Oral potentially malignant disorders (OPMDs) are precursor lesions that may undergo malignant transformation to oral cancer. These lesions most commonly present clinically as white patches (leukoplakia). However, they may also be red (erythroplakia), or red and white (erythroleukoplakia). There are many risk factors associated with the development of an OPMD, and with the risk of malignant transformation of the lesion. A biopsy with subsequent microscopic examination from the lesional tissue is necessary in identification of OPMD. This article reviews the clinical appearance of OPMDs, associated risk factors, diagnosis and histologic appearance, and treatment.
Key points
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Oral potentially malignant disorders are epithelial lesions that may present clinically as white (leukoplakia), red (erythroplakia), or red and white (erythroleukoplakia) patches.
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There are many factors that increase patients’ risk for developing a potentially malignant lesion.
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A biopsy of the lesion is the gold standard to differentiate between a potentially malignant lesion and other entities, and to diagnosis and grade epithelial dysplasia.
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After the diagnosis of a premalignant lesion is made, many patient-related and lesion-related factors influence the type and extent of treatment of the lesion.
Introduction
Oral potentially malignant disorder (OPMD) is defined as an epithelial lesion or disorder that has an increased risk for malignant transformation. The diagnosis of OMPD begins with a clinical examination, and, when present, it is most commonly described as a white lesion (leukoplakia) or less often as a red lesion (erythroplakia). These diagnoses are only clinical, and a definitive diagnosis must be determined through biopsy and histopathologic examination. Once the diagnosis of an OPMD is made, the patient’s risk factors must be evaluated to determine the risk for malignant transformation and appropriate treatment. This article reviews the clinical presentation of OMPDs, including leukoplakia and erythroplakia; the risk factors, including tobacco, alcohol, actinic damage, and human papilloma virus (HPV); the necessary microscopic features to make the diagnosis; and the treatment and management of these lesions.
Leukoplakia
Oral leukoplakia is the most frequently seen potentially malignant disorder in the oral cavity. Leukoplakias were first reported in the literature in 1877, when the term was applied to any white lesion occurring in the oral cavity. Leukoplakias are now defined as white, irreversible, and nonscrapable plaques that carry a questionable risk to transform into cancer. More specifically, these lesions cannot be associated with any chemical, physical, or infectious causative agents except for tobacco, alcohol, or betel quid. In the general population the overall prevalence is approximately 2%, with increasing prevalence for older populations. Leukoplakia has a male predilection and is usually seen in the fifth to sixth decades of life. One prospective study on leukoplakia found the incidence rates to be 1.1 to 2.4 per 1000 patients per year for men and 0.2 to 1.3 per 1000 patients per year for women.
Clinically, leukoplakias can be classified according to their surface and morphologic features. Leukoplakias can be homogeneous in appearance and have a smooth, white, flat surface, with well-demarcated borders ( Figs. 1 and 2 ). Nonhomogeneous leukoplakia is classified into 3 clinical categories:
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Speckled leukoplakia
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Nodular leukoplakia
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Verrucous leukoplakia
Speckled leukoplakia is defined as a predominately leukoplakic lesion with areas of erythema appearing as small, dotlike spots, or larger, irregular patches. Speckled leukoplakia is now termed erythroleukoplakia and is discussed in more detail later. Nodular leukoplakia presents as an exophytic polypoid structure that is rounded and composed of both erythematous and leukoplakic surfaces. Verrucous leukoplakia has an elevated, proliferative, wrinkled, or corrugated surface Most importantly, nonhomogeneous leukoplakia presents a higher risk for malignant transformation than homogeneous leukoplakia. There is an overall malignant transformation rate of 1.5% to 34% for oral leukoplakic lesions. This rate can be further broken down to a transformation rate of 3% for homogeneous lesions and 13.4% to 14.5% for nonhomogeneous lesions. Furthermore, 1 study showed that verrucous leukoplakia has a transformation rate of 4.6%, with erosive lesions having a 28% risk of malignant transformation.
Leukoplakic lesions can occur at any site in the oral cavity. The most common sites include the lateral border of the tongue and the floor of the mouth, followed by buccal mucosa, hard and soft palate, and gingival/alveolar mucosa. Oral leukoplakia may be localized to 1 site or present as diffuse and widespread oral mucosal disease.
Proliferative verrucous leukoplakia (PVL) is a rare but high-risk form of leukoplakia. PVL most commonly presents in women more than 60 years of age who lack a clinical history of tobacco or alcohol use. An ethnic predilection is not seen. A strong female predilection of 4:1 has been reported with PVL. Initially, lesions of PVL present as asymptomatic, small, well-defined white patches or plaques with or without surface thickening. As the disease progresses, the lesions slowly enlarge and involve diffuse surfaces along multiple sites of the oral mucosa. Lesions of PVL evolve from flat patches to become increasingly exophytic and verrucous ( Figs. 3 and 4 ). PVL may involve multiple sites of the oral cavity, including the gingiva, alveolar mucosa, tongue, palate, and buccal mucosa. The gingiva is the most commonly affected area. Furthermore, gingival and palatal lesions are the most commonly affected sites to undergo malignant transformation. The reported malignant transformation rate for lesions of PVL is 63.3% to 100%. Even with ablative treatment, PVL has a recurrence rate of up to 85%. Therefore, close surveillance of patients with PVL is of the utmost importance. Because of the serious nature of PVL, making the correct diagnosis is critical for the health of the patient. Criteria for the diagnosis of PVL include:
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Existence of a verrucous area
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Involvement of more than 2 sites
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Lesions that have increased in size and spread to other sites during the development of the disease over at least 5 years
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Recurrence in a previously treated area
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Representative biopsy samples of lesional tissue have been microscopically examined, and the presence of an invasive squamous cell carcinoma has been ruled out
Despite these criteria, all lesions of PVL do not have a verrucous surface. A more inclusive term for this condition, proliferative multifocal leukoplakia, has been suggested.
The differential diagnosis for leukoplakic lesions can be separated into the broad categories of congenital, infectious, inflammatory, and mucosal injury. Common congenital white lesions include leukoedema, which disappears after stretching of the mucosa, and white sponge nevus (also known as Cannon disease or familial white folded dysplasia), which typically affects the buccal mucosa bilaterally. White lesions of infectious cause include pseudomembranous candidiasis and oral hairy leukoplakia. However, pseudomembranous candidiasis presents as a white membrane that can be physically wiped away leaving a raw erythematous mucosal base. Oral hairy leukoplakia occurs as a secondary manifestation in patients with compromised immune systems and infected with the Epstein Barr virus and is also known as human herpesvirus 4. Leukoplakic lesions of inflammatory cause present with a lichenoid appearance and include lichen planus, lichenoid mucositis as a result of medication side effects and contact hypersensitivities, oral lesions of systemic lupus erythematosus, and graft-versus-host disease in patients with a history of bone marrow transplant. A detailed clinical history aids in differentiation of inflammatory lesions from true leukoplakia. Chemical and thermal mucosal burns, morsicatio, linea alba, and frictional keratoses all present as white areas as a result of mucosal injury. The diagnosis of a mucosal injury can be reached by determining the location of the injury and detailed questioning of the patient.
Erythroplakia
Erythroplakia is defined as a potentially malignant disorder of the oral cavity that presents as a red patch of the oral mucosa that cannot be diagnosed as any other definable lesion. The lesion cannot have traumatic, vascular, or inflammatory causes. Erythroplakia occurs in middle-aged and elderly patients, most commonly in the sixth and seventh decades of life. It occurs with equal frequency in both genders. Erythroplakia has a prevalence range from 0.02% to 0.83%, with a mean prevalence of 0.11% in the general population. Although erythroplakia is rare, it has a much higher rate of malignant transformation than other premalignant conditions, such as leukoplakia and submucous fibrosis. The reported transformation rates range from 14% to 50%, 4 times greater than the malignant transformation rates of leukoplakic lesions. Systematic reviews have shown a range of 1.3% to 34% of malignant transformation in erythroplakic lesions in the global population.
Clinically, erythroplakia presents as an erythematous mucosal lesion that is often smooth in appearance ( Fig. 5 ). Erosive, granular, or nodular changes can be seen in long-standing lesions. Rarely, lesions can be depressed below the mucosal surface, alluding to their atrophic nature. Typically, these lesions are asymptomatic. Visually, a well-defined margin can be appreciated between the lesional tissue and adjacent normal mucosa. Most commonly, erythroplakia presents as a solitary lesion. However, examples of multicentric lesions and lesions involving extensive portions of oral mucosa have been reported. When palpated, erythroplakias are typically soft. Indurated areas or lesions that are firm to palpation occur when malignant transformation and invasion are present. The soft palate is the most common site for erythroplakia to occur. Other common sites include ventral tongue, floor of mouth, and tonsillar pillars. Other areas of the tongue are rarely affected. A diagnostic biopsy is required to differentiate between a true erythroplakia and other pathologic entities of the oral cavity. Microscopic examination of affected tissue aids in distinguishing a true erythroplakia from erythematous candidiasis and lichenoid lesions, including lichen planus, lichenoid mucositis, and oral lesions of lupus erythematosus, which can have similar clinical appearances. In addition, a biopsy can also rule out hemangiomas and other vascular anomalies, Kaposi sarcoma, median rhomboid glossitis, lesions secondary to local irritation, and erythema migrans. Disorders manifesting as desquamative gingivitis present as erythema of the gingiva, and include lichen planus, pemphigus vulgaris, and mucous membrane (cicatricial) pemphigoid.
