Definition<unk>  is a diagnosis of exclusion, meaning that which lesions are included depends upon what diagnoses are currently considered acceptable. Accepted definitions of<unk>  have changed over time and are still controversial. It is possible that the definition will be further revised as new knowledge becomes available. In 1984 an international symposium agreed upon the following definition: "a whitish patch or plaque, which cannot be characterized clinically or pathologically as any other disease, and is not associated with any physical or chemical agent except the use of tobacco." There were, however, problems and confusion in applying this definition. At a second international symposium held in 1994, it was argued that whilst tobacco was a likely causative factor in the development of<unk> , some white patches could be linked directly to the local effects of tobacco by virtue of their disappearance following smoking cessation, suggesting that this kind of white patch represents a reactive lesion to local tissue irritation rather than a lesion caused by carcinogens in cigarette smoke, and could be better termed to reflect this etiology, e.g. smokers' keratosis. The second international symposium, therefore, revised the definition of<unk>  to: "a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion." In the mouth, the current definition of oral<unk>  adopted by the World Health Organization is "white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer". However, this definition is inconsistently applied in the medical literature, and some refer to any oral white patch as<unk> ". The term has been incorrectly used for white patches of any cause (rather than specifically referring to idiopathic white patches) and also to refer only to white patches which have a risk of cancerous changes. It has been suggested that<unk>  is an unhelpful term since there is so much inconsistency surrounding its use, and some clinicians now avoid using it at all. Biopsy Microscopic examination of keratinocytes scraped from the buccal mucosa Tissue biopsy is usually indicated to rule out other causes of white patches and also to enable a detailed histologic examination to grade the presence of any epithelial dysplasia. This is an indicator of malignant potential and usually determines the management and recall interval. The sites of a<unk>  lesion that are preferentially biopsied are the areas that show induration (hardening) and erythroplasia (redness), and erosive or ulcerated areas. These areas are more likely to show any dysplasia than homogenous white areas. Brush biopsy/exfoliative cytology is an alternative to incisional biopsy, where a stiff brush is scraped against the lining of the mouth to remove a sample of cells. This is then made into a smear which can be examined microscopically. Sometimes the biopsy site can be selected with adjunct methods which aim to highlight areas of dysplasia. Toluidine blue staining, where the dye is preferentially retained by dysplastic tissue, is sometimes used, but there is high false positive rate. Other methods involve the use of luminescence, relying on either the property of normal autoflorescent molecules in mucosa such as collagen and keratin which is lost from areas of dysplasia or carcinoma under blue light or by initially staining of the mucosa with toluidine blue or dilute acetic acid and examination under white light. Histologic appearance<unk>  has a wide range of possible histologic appearances. The degree of hyperkeratosis, epithelial thickness (acanthosis/atrophy), dysplasia and inflammatory cell infiltration in the underlying lamina propria are variable. In mucous membranes, hyperkeratosis can be defined as "an increase in the thickness of the keratin layer of the epithelium, or the presence of such a layer in a site where none would normally be expected." In<unk> , the hyperkeratosis varies in thickness and may be either ortho- or para-keratosis, (depending upon whether cell nuclei are lost or retained in the superficial layers respectively), or a mixture of both in different areas of the lesion. The epithelium may show hypertrophy (e.g. acanthosis) or atrophy. Red areas within<unk>  represent atrophic or immature epithelium which has lost the ability to keratinize. The transition between the lesion and normal surrounding mucosa may be well-demarcated, or poorly defined. Melanin, a pigment naturally produced in oral mucosa, can leak from cells and give a grey color to some<unk>  lesions. Hyperkeratosis and altered epithelial thickness may be the only histologic features of a<unk>  lesion, but some show dysplasia. The word "dysplasia" generally means "abnormal growth", and specifically, in the context of oral red or white lesions, refers to microscopic changes ("cellular atypia") in the mucosa that indicate a risk of malignant transformation. When dysplasia is present, there is generally an inflammatory cell infiltration in the lamina propria. The following are commonly cited as being possible features of epithelial dysplasia in<unk>  specimens: * Cellular pleomorphism, in which cells are of abnormal and different shapes. * Nuclear atypia, in which the nuclei of cells varies in size, any may be increased in size relative to the cytoplasm, shape, and may stain more intensely. There may also be more prominent nucleoli. * Increased number of cells seen undergoing mitosis, including both normal and abnormal mitoses. Abnormal mitosis may be abnormally located, e.g. occurring in suprabasal cells (cell layers more superficial to the basal cell layer) or of abnormal form, e.g. "tri-radiate mitoses" (a cell splitting into 3 daughter cells rather than only 2) * Loss the normal organization of the epithelial layers. The distinction between the epithelial layers may be lost. Normally stratified squamous epithelium shows progressive changes in the form of cells from the basal to the superficial layers, with cells becoming more flat ("squames") towards the surface as a continuous maturation process. In dysplastic epithelium, cells may become vertically orientated rather than becoming flat towards the surface. * There may be abnormal keratinization, where keratin is formed below the normal keratin layer. This can occur in individual cells or groups of cells, forming an intraepithelial keratin pearl. There may be an increase in the number of basal cells, and they may lose their cellular orientation (losing their polarity and long axis). * Alteration of the normal epithelial-connective tissue architecture - the rete pegs may become "drop shaped". wider at their base than more superficially. Generally, dysplasia is subjectively graded by pathologists into mild, moderate or severe dysplasia. This requires experience as it is a difficult skill to learn. It has been shown that there is high degree of inter-observer variation and poor reproducibility in how dysplasia is graded. Severe dysplasia is synonymous with the term carcinoma in situ, denoting the presence of neoplastic cells which have not yet penetrated the basement membrane and invaded other tissues. Differential diagnosis Cause Diagnosis Normal anatomic variation Fordyce's spots (Fordyce's granules) Developmental White sponge nevus Leukoedema Pachyonychia congenita Dyskeratosis congenita Tylosis Hereditary benign intraepithelial dyskeratosis Darier's disease (follicular keratosis) Traumatic Frictional keratosis (e.g. morsicatio buccarum, linea alba, factitious injury) Chemical burn Infective Oral candidiasis Oral hairy<unk>  Syphlytic<unk>  Immunologic Lichen planus Lichenoid reaction (e.g. Lupus erythematosus, Graft versus host disease, Drug-induced lichenoid reaction) Psoriasis Idiopathic and smoking related<unk>  Smoker's keratosis (Stomatitis nicotina) Others e.g. Smokeless tobacco keratosis ("tobacco pouch keratosis") Neoplastic Oral squamous cell carcinoma Carcinoma in situ Other Oral keratosis of kidney failure Skin graft There are many known conditions that present with a white lesion of the oral mucosa, but the majority of oral white patches have no known cause. These are termed<unk>  once other likely possibilities have been ruled out. There are also few recognized subtypes of<unk> , described according to the clinical appearance of the lesion. Almost all oral white patches are usually the result of keratosis. For this reason, oral white patches are sometimes generally described as keratoses, although a minority of oral white lesions are not related to hyperkeratosis, e.g. epithelial necrosis and ulceration caused by a chemical burn (see: Oral ulceration#Chemical injury). In keratosis, the thickened keratin layer absorbs water from saliva in the mouth and appears white in comparison with normal mucosa. Normal oral mucosa is a red-pink color due to the underlying vasculature in the lamina propria showing through the thin layer of epithelium. Melanin produced in the oral mucosa also influences the color, with a darker appearance being created by higher levels of melanin in the tissues (associated with racial/physiologic pigmentation, or with disorders causing melanin overproduction such as Addison's disease). Other endogenous pigments can be overproduced to influence the color, e.g. bilirubin in hyperbilirubinemia or hemosiderin in hemochromatosis, or exogenous pigments such as heavy metals can be introduced into the mucosa, e.g. in an amalgam tattoo. Almost all white patches are benign, i.e. non-malignant. The differential diagnosis of a white lesion in the mouth can be considered according to a surgical sieve (see table).<unk>  cannot be rubbed off the mucosa, distinguishing it readily from white patches such as pseudomembraneous candidiasis, where a white layer can be removed to reveal an erythematous, sometimes bleeding surface underneath. The white color associated with leukoedema
Leukoplakia
Lichen planus
Malakoplakia
Oral candidiasis
Hairy leukoplakia
Keratosis
Polypill
Geographic tongue