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.

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 (Photodithazine® (PDZ)) with photosensitizing dyes such as methylene blue or toluidine blue, ^{[7, 8]} and an aqueous extract of garlic mouthrinse to reduce denture stomatitis caused by Candida. ^[9]

Also see Candidiasis, Candidiasis Empiric Therapy, Mucosal Candidiasis, Chronic Mucocutaneous Candidiasis, and Noncandidal Fungal Infections of the Mouth.

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 ^[10] 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. ^[11] 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. ^[12] 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. ^[13] 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. ^[14] 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, 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. ^[15]

Nonetheless, given the potential for cervical cancer, as well as neoplasms of the tongue and tonsils, consequent to HPV-16 infection, the US Centers for Disease Control and Prevention (CDC) recommends routine vaccination at age 11 or 12 years for girls and boys (the vaccine series can be started at age 9 years). Vaccination is also recommended for persons aged 13-26 years who have not been vaccinated previously or who have not completed the vaccine series. ^[16]

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, ^[17] imiquimod ointment, or fluorouracil 2% topical preparations. ^[18] 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. ^[19] 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). ^[20]

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, ^[21] 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. ^[22]

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. ^[23] 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%. ^[24] 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. ^[25] 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. ^[26]

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. ^[27]

Large lesions may be excised with carbon dioxide laser. ^[28] This procedure is quite useful in regions with high vascularity as it produces a bloodless surgical field. ^[29]  A prospective study by Rodriguez-Lujan et al found that 18 months after treatment with carbon dioxide laser, the recurrence rate of oral leukoplakia was 54% and the malignant transformation rate was 2%. ^[30]

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. ^[31]

Curettage and electrodesiccation may also be considered for the excision of larger lesions. ^[32]

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. ^[33] 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. ^[34]

Beta-carotene has been shown to support remission of oral leukoplakia. ^{[35, 36]}

In a pilot crossover study, subjects who smoked demonstrated better improvement than nonsmokers (81.2% vs 28.6%). ^[37]

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 of 50 subjects (8%) 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. ^[38]

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. ^[39]

The use of isotretinoin (13-cis retinoic acid [13-cRA]) has been associated with a number of adverse reactions, ^[40] including hyperuricemia, ^[41] 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. ^{[42, 43]} 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. ^[44] It should be appreciated that a 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. ^[45]

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. ^[46]

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. ^{[47, 48, 49, 50]} 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. ^[51]

Evidence suggests that topical (vs systemic) 5-aminolevulinic acid photodynamic therapy (ALA-PDT) may effectively eliminate oral verrucous hyperplasia as well as oral erythroleukoplakia. ^[52] 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. ^[53] Similar results were found for the management of biopsy-confirmed dysplasia. ^[53]

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. ^[54]

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. ^[51] 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. ^[50]

Adverse reactions associated with the procedure are temporary and include edema, pain, hoarseness, and skin phototoxicity. ^[50] 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. ^[55]

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. ^[56]

Discontinuation of cinnamon effectively eliminates hyperkeratosis associated with its use. ^[57]

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

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. ^[58] 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. ^[59] OLP is a chronic disease without a known cure. Painful lesions are best managed symptomatically. ^[60] 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, ^[61] but this declaration is not without controversy. ^[62] 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. ^{[63, 64]} The literature on OLP now includes the term “oral lichenoid lesions” as a descriptor for lesions that do convert to squamous cell carcinoma. ^[64]

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. These 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. ^[65]  A study by Németh et al suggests that OLP and oral SCC share multiple epigenetic alterations and hypothesizes that OLP is a precursor lesion of oral SCC. ^[66]

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. ^[67] 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). ^[68]

A vast number of interventions for the treatment of OLP are described in the literature. These include topical tacrolimus, ^[69] aloe vera, ^[70] topical cyclosporin, ^[71] intralesional ^[72] or topical/systemic steroids, ^{[73, 74]} rapamycin (a drug with both immunosuppressive and antitumor properties), ^[75] drug combinations (eg, cyclosporine with triamcinolone acetonide, ^[71] tacrolimus powder in Orabase 0.1%), ^[76] and retinoids (both systemic [etretinate] and topical [tretinoin]). ^[77]

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, one systematic review concludes that prospective randomized controlled trials evaluating the various pharmacologic strategies for managing OLP over time are limited; and another review ^[78] does not appear to support the efficacy of one specific treatment over another. ^[79]

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. ^[77] 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. ^[80] If the mucosal lichenoid condition is related to contact with dental material, ^[81] the offending source of the lesions should be removed. ^[82]

Surgical techniques include the use of scalpel surgery or carbon dioxide laser ablation. ^[83]

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