situ, or squamous cell carcinoma, use of an incisional
technique allows the cancer surgeon (eg, oral surgeon, ear nose throat [ENT] surgeon,
oncologist) and the cancer team to more precisely determine the margins of the original
condition.

Post incisional biopsy, assuming the histology is consistent only with mild dysplasia, a number
of therapeutic interventions may be considered depending on the extent of the lesion(s). As
previously noted, if biopsy results show the lesion to be a squamous cell carcinoma, referral to a
cancer specialist should follow so that the condition can be adequately triaged for management.
[25]

Surgical intervention

Isolated and relatively small leukoplakia or mildly dysplastic lesions that can be easily accessed
can be removed by scalpel surgery (excisional biopsy). With lesions less than 5 mm in diameter,
a punch biopsy may work well. If surgical excision is to be considered, care must be taken to
excise beyond the obvious margins of the plaque to ensure total elimination of the dysplasia. If
the lesion is located on the ventral tongue or floor of the mouth, frequent follow-up should be
provided post removal because of potential recurrence and squamous conversion. [26]

Large lesions may be excised with carbon dioxide laser. [27] This procedure is quite useful in
regions with high vascularity as it produces a bloodless surgical field. [28]

Transoral carbon dioxide laser resection has also been used by cancer specialists to treat T1/T2-
staged oral squamous cell carcinoma (low-risk carcinoma). In a prospective study, 90 patients
with lesions of the tongue, floor of the mouth, and buccal mucosa were treated with carbon
dioxide laser resection and assessed for 3-year disease-specific and disease-free survival. Eighty-
one patients had T1N0 and 9 had T2N0 disease. Most of the patients had moderately
differentiated oral squamous cell carcinoma, with the rest having moderately to poorly
differentiated carcinoma. The depth of the lesions was determined to be a mean of 5.7 mm, and
tumor clearance post treatment was thought to have been achieved in 73 patients.

Recurrence was reported in 12% of patients (11), with this showing as an ulcer of the tongue or
buccal mucosa. Most of these patients were self-reported ex-smokers or drinkers. The 3-year
survival rate was 86.7%, but 9 of the 12 who died did so from non–cancer-related causes. [29]
Curettage and electrodesiccation may also be considered for the excision of larger lesions. [30]

Chemotherapeutic intervention

Chemopreventative approaches currently include the use of drugs such as beta-carotene, trans -
retinoic acid, and 5-fluorouracil. Currently undergoing investigation is the cyclooxygenase
(COX)–2 formulation, celecoxib, and imiquimod has been showing promise for future use.

Imiquimod is an immunomodulatory agent that has been found to reduce mild dysplasia to
hyperkeratosis in an animal model of carcinogenesis. [31] To achieve these results, 5% imiquimod
cream was applied to the dysplastic lesions for 16 weeks. Celecoxib is currently being studied in
a phase II trial to determine if it is effective in preventing cancer in patients with leukoplakia or
dysplasia. [32]

Beta-carotene has been shown to support remission of oral leukoplakia. [33, 34]

In a pilot crossover study, subjects who smoked demonstrated better improvement than
nonsmokers (81.2% vs 28.6%). [35]

In a multicenter, double-blind, placebo-controlled trial, 50 subjects received beta-carotene at 60

mg/d for 6 months, with half then randomized to receive a placebo for 12 months and the other
half to continue beta-carotene. Thirty-eight of the 50 participants were determined to have
dysplasia at initial biopsy. A second biopsy at 6 months revealed improvement in the degree of
dysplasia in 39% of subjects.

Only 4 (8%) of 50 subjects demonstrated disease progression at 6 months, with one having
biopsy-confirmed squamous cell carcinoma. Typically, a pinkish color returned to the tissue
following a thinning of the leukoplakic lesion. This was followed by a decrease in the size of the
lesion. A significant difference in response was observed between those on placebo and those
continuing the drug. These results were sustained for 1 year. [36]

The long-term efficacy of retinoid therapy, however, has been called into question, as systematic
reviews assessing multiple studies have suggested that the frequency of relapse may be high in
subjects using beta-carotenes. [37]

The use of isotretinoin (13-cis retinoic acid [13-cRA]) has been associated with a number of
adverse reactions, [38] including hyperuricemia, [39] and it also must be avoided in women planning
to become pregnant. Therefore, it should not be considered first-line therapy. If it is used,
baseline and periodic serology studies and close monitoring for adverse effects (eg, elevated
triglycerides) should be performed. If clinicians are willing to prescribe the isotretinoin
(Accutane), they must first enroll in an FDA-sponsored iPledge system in order to receive the
medication. In addition, iPledge does not allow the use of the drug to exceed 5-6 months, so its
off-label use for the management of dysplasia may not be feasible.

Other chemotherapeutic agents with limited support include vitamin E, beta-carotene, and
selenium. [40, 41] Selenium supplementation as a means of reducing oral dysplasia has not been
well studied, but there is evidence that selenium levels may be low in men with oral cancer who
smoke. [42] It should be appreciated that a recent Cochrane report involving systematic review of
numerous studies involving selenium (none involving oral dysplasia, however) found no
convincing evidence to support selenium supplementation and cancer risk reduction. [43]

Photodynamic therapy

Photodynamic therapy involves the preinjection of a photosensitizer agent, typically porfimer

sodium (Photofrin), followed by exposure to light of variable wavelength. The sensitizing agent
enters all cells but is eliminated from healthy cells within 24-72 hours, leaving damaged,
dysplastic, or neoplastic cells susceptible to an active form of oxygen that is released from cells
with the drug upon light exposure. The FDA has approved this technique for treatment of
esophageal cancer and non–small cell lung cancer, as well as for Barrett esophagus, a
precancerous condition. [44]

The application of this therapy in dentistry is a recent occurrence, and a number of studies
suggest it may be a useful strategy in treating oral dysplasia as well as cancer. [45, 46, 47, 48] Light
penetration of tissue is limited to only a few millimeters, so the use of this system in the mouth,
which also provides reasonable access, has promise. However, the outcome may be dependent on
a number of tissue parameters, including lesion size, color, degree of dysplasia, and surface
keratin thickness. [49]

Evidence suggests that topical (vs systemic) 5-aminolevulinic acid photodynamic therapy (ALA-
PDT) may effectively eliminate oral verrucous hyperplasia as well as oral erythroleukoplakia. [50]
Research related to the light dynamics suggests that light-emitting diode (LED) light is as
effective for treating lesions as laser light. In a prospective, nonrandomized, comparative study
reported by Yu and colleagues, 20 oral erythroleukoplakia lesions were treated with topical
ALA-PDT using 635-nm LED light and 26 oral erythroleukoplakia lesions were treated with
topical ALA-PDT using 635-nm laser light. The difference in clinical outcomes was not found to
be significant. All 40 lesions were reported as exhibiting a complete response to therapy after 3.6
treatments. Greater response rates occurred with small lesions, pink-to-red lesions, and lesions
with epithelial dysplasia or thin keratin. [51] Similar results were found for the management of
biopsy-confirmed dysplasia. [51]

Oral squamous cell carcinoma appears to be effectively treated with photodynamic therapy. In
one prospective clinical study, the effect of surface illumination m-tetrahydroxyphenylchlorin
(mTHPC) photodynamic therapy on T1/T2-weighted N0 squamous cell carcinoma of the tongue,
floor of the mouth, and buccal mucosa was evaluated in 38 patients (with 89.5% self-identified
as ex-smokers or current smokers). After several treatment applications spaced over 6-7 months,
26 of 38 patients demonstrated healthy oral mucosa at the primary tumor site. Subsequent
biopsies revealed 10 of the original study cohort with dysplasia and 6 with recurrent squamous
cell carcinoma. The overall recurrence rate was 15.8%, and the 5-year survival rate was 84.2%,
suggesting the intervention was as potentially useful for treating low-risk cancer as other more
invasive strategies. [52]
The precise number of applications appears variable, but the authors of one study suggest
complete remission can be achieved with fewer than 7 applications delivered once a week. [49]
The degree of light is another variable that may differ depending on the type of pathology
present. In one study, the light dose used therapeutically for dysplasia was 50 J/cm2 and for
carcinoma was 75 J/cm2. [48]

Adverse reactions associated with the procedure are temporary and include edema, pain,
hoarseness, and skin phototoxicity. [48] In an attempt to reduce irradiation of healthy tissue and
eliminate some of the adverse effects of photodynamic therapy, a “lightpipe” device has been
studied and described and may prove useful. [53]

Nicotinic Stomatitis and Cinnamon Stomatitis

The treatment of nicotinic contact stomatitis is to eliminate the offending nicotine product.
However, dental therapy is complicated by psychosocial issues that include addiction, so
multidisciplinary referral should be considered for what is likely to be complex behavioral
management. [54]

Discontinuation of cinnamon effectively eliminates hyperkeratosis associated with its use. [55]

For additional information, see Nicotine Stomatitis, Contact Stomatitis, Aphthous Stomatitis, and
Denture Stomatitis.

Lichen Planus and Lichenoid Reactions

Oral lichen planus (OLP) has a variety of clinical presentations, including a reticular form
characterized by lacy striations or lines termed Wickham striae; annular lesions; solid, whitened,
slightly elevated plaques of variable size; or a combination of these features. Reticular lesions
are reported to constitute approximately 70% or more of the disease presentations. [56] The lesions
of reticular OLP are typically painless and occur most frequently on the buccal mucosa, gingiva,
and tongue. When OLP involves mucosal erythema along with the whitened lesions (termed
erosive lichen planus), the condition can be painful. [57] OLP is a chronic disease without a known
cure. Painful lesions are best managed symptomatically. [58] Reticular lesions do not need
management as they are not typically painful.

The World Health Organization (WHO) has classified OLP as a potentially premalignant lesion,
[59]
but this declaration is not without controversy. [60] Lesions that do transform are observed to
include both whitened tissue as well as erythema. The conversion rate is estimated to be 0.4-
7.1% per year. [61, 62] The literature on OLP now includes the term “oral lichenoid lesions” as a
descriptor for lesions that do convert to squamous cell carcinoma. [62]

A systematic review evaluated evidence regarding malignant transformation of oral lichen planus
(OLP) to squamous cell carcinoma (SCC). The study concluded that a small subset of patients
with a diagnosis of OLP eventually developed SCC. The most common demographic
characteristics of patients in this subset were similar to the most common demographic
characteristics associated with OLP in general. This included being female, older, and affected in
areas common to this condition. The authors further concluded that it is prudent for clinicians to
pursue continued regular observation and follow-up in patients with these conditions, even in
patients who do not fit a traditional high-risk category for oral SCC. [63]

Conversion to lichenoid dysplasia is of potential concern because the condition may be neglected
owing to the clinician thinking it is reticular in nature and benign. [64] Hence, best practice is to
obtain a biopsy specimen from white lesions that involve adjacent erythema when reasonable
intervention fails to provide resolution. Routine follow-up is also highly recommended in
patients with potential for conversion (eg, those with mucosal sites demonstrating erosive or
erythematous change). [65]

A vast number of interventions for the treatment of OLP are described in the literature. These
include topical tacrolimus, [66] aloe vera, [67] topical cyclosporin, [68] intralesional [69] or
topical/systemic steroids, [70, 71] rapamycin (a drug with both immunosuppressive and antitumor
properties), [72] drug combinations (eg, cyclosporine with triamcinolone acetonide, [68] tacrolimus
powder in Orabase 0.1%), [73] and retinoids (both systemic [etretinate] and topical [tretinoin]). [74]

The problem is that no standard intervention exists for OLP, regardless of type, and the treating
clinician is left to define a protocol on the basis of authoritarian texts versus evidence-based
support. Underscoring this difficulty is a recent systematic review suggesting that there are few
prospective randomized controlled trials evaluating the various pharmacologic strategies for
managing OLP, and, as a result, scant evidence supports the efficacy of one specific treatment
over another. [75]

At present, the factors that should be considered by a clinician treating OLP are the chronic
nature of the condition and the potential adverse effects of medications used over a prolonged
period. Best practice includes using low doses, alternate-day therapy, and adjunctive therapy
when appropriate. [74] It should be appreciated that other than surgery, no medication-based
treatment eliminates reticular OLP lesions.

In cases of a lichenoid reaction following medication usage, consultation with the patient’s
physician regarding withdrawal and substitution, over time, may improve the condition. [76] If the
mucosal lichenoid condition is related to contact with dental material, [77] the offending source of
the lesions should be removed. [78]

Surgical techniques include the use of scalpel surgery or carbon dioxide laser ablation. [79]

For additional information, see Oral Lichen Planus and Oral Manifestations of Drug Reactions.