White lesions in the oral cavity may be diverse in etiology and may present with significant clinical and sometimes histologic overlap between categories, making accurate diagnosis difficult at times. Although white lesions of immune and infectious etiology are covered in another article, this article discusses the differential diagnosis between developmental, reactive, idiopathic, premalignant, and malignant white lesions focusing on clinical features of each category.
Key points
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Developmental oral white lesions are often bilateral/symmetric, slow changing, and present for a long duration.
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Reactive oral white lesions frequently present along areas of chronic trauma such as occlusal plane of the buccal mucosa/tongue or edentulous alveolar ridge crest and often appear shaggy, without distinct demarcation.
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Idiopathic oral white lesions may overlap with reactive/premalignant lesions and may require additional follow-up to confirm diagnosis.
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Verrucous carcinoma may be mistaken for a nonmalignant lesion even on biopsy due to benign histologic appearance or sampling issues.
Introduction
White lesions of the oral mucosa demonstrate a full spectrum of etiologies including developmental, reactive, immune-related, idiopathic, and premalignant or malignant conditions. Developmental lesions develop early or later on in life, are often present bilaterally or symmetrically, and are generally stable over time. Reactive lesions may have an obvious traumatic source or be more nuanced in presentation. Immune-related white lesions, most commonly oral lichen planus or oral lichenoid mucositis, may fluctuate in clinical presentation and severity and even remit.
Lichenoid conditions are covered extensively in Chapter 4 and thus will only be discussed in this article in the context of differential diagnosis. In addition, lesions related to immunosuppression such as oral hairy leukoplakia (OHL) may also be considered in a differential diagnosis of white lesions and are addressed in Chapter 3. White lesions of candidiasis are addressed in Chapter 1 and may also be considered in the differential diagnosis but can often be clinically distinguished from other entities as superficially adherent plaques that wipe off easily, although hyperplastic candidiasis may overlap more significantly with other plaque-like white lesions of the oral cavity.
Many white lesions with nonobvious traumatic etiology and an uncertain behavior may fit into a group of lesions termed idiopathic leukoplakia, hyperkeratosis-nonreactive, or keratosis of unknown significance (KUS). This group may also have significant overlap with early dysplastic lesions or lesions within the proliferative verrucous leukoplakia (PVL) spectrum. Premalignant lesions with unifocal or multifocal presentation may present as white lesions with varying levels of surface change and divergent clinical features, and malignant lesions such as verrucous carcinoma (VC) may present only as an isolated papillary white lesion resembling a large papilloma/condyloma.
Although some white lesions of the oral cavity may be diagnosed clinically, the extent of clinical overlap between premalignant and benign oral white lesions may often necessitate a biopsy to accurately manage many of these conditions.
Developmental or Hereditary Lesions
Developmental oral lesions may be hereditary or acquired and commonly or rarely encountered. Two examples at differing ends of this spectrum are leukoedema, which occurs commonly with an imprecise etiology and white sponge nevus (WSN), a rare autosomal dominant condition.
Leukoedema represents one of the most common white lesions in the oral cavity and may represent a variation of normal anatomy. Although the etiology is unknown, it is generally thought to be developmental in origin, and irritation may also play a role with some studies noting increased incidence in patients using tobacco or betel products. , Leukoedema is a common occurrence in patient populations with higher melanin pigmentation levels of the skin, occurring in up to nearly 90% of patients of African American ethnicity, for example, with incidence increasing among patients within a population as level of pigmentation in the skin increases. , , It may occur in both children and adults. Leukoedema presents bilaterally in over 90% of cases. The clinical presentation of leukoedema is striking and characteristic, with a diffuse homogenous milky white appearance to the buccal mucosa, sometimes with a wrinkled appearance, that disappears when the tissue is stretched out — a feature that differentiates it from all other white lesions ( Fig. 1 ). Although the diagnosis rarely requires a biopsy, the histologic appearance exhibits hyperparakeratosis with marked intracellular edema without atypia or dysplasia, which may resemble other conditions such as WSN, OHL, or traumatic hyperkeratosis. Unlike lesions of OHL, no nuclear inclusions of Epstein–Barr virus are observed, and immunohistochemical testing using EBER (Epstein-Barr encoding region) in-situ hybridization would be expected to be negative.
WSN is an autosomal dominant condition with variable clinical expression associated with mutation of keratin 4 and 13 genes. , It generally presents at an early age suggesting hereditary origin and is most frequently bilateral in nature. The buccal mucosa is most frequently affected but the tongue, labial mucosa, floor of mouth, or gingiva, or non-oral mucosal locations may also be involved. , Clinically, the lesions present as asymptomatic thick corrugated diffuse white plaques, which require differentiation from premalignant oral lesions ( Fig. 2 ). Similar oral lesions accompanied by ocular lesions may be seen in hereditary benign intraepithelial dyskeratosis ( HBID ), though this condition has been typically identified in a fairly narrow ancestry profile originating in the eastern United States. , Other genodermatoses such as dyskeratosis congenita may also have overlapping clinical presentation but with a wider range of non-oral signs and symptoms. Histologically, WSN demonstrates hyperparakeratosis and intracellular edema similar to leukoedema, but also exhibits intracellular degeneration of keratinocytes with eosinophilic deposits in a perinuclear manner that is distinctive to this condition. Lesions of HBID exhibit hyperparakeratosis with dyskeratosis and a “cell-within-a-cell” pattern without the perinuclear eosinophilic deposits noted in WSN. WSN is asymptomatic and treatment is not necessary once the diagnosis has been established.
Reactive Lesions
Reactive lesions of the oral cavity are frequently white in appearance due to proliferation of the surface epithelium in response to chronic or acute trauma, often from chewing, aggressive toothbrushing, habitual cheek or tongue biting, or an irritation mediated contact reaction to a topical product such as chewing tobacco, cinnamon, gums/mints/lozenges, toothpastes, or mouth rinses. Traumatic hyperkeratosis clinically appears shaggy with poorly demarcated borders, often presents in a generalized or symmetric manner, and is frequently located in areas subjected to trauma such as the crest of the edentulous ridge or the occlusal plane of the buccal mucosa or lateral tongue.
Alveolar ridge hyperkeratosis (also known as benign alveolar ridge keratosis or BARK) is commonly found on edentulous ridges particularly in areas with opposing natural dentition. The retromolar pad is frequently affected in a bilateral manner ( Fig. 3 ). Smokers are also commonly affected. , Lesions typically are limited to the crestal aspect of the alveolar ridge, often lack distinct borders, but may be symmetric and bilateral, particularly on the retromolar pad. Ulceration or erythema should provoke concern for dysplasia or neoplasia. Histologic examination generally reveals hyperkeratosis with “wedge-shaped” hypergranulosis without dysplasia or atypia, sometimes with a surface corrugation that may overlap slightly with premalignant verrucous lesions such as those within the PVL spectrum.
Frictional keratosis limited to the facial attached gingiva has rarely been described related most frequently to aggressive toothbrushing habit. It may clinically and histologically overlap with PVL lesions due to sharp demarcation and thickened surface features. However, the location at the crest of the ridge and not the marginal gingiva is helpful in distinguishing it from PVL, and the histologic features are most similar to those of alveolar ridge hyperkeratosis. Also, no clinical progression is reported, and lesions resolve quickly after oral hygiene habits are altered.
Morsicatio buccarum and morsicatio linguarum (cheek chewing and tongue chewing, respectively) are parafunctional sequelae that patients may or may not be cognizant of as habits. Lesions generally appear as shaggy, poorly demarcated white lesions running along the occlusal plane of the buccal mucosa or tongue and are often symmetric in appearance ( Figs. 4 and 5 ). The histologic appearance exhibits hyperparakeratosis with frayed surface keratin, sometimes demonstrating adherent bacterial colonization, a lack of atypia or dysplasia, and minimal inflammation of the underlying connective tissue.
More localized or asymmetric traumatic/reactive hyperkeratosis, such as those associated with a sharp or broken tooth or restoration, are often confined only to the area approximating the offending tooth, although lesions that do not resolve after adjustment or restoration of the tooth require biopsy to rule out dysplasia or neoplasia ( Fig. 6 ). The histologic appearance of localized traumatic hyperkeratosis is characterized by hyperparakeratosis and acanthosis in most cases, without atypia or dysplasia.
Contact irritation stomatitis often appears as superficial sloughing or peeling adherent white plaques. Toothpaste ingredients such as sodium lauryl sulfate, triclosan, or tetrasodium pyrophosphate, along with various mouth rinses have been associated with superficial sloughing of the epithelium. It contains stringy or ropey exfoliating parakeratin or cellular debris that often can be noted in the vestibular areas but also may be widespread ( Fig. 7 ). , Mild sensitivity may be present, or the lesions may be asymptomatic. Cessation of the offending agent generally resolves the condition. Other contact-related keratotic type lesions may appear thicker and more adherent, complicating the differential diagnosis. These have been associated with chronic use of cinnamon, gums/mints/lozenges, or other products ( Figs. 8 and 9 ). Amalgam restorations can also provoke a keratotic contact reaction in addition to a lichenoid appearing lesion. If lesions cannot be resolved by discontinuation of a suspected agent, then a biopsy may be indicated. The histology of irritation contact hyperkeratotic lesions generally appears nonspecific and exhibits hyperkeratosis along with mucositis in some cases.
