INTRODUCTION — Oral leukoplakia is an oral potentially malignant disorder (OPMD) that presents as white patches of the oral mucosa. According to the World Health Organization, the term leukoplakia should be reserved for "white plaques of questionable risk, having excluded other known diseases or disorders that carry no increased risk for cancer" [1].
A separate disorder that is not premalignant is oral hairy leukoplakia (picture 1), an Epstein-Barr virus-induced lesion that occurs almost entirely in HIV-infected patients. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Oral hairy leukoplakia'.)
EPIDEMIOLOGY AND RISK FACTORS — Oral leukoplakia is not a rare condition; a systematic review pooling data from studies with at least 1000 individuals estimated that the prevalence in the general population is between 1.5 and 4.3 percent [2,3]. Risk factors for oral leukoplakia are similar to those for squamous cell carcinoma (SCC), including tobacco use (smoked and especially smokeless) and alcohol drinking [4]. In addition, leukoplakia has been shown to be associated with human papillomavirus (HPV) infection [5].
CLINICAL PRESENTATION — Leukoplakia presents as white patches of the oral mucosa that cannot be wiped off with a gauze. It is clinically classified into two forms, homogeneous and nonhomogeneous leukoplakia, with the latter carrying a higher risk of oral cancer compared with the homogeneous form [6]:
●Homogenous leukoplakia typically presents as a uniformly white, thin plaque with well-defined margins (picture 2A-B).
●Nonhomogeneous leukoplakia presents with speckled (red and white, but predominantly white) lesions; erythroleukoplakia (red and white lesions) (picture 3); or granular, nodular, or verrucous, white lesions.
Oral proliferative verrucous leukoplakia (OPVL) is a rare, multifocal, aggressive form of nonhomogeneous leukoplakia associated with an extremely high risk of malignant transformation. (See 'Oral proliferative verrucous leukoplakia' below.)
RISK OF ORAL CANCER — Leukoplakia is in itself a benign and asymptomatic condition. However, some patients will eventually develop squamous cell carcinoma (SCC), even among those with lesions showing only "benign hyperkeratosis" without dysplasia on histology.
The rate of cancer incidence among patients affected by oral leukoplakia is unknown; reported rates vary widely across studies, from <1 to 36 percent, due to differences in inclusion criteria among studies [7,8]. Mathematical models using worldwide data on prevalence of leukoplakia and incidence of oral cancer range have estimated an upper limit of annual transformation of <1 percent [9].
Nonhomogeneous clinical subtype, large size (>4 cm in largest diameter), extension over more than one anatomical site, localization (lateral border of the tongue and floor of the mouth), and especially the presence of dysplasia on histologic examination are the most important predictors of cancer [10-13]. The extent or grade of dysplasia is widely used to assess risk of transformation, despite the high variability among pathologists in the identification and grading of epithelial dysplasia [14,15].
The molecular mechanisms underlying the progression from dysplasia to invasive cancer are not well understood. Genetic abnormalities that have been found in both oral SCC and nondysplastic leukoplakia include genome instability (eg, aneuploidy, loss of heterozygosity, telomerase dysfunction), DNA hypermethylation, increased expressions of microRNAs, and altered expression of p53 and p16INK4a [7,16-18].
However, no single molecular marker appears to be predictive of malignant transformation in leukoplakia biopsies [10,19,20].
DIAGNOSIS — The diagnosis of leukoplakia is suspected in patients presenting with a white lesion of the oral mucosa that cannot be wiped off with a gauze and that persists after eliminating potential etiologic factors, such as mechanical friction, for a six-week period [6]. The definitive diagnosis requires a biopsy for histopathologic examination to assess the presence and grade of dysplasia and to exclude other oral disorders that present with white lesions (algorithm 1). Sampling multiple areas of the lesion is recommended. (See "Oral lesions", section on 'White and red oral lesions'.)
Histopathology — Histopathologic features of leukoplakia may include benign hyperkeratosis, parakeratosis, atrophy, inflammation, hyperplasia without dysplasia, or various grades of dysplasia; sometimes areas of carcinoma in situ or even invasive carcinoma can be found in contiguity or within leukoplakia lesions [21,22].
Epithelial dysplasia, oral squamous cell carcinoma (SCC) in situ, or invasive SCC have been reported with variable frequency across studies, ranging from approximately 10 to up to 60 percent of lesions. It should be noted that the diagnosis of dysplasia may be difficult, and there is considerable variability among pathologists in detection and grading of epithelial dysplasia [14]. (See "Pathology of head and neck neoplasms", section on 'Squamous dysplasia'.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis includes a wide range of conditions presenting as white patches or plaques, including frictional keratosis, lichen planus, discoid lupus erythematosus, submucous fibrosis, candidiasis, and hairy leukoplakia (algorithm 1). (See "Oral lesions", section on 'White and red oral lesions'.)
MANAGEMENT — Our approach to the management of patients presenting with leukoplakia is discussed below. (See 'Our approach' below.)
General considerations — The primary aim of leukoplakia treatment is to prevent or decrease the risk of oral squamous cell carcinoma (SCC) [23]. However, there is limited evidence from high-quality studies to guide clinicians in the choice of treatment, and there is no consensus among experts on the management approach [23,24].
Treatment options include surgery, destructive therapies (eg, laser ablation, cryosurgery), medical therapies (eg, retinoids, vitamin A, carotenoids, nonsteroidal anti-inflammatory drugs [NSAIDs]), and watchful waiting with close clinical and histologic follow-up. The main drawback of destructive treatments is that they do not allow histopathologic examination of the entire lesion, which may present pathologic features (high-grade dysplasia, occult cancer foci) that were not present in the diagnostic biopsy specimens [25].
Surgical techniques for removal of oral leukoplakias include conventional cold scalpel excision and laser excision using lasers of different wavelengths, such as carbon dioxide (CO2), neodymium:yttrium aluminum garnet (Nd:YAG), erbium:yttrium aluminum garnet (Er:YAG), and diode. Laser excision might offer some advantages, such as good hemostasis during the procedure and more rapid wound healing, particularly in case of large lesions. However, this technique may cause tissue alterations that may jeopardize histopathologic analysis.
Although surgery is considered first-choice treatment by many relevant specialists [23,26], there is only one randomized trial evaluating its efficacy in the prevention of oral cancer. It showed that surgical excision of nondysplastic lesions provided no benefits when compared with standard care (follow-up visits every six months and repeated biopsies as needed) [27]. Limited data from observational studies and retrospective case series indicate recurrence rates of approximately 15 to 30 percent following surgical excision, irrespective of the technique used, and development of oral SCC in 4 to 20 percent [23,26,28-32].
A 2016 Cochrane systematic review of 14 randomized trials (909 participants) evaluated the efficacy of medical and complementary therapies, including vitamin A, carotenoids, retinoids, NSAIDs (ketorolac and celecoxib), and chemotherapeutic agents [26]. The rationale for using retinoids, vitamin A, and carotenoids is their putative effect on epithelial turnover. For NSAIDs, it is their modulating effect on specific prostaglandins possibly involved in carcinogenesis, while chemotherapeutic agents may act directly on early neoplastic cells. The authors concluded that none of these treatments was more effective than placebo in reducing the risk of oral SCC, although some of them, namely systemic vitamin A, beta carotene, and lycopene, were more effective than placebo in inducing the clinical resolution of the lesions [26].
In clinical practice, the choice of treatment is made based upon the lesion size and type (eg, homogeneous versus nonhomogeneous), presence and grade of histopathologic dysplasia, patient's preference, and clinical experience [21]. Regardless of the treatment choice, all patients should be educated about the importance of avoiding the exposure to known risk factors for oral cancer, such as the use of tobacco (smoked and smokeless) and alcohol. Our approach to the management of patients with oral leukoplakia is outlined below.
Our approach — Our approach to the management of patients presenting with leukoplakia is as follows:
●Following histologic assessment of the lesion through multiple biopsy sampling (see 'Diagnosis' above and 'Histopathology' above), we surgically remove leukoplakias of small size that are clinically nonhomogeneous, those located in high-risk areas (eg, lateral/ventral border of the tongue, floor of the mouth), and those with histopathologic findings of severe dysplasia.
●We typically see patients every three months in the first year after surgery and once per year thereafter. Recurrent lesions or new lesions noted at follow-up visits should be biopsied for histopathologic evaluation. (See 'Prognosis and follow-up' below.)
●Leukoplakias that cannot be surgically removed because of their large size or because of patient preference, as well as lesions that show no or mild epithelial dysplasia on biopsy, may be managed with conservative approaches, including cessation of risk habits (eg, tobacco and alcohol use) and clinical and histologic surveillance. We see patients at intervals of 3 to 18 months, depending on the clinical characteristics of the lesion and the patient's assessed risk of oral cancer (eg, current heavy smokers, alcohol drinkers) (see 'Risk of oral cancer' above). At each follow-up visit, lesions showing clinical changes suggesting cancer (ie, increased heterogeneity, occurrence of erythematous or ulcerated areas, hardening of involved mucosa, lymphadenopathy) must be biopsied.
PROGNOSIS AND FOLLOW-UP — Local recurrence or development of oral squamous cell carcinoma (SCC) occurs despite surgical removal of leukoplakia. Data on recurrence rates are limited and mainly derived from retrospective studies of poor methodologic quality. Local recurrence or new lesions have been reported in 2 to 57 percent of patients undergoing scalpel excision, laser therapy, or cryosurgery, with 0 to 20 percent of patients developing an invasive oral SCC [23].
Regular lifetime monitoring for recurrence or further suspicious mucosal changes is recommended. We typically see patients every three months in the first year after surgery. In the absence of recurrences or development of new mucosal lesions, patients can be seen once per year thereafter. Recurrent lesions or new lesions noted at follow-up visits should be biopsied for histopathologic evaluation.
ORAL PROLIFERATIVE VERRUCOUS LEUKOPLAKIA — Oral proliferative verrucous leukoplakia (OPVL) is a rare, aggressive form of nonhomogeneous oral leukoplakia characterized by verrucous appearance, multifocality, slow growth, and high rate of malignant transformation [33-35]. A systematic review of 20 studies including over 300 patients found a rate of transformation into oral squamous cell carcinoma (SCC) of approximately 64 percent over an average follow-up period of seven years [35].
It occurs in all ethnic groups and appears to be more frequent in older women. The cause is unknown, and there is no clear association with tobacco or alcohol use or human papillomavirus (HPV) infection [35].
OPVL initially presents as a single or multiple leukoplakic area located on the gingiva, oral mucosa, or tongue. Over time, lesions tend to become diffuse and develop exophytic, wart-like, or erythroplakic areas, which may transform into SCC (picture 4).
Diagnosis — The diagnosis of OPVL is based upon combined clinical and histopathologic features. The diagnosis is particularly difficult in the early stages of disease because lesions may mimic clinically and histologically conventional leukoplakia or oral lichen planus. Clinical clues to the diagnosis of OPVL include multifocal lesions or a single, large lesion (>4 cm involving one site or >3 cm involving contiguous sites), presence of verrucous areas, lesions recurring after treatment, female sex, and lack of exposure to tobacco [36]. Early pathologic features that may suggest OPVL include a dense, lichenoid, chronic inflammation (basal vacuolar degeneration, apoptotic cells, eosinophilic bodies, and a band-like lymphocytic infiltrate); wavy hyperorthokeratosis; and exophytic, warty configuration (picture 5).
Proposed diagnostic criteria for OPVL include [37]:
●White keratotic lesions that may be smooth, fissured, verrucous, or erythematous with or without ulceration.
●Multifocal, noncontiguous lesions or a single, large lesion >4 cm involving one site or a single, large lesion >3 cm involving contiguous sites.
●Lesions that progress or expand in size and/or develop multifocality over time.
●Histopathology that, if not overtly exhibiting dysplasia or carcinoma, shows hyperkeratosis, parakeratosis, atrophy, or acanthosis with minimal or no cytologic atypia, or verrucous hyperplasia, with or without a band-like lymphocytic infiltrate; these features must not support a diagnosis of frictional or reactive keratosis. (See "Oral lesions", section on 'Morsicatio buccarum and frictional keratosis'.)
Treatment — There is no curative treatment for OPVL. Multiple therapies have been tried for temporary control of the disease, including surgical excision, carbon dioxide (CO2) and neodymium:yttrium aluminum garnet (Nd:YAG) laser ablation, cryotherapy, radiation therapy, photodynamic therapy, topical bleomycin, and oral retinoids. Nevertheless, more than 70 percent of patients experience recurrence and/or progression to carcinoma despite interventions [38,39].
Prognosis and follow-up — Patients with OPVL require lifelong close clinical and histopathologic monitoring for the development of SCC [37]. Similar to classic leukoplakia, patients with OPVL should undergo regular follow-up at intervals of 3 to 12 months. Lesions that show suspicious changes, such as increased heterogeneity, ulcerated areas, hardening of involved mucosa, and lymphadenopathy, should be biopsied for histopathologic examination. The mortality rate after an average follow-up time of 10 years is approximately 30 percent [35].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)
SUMMARY AND RECOMMENDATIONS
●Oral leukoplakia is an oral potentially malignant disorder (OPMD) that presents as white patches of the oral mucosa. It is relatively common, with a prevalence rate of approximately 4 percent. Risk factors for oral leukoplakia are similar to those for squamous cell carcinoma (SCC), including tobacco use (smoked and especially smokeless) and alcohol drinking. (See 'Epidemiology and risk factors' above.)
●Oral leukoplakia is clinically classified in two forms, homogeneous (picture 2A-B) and nonhomogeneous (picture 3), with the latter carrying a higher risk of oral cancer. (See 'Clinical presentation' above and 'Risk of oral cancer' above.)
●The diagnosis of leukoplakia requires a biopsy for histopathologic examination. Pathologic features of leukoplakia include hyperkeratosis, parakeratosis, atrophy, and inflammation, with or without dysplasia. (See 'Diagnosis' above.)
●The differential diagnosis includes a wide range of benign and premalignant conditions presenting as white patches or plaques of the oral mucosa (algorithm 1). (See 'Differential diagnosis' above.)
●We suggest surgical excision for small leukoplakias that are clinically nonhomogeneous, are located in high-risk areas, and for those with histopathologic findings of severe dysplasia (Grade 2C). Leukoplakias that cannot be surgically removed because of their large size or because of patient preference, as well as those with no or mild epithelial dysplasia on biopsy, may be managed with a conservative approach, including cessation of risk habits (eg, tobacco and alcohol use) and close clinical and histologic surveillance. (See 'Our approach' above.)
●As local recurrence or development of oral SCCs occur despite surgical removal of leukoplakia, lifelong close clinical follow-up and histologic examination of all recurrent or new lesions is recommended following treatment. (See 'Prognosis and follow-up' above.)
●Oral proliferative verrucous leukoplakia (OPVL) is a rare, aggressive form of nonhomogeneous oral leukoplakia characterized by verrucous appearance, multifocality, slow growth, and high rate of malignant transformation (picture 4). Surgical excision, laser ablation, radiation therapy, topical bleomycin, and oral retinoids have been tried for temporary control of OPVL. However, recurrence and/or progression to carcinoma occur in more than 70 percent of patients, with a mortality rate of approximately 30 percent at 10 years. (See 'Oral proliferative verrucous leukoplakia' above.)
