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).Leukoplakia 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 disappears when the mucosa is stretched. A frictional keratosis will generally be adjacent to a sharp surface such as a broken tooth or rough area on a denture and will disappear when the causative factor is removed. Some have a suggested as general rule that any lesion that does not show signs of healing within 2 weeks should be biopsied. Morsicatio buccarum and linea alba are located at the level of the occlusal plane (the level at which the teeth meet). A chemical burn has a clear history of placing an aspirin tablet (or other caustic substance such as eugenol) against the mucosa in an attempt to relieve toothache. Developmental white patches usually are present from birth or become apparent earlier in life, whilst leukoplakia generally affects middle aged or elderly people. Other causes of white patches generally require pathologic examination of a biopsy specimen to distinguish with certainty from leukoplakia.
While the degree of dysplasia has been shown to be an important predictor of malignant change, many have challenged its use due to the low predictive value from the lack of objectivity of grading dysplasia. While 10% of leukoplakia lesions show dysplasia when biopsied, as many as 18% of oral lesions undergo malignant change in the absence of dysplasia. Leukoplakia located on the floor of the mouth, the posterior and lateral tongue, and the retromolar areas (the region behind the wisdom teeth) have higher risk, whereas white patches in areas such as the top surface of the tongue and the hard palate do not have significant risk. Although these "high risk" sites are recognized, statistically, leukoplakia is more common on the buccal mucosa, alveolar mucosa, and the lower labial mucosa. Leukoplakia of the floor of the mouth and tongue accounts for over 90% of leukoplakias showing dysplasia or carcinoma on biopsy. This is thought to be due to pooling of saliva in the lower part of the mouth, exposing these areas to more carcinogens held in suspension. Red lesions (erythroplasia) and mixed red and white lesions (erythroleukoplakia/"speckled leukoplakia") have a higher risk of malignant change than homogeneous leukoplakia. Verrucous or nodular areas have a higher risk. Although smoking increases risk of malignant transformation, smoking also causes many white patches with no dysplasia. This means that statistically, white patches in non-smokers have a higher risk. Older people with white patches are at higher risk. Larger white patches are more likely to undergo malignant transformation than smaller lesions.