Oral leukoplakia

INTRODUCTION — Oral leukoplakia is an oral potentially malignant disorder 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 patients infected with human immunodeficiency virus (HIV). Oral lichen planus is also reviewed separately. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Oral hairy leukoplakia' and "Oral lichen planus: Pathogenesis, clinical features, and diagnosis" and "Oral lichen planus: Management and prognosis".)

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 0.3 and 4.1 percent, with high heterogeneity among continents and the highest prevalence rates recorded in Asia and Oceania [2,3]. Risk factors for oral leukoplakia are similar to those for squamous cell carcinoma (SCC), including tobacco use (smoked and smokeless) and alcohol drinking [4]. In addition, leukoplakia has been shown to be associated with human papillomavirus (HPV) infection [5].

PATHOGENESIS — The pathogenesis of oral leukoplakia is largely unknown. It is considered an intermediate stage in oral carcinogenesis, driven by multiple somatic genetic mutations affecting keratinocyte growth, survival, and cycle control. These result in histopathologic (hyperkeratosis, hyperplasia, dysplasia) and clinical (change of color, thickness, and texture) modifications.

Genetic and molecular alterations — Copy number alterations that originate from gains, amplifications, deletions, and insertions of deoxyribonucleic acid (DNA) sequences involving known oncogenic drivers (eg, CDKN2A, CCND1, EGFR, and MYC) have been found with high frequency in oral leukoplakia [6]. Other common features of oral leukoplakia include DNA ploidy abnormalities; positive telomerase activity; loss of heterozygosity (particularly on 3p, 4q, 9p, and 17p); and gene mutations, the most frequent being those affecting TP53, followed by NOTCH1, FAT1, CDKN2A, KMT2C, and PIK3CA [7-9].

Immune profile — Increased expression of human leukocyte antigen (HLA) G/E, interleukin (IL) 10, transforming growth factor (TGF)-beta 2/3, programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1) has been demonstrated in oral leukoplakia, irrespective of the degree of epithelial dysplasia [10,11]. Increased density of CD8⁺ T cells, cytotoxic T cells, and T regulatory cells, as well as overexpression of PD-L1, has been demonstrated in proliferative verrucous leukoplakia (PVL) [12].

Oral microbiota — It has been hypothesized that dysbiosis might play a role in the development of leukoplakia and oral potentially malignant disorders. A few studies investigating the microbiome associated with oral leukoplakia showed that Haemophilus, Fusobacterium, Leptotrichia, and Campylobacter were found to be significantly more abundant in oral leukoplakia compared with nonaffected tissues; the genera found were different from those associated with oral squamous cell carcinoma (SCC) [13].

Biomarkers and risk of oral cancer — The molecular mechanisms underlying the progression from dysplasia to invasive cancer involve the accumulation of genetic alterations in tumor suppressor genes and oncogenes [14]. Genetic abnormalities that have been found in both oral SCC and nondysplastic leukoplakia include copy number alterations, DNA hypermethylation, increased expressions of microribonucleic acids (microRNAs), and altered expression of p53 and p16INK4a [15-18]. Despite the existing extensive literature on the topic, there is insufficient evidence to support the clinical use of any marker to predict oral cancer development in patients affected by oral leukoplakia, although DNA ploidy and expression of podoplanin might be the most promising among the biomarkers investigated [19].

CLINICAL PRESENTATION

Clinical subtypes — 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 [20].

●Homogeneous leukoplakia – Homogeneous leukoplakia typically presents as a uniformly white plaque with regular texture and well-defined margins (picture 2A-B).

●Nonhomogeneous leukoplakia – 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.

●Proliferative verrucous leukoplakia – Proliferative verrucous leukoplakia (PVL) is a rare, multifocal, aggressive form of nonhomogeneous leukoplakia associated with an extremely high risk of malignant transformation (picture 4). (See 'Proliferative verrucous leukoplakia' below.)

Clinical features associated with increased risk of oral cancer — 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 [21-24]. 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 [25,26].

DIAGNOSIS

Clinical suspicion — 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; that does not appear of traumatic, frictional, or otherwise reactive nature; and/or persists after eliminating potential etiologic factors, such as mechanical friction, for a six-week period [20]. (See "Oral lesions", section on 'White and red oral lesions'.)

Biopsy and histopathology — 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.

Histopathologic features of leukoplakia may include:

●Benign hyperkeratosis (not reactive)

●Parakeratosis

●Atrophy

●Inflammation

●Hyperplasia, including atypical verrucous hyperplasia (not reactive), without dysplasia

●Various grades of dysplasia (mild, moderate, severe, or alternatively defined as low or high grade)

Sometimes, areas of carcinoma in situ or even invasive carcinoma can be found in contiguity or within leukoplakia lesions [27,28].

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 [25,29]. (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.)

Choice of treatment — The primary aim of leukoplakia treatment is to prevent or decrease the risk of oral squamous cell carcinoma (SCC) [30]. 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 [30,31]. For this reason, patients must undergo a surveillance program at regular intervals, depending on risk stratification. In clinical practice, the choice of treatment is made based upon lesion size and type (eg, homogeneous versus nonhomogeneous), presence and grade of histopathologic dysplasia, clinical experience, and the patient's characteristics (age and comorbidities) and preferences [27].

Treatment options include surgery, destructive therapies (eg, laser ablation, cryosurgery), medical therapies (eg, retinoids, vitamin A, carotenoids, nonsteroidal anti-inflammatory drugs [NSAIDs], immunomodulators [imiquimod]), 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 [32].

Our approach to the management of patients with oral leukoplakia is outlined below. (See 'Our approach' below.)

Surgical therapies — Surgical techniques for removal of oral leukoplakia include conventional cold scalpel excision and laser excision using lasers of different wavelengths, such as carbon dioxide (CO₂), neodymium-doped yttrium aluminum garnet (Nd:YAG), erbium-doped yttrium aluminum garnet (Er:YAG), and diode. 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 [30,33-38].

●Surgical excision – Although surgery is considered first-choice treatment by many relevant specialists [30,33], there is only one randomized trial evaluating its efficacy in the prevention of oral cancer. The trial 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) [39].

●Laser excision – 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. Reported recurrence rates following CO₂ laser excision range from 10 to over 50 percent [40,41].

●Photodynamic therapy – Photodynamic therapy employing different photosensitizers (aminolevulinic acid, photofrin, methylene blue, and chlorin e6) and different parameters (wavelength, duration of irradiation, and power density) for the treatment of oral leukoplakia has been described in several studies. However, none of the studies included in a systematic review used oral cancer onset as an outcome [42]. A clinical study using ablative fractional laser-assisted photodynamic therapy showed a high rate of recurrence and cancer incidence [43].

Medical and complementary therapies — Medical therapies include retinoids, vitamin A, carotenoids, and NSAIDs. 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.

A 2016 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 [33]. 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 [33].

Our approach — Our approach to the management of patients presenting with leukoplakia is as follows (algorithm 2):

●The decision about treatment approach should be discussed with the patient. The patient should be informed about the scopes, methods, risks, and possible alternatives. Regardless of the treatment choice, all patients should be educated about the importance of avoiding exposure to known risk factors for oral cancer, such as the use of tobacco (smoked and smokeless) and alcohol. In addition, regardless of the treatment approach, the patient must agree on a surveillance program aimed to make an early diagnosis in case of cancer onset.

●Following histologic assessment of the lesion through multiple biopsy sampling (see 'Diagnosis' above and 'Biopsy and histopathology' above), we suggest surgical removal for leukoplakia of small sizes (up to 3 cm in the major axis), particularly when they are clinically nonhomogeneous, located in high-risk areas (eg, lateral/ventral border of the tongue, floor of the mouth), or show dysplasia on biopsy. We perform surgery with cold blade or diode laser, depending on the size of the lesion and the surgeon's preference.

●Patients who undergo surgical excision are followed up at regular intervals. We typically see patients every three months in the first year after surgery and once a year thereafter. Recurrent lesions or new lesions noted at follow-up visits should be biopsied for histopathologic evaluation. (See 'Prognosis' below.)

●Leukoplakias that cannot be completely removed surgically because of their large size (>3 cm in largest diameter), multifocality, or the patient's 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 do not use any chemopreventive agent to treat patients with oral leukoplakia.

We see patients at intervals of 3 to 12 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 'Clinical features associated with increased 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

Local recurrence — Local recurrence or development of oral squamous cell carcinoma (SCC) occurs despite surgical removal of leukoplakia. 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 [30]. In a prospective study of 103 patients with oral leukoplakia who underwent surgical excision of the entire lesion, recurrence was noted in 42 percent; the cumulative incidence of recurrence was 49 percent after five years [44].

Malignant transformation — Leukoplakia is a benign and asymptomatic condition. However, some patients will eventually develop 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. Data are limited and range from <1 to 36 percent across studies [15,45]. In a retrospective cohort of 170 patients with oral leukoplakia followed up for 12 to 219 months (median 54), malignant transformation occurred in 23 percent of patients, with an annual transformation rate of 4.9 percent [46]. 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 [47].

FOLLOW-UP — 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 (algorithm 2). 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.

PROLIFERATIVE VERRUCOUS LEUKOPLAKIA — Proliferative verrucous leukoplakia (PVL) is a rare, aggressive form of nonhomogeneous oral leukoplakia characterized by verrucous appearance, multifocality, slow growth, and high rate of malignant transformation [48-50]. 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 [50].

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 [50].

PVL 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 PVL 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 [51]. Clinical clues to the diagnosis of PVL 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 [52].

Early pathologic features that may suggest PVL include a dense, lichenoid, chronic inflammation (basal vacuolar degeneration, apoptotic cells, eosinophilic bodies, and a band-like lymphocytic infiltrate); wavy (corrugated) hyperorthokeratosis; and exophytic, warty configuration (picture 5).

Proposed diagnostic criteria for PVL include [53]:

●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 PVL. Multiple therapies have been tried for temporary control of the disease, including surgical excision, carbon dioxide (CO₂) and neodymium-doped 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 [54,55].

Prognosis and follow-up — Patients with PVL require lifelong close clinical and histopathologic monitoring for the development of SCC [53]. As for classic leukoplakia, patients with PVL 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 [50].

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

●Definition and risk factors – Oral leukoplakia is an oral potentially malignant disorder 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.)

●Clinical presentation – 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 'Clinical features associated with increased risk of oral cancer' above.)

●Diagnosis – 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.)

●Differential diagnosis – 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.)

●Management – All patients should be counseled regarding tobacco and alcohol cessation. The management is based on the lesion size and type, histopathologic findings, and patient's assessed risk for oral cancer (algorithm 2).

•For patients with small (<3 cm) leukoplakias that have any of the following risk factors, we suggest surgical excision (Grade 2C):

-Nonhomogeneous appearance

-Location in a high-risk area (lateral/ventral border of the tongue, floor of the mouth)

-Dysplasia

•For patients with small (<3 cm) leukoplakias lacking any of the above risk factors, surveillance is appropriate.

•Patients with large or multifocal leukoplakias that are not amenable to surgical removal should be offered clinical and histologic surveillance.

●Follow-up – As local recurrence or development of oral SCCs occur despite surgical removal of leukoplakia, lifelong close clinical follow-up every 3 to 12 months and histologic examination of all recurrent or new lesions are recommended following treatment. (See 'Prognosis' above.)

●Proliferative verrucous leukoplakia – Proliferative verrucous leukoplakia (PVL) 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 PVL. 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 'Proliferative verrucous leukoplakia' above.)