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Speight and colleagues state that though many oral cancers probably occur in normal oral mucosa (estimated by Speight as around 50% [102]), some oral cancers are preceded by a potentially- malignant lesion [103]. Potentially malignant lesions can be white patches (leukoplakia), red patches (erythroplakia) or patches which contain both white and red elements (erythroleukoplakia), but there are also potentially malignant conditions, such as oral submucous fibrosis (OSF) and oral lichen planus (OLP) [103]. Reibel stated that malignant transformation of oral potentially-malignant lesions ranges from less than 1% to 18%, and that 16-62% of cases of oral squamous cell carcinomas have been associated with leukoplakic lesions [104]. Flowever, Reibel also states that rates for malignant transformation depend on study design, i.e. w hether or not studies carry an elem ent of case-bias because they take place in specialist units or hospitals [104]. W ork summarising the conclusions of the World Flealth Organisation (WFIO) Collaborating Centre for Oral Cancer and Precancer, convened in 2005, stated that the preferred nomenclature for any clinical presentation which possessed a risk to potentially undergo malignant transformation, be called a "potentially malignant disorder" [105]. Flowever, as many publications also use the terms "potentially malignant lesion" and "potentially malignant condition", the researcher, whilst acknowledging the preferred term is "potentially malignant disorder", uses these alternative, once accepted, terms too. At the same meeting of this WHO working group, the idea of having a binary dysplasia grading system was also proposed, to reduce grading variablility, whereby dysplasia could either be graded as low risk (showing signs of no.

questionable or mild dysplasia) or high risk (moderate or severe dysplasia) [106], though again, in much available literature, mild, moderate and severe are commonly used, so these terms have been used by the researcher.

Schwimmer first used the term "leukoplakia" to describe a white lesion of the tongue, in 1877 [107], and the World Health Organisation later defined leukoplakia as "a white patch or plaque th a t cannot be characterized clinically or pathologically as any other disease." [108]. If biopsy reveals the lesion suspected to be leukoplakia to be attributable to any other condition, the term leukoplakia can no longer be applied [84]. Leukoplakia is the commonest potentially-malignant lesion (PML) type, as Bouquot and colleagues citing the work of Axwell and colleagues, state that it accounts for 80% of PMLs [109], and tends to occur on the buccal mucosa (cheek lining), gingiva and lip border, but those which progress to dysplasia and carcinoma tend to be found on the floor of the mouth, tongue and lip border [103]. Homogeneous leukoplakic lesions are those which not only present a homogeneous white colour, but also a smooth, thin, flat lesion surface [110]. Leukoplakic lesions are thought to occur in 2-4% of the adult population and transformation to malignancy is thought to occur in 4-6%, though this is dependent upon the site in the oral cavity where the lesion occurs [103]. Speight and colleagues also cite the work of several groups in stating that though rarely biopsied, leukoplakic lesions which are can demonstrate dysplastic changes in 5-25% of cases [103]. Dysplastic leukoplakic lesions tend to present as erythroleukoplakic lesions, i.e. as predominantly white patches with areas which are red, which Speight and colleagues suggest are due to lack of keratin resulting from

immature epithelial cells, and these lesions present a greater risk of malignancy of approximately 25- 33% [103]. Erythroleukoplakic lesions, due to their non-homogeneous colour, can be considered non- homogeneous leukoplakic lesions [110]. In 1975, Waldron and Shafer conducted a study on

leukplakic lesions which had been presented to two pathology departments over a period of 13 years [111]. They found that leukoplakias accounted for 6.2% of lesions, and biopsies of these leukoplakic lesions revealed that 7.6% of them were SCC, carcinoma in situ or severe dysplasia and 12.2% showed mild to moderate dysplasia [111]. Certain oral sites were judged to be high risk, given the number of leukoplakic lesions in these areas which were found to be dysplastic or cancerous. Leukoplakic lesions of the floor of the mouth were dysplastic or cancerous in 42.9% of cases, and dysplasia/ carcinoma was found in 24.2% of tongue leukoplakia, and 20% of lip leukoplakia [111]. Silverman and colleagues also conducted a study on oral leukoplakic lesions and found that of 257 patients who presented with leukoplakic lesions, malignant transformation occurred in 45, giving a malignant transformation rate of approximately 17.5% over an average of 8.1 years [112].

Another type of leukoplakic lesion is the proliferative verrucous leukoplakia, which as the name suggests, has a nodular, irregular appearance [103], i.e. could be classed as a non-homogeneous leukoplakic lesion [110]. They tend to have a long lifespan, but also tend to undergo dysplastic change, and transform into invasive SCCs [103]. Bouquot and colleagues also detail another variation of the leukoplakic lesion-palatal leukoplakia (a thick layer of keratin accumulation on the hard palate), resulting from reverse smoking, i.e. in which the lit end of the cigarette or cigar is in one's mouth, and state that this lesion type is associated with a high incidence of malignant transformation [109].

Like leukoplakia, erythroplakia was defined by the WHO as being a lesion (red rather than white) whose appearance cannot be diagnosed as any specific clinical condition or disease [108], and is often asymptomatic (though some patients describe experiencing a burning sensation) [84]. However, the first use of the term "erythroplakia" was not to describe an oral lesion at all, rather it was used by Queyrat to describe a red penile lesion which was precancerous in nature [113]. W ith regards to erythroplakia found in the oral mucosa, erythroplakic lesions are less common than leukoplakic lesions and are rare in people under the age of 35 years, however Speight and colleagues cite many works which suggest that this lesion type presents a risk of malignant transformation of 50% or greater [103]. Shafer and Waldron, as they did for leukoplakia, conducted a study o f cases reported to tw o pathology departments, this tim e over a period of 24 years [114]. They found th a t of the 64 354 lesions examined, 58 (0.09%) were cases of erythroplakia, suggesting that erythroplakic lesions were much less common than leukoplakic lesions [114]. Shafer and Waldron also found that erythroplakic lesions tended to be presented by people of 60-70 years of age [114]. The authors also found that of the 65 biopsies performed for the 58 cases, 51% were diagnosed as invasive carcinoma, 40% as carcinoma in situ or severe dysplasia and 9% were mild to moderate dysplasia, leading the authors to conclude that most, if not all, cases of erythroplakia were dysplastic or cancerous [114]. Speight and colleagues cite the work of Bouquot and colleagues when stating that when biopsied, the vast majority of erythroplakic lesions contain cells of a dysplastic nature [103], and also state that erythroplakic lesions commonly present as severe dysplasia or carcinoma in situ, but 5-10% present as micro-invasive squamous cell carcinomas [103]. One of the problems in diagnosing dysplasia is that it shares histopathological features with normal, regenerating epithelium [103]. However, the signs of dysplasia include increased nuclear-to-cytoplasmic ratio, mitoses in the interm ediate epithelial "prickle" layer, nuclear hyperchromatism (excessive staining of the nuclear area),

abnormally increased (hyperplasia) proliferation of basal cells, loss of epithelial stratification, loss of cell adherence and appearance of keratin pearls [103].

o th e r potentially malignant disorders include Candida albicans and oral lichen planus. It has been suggested that the fungal infection, Candida albicans, is linked with epithelial dysplasia, and a number of leukoplakic lesions seem to be infected by Candida [103], though the malignant transformation rate is not known.

The autoimmune disorder lichen planus is thought to be a fairly common disorder affecting mucous membranes, and presents in the oral cavity as patterns of white lines, typically in people of middle- age [103]. Several studies have also suggested that oral lichen planus is linked to an increased risk of oral cancer development [115-117], however Bouquot and colleagues cite a rate of malignant transformation of 1% for lichen planus [109], which is in agreement with that stated by van der Waal [118]. Bouquot and colleagues also state that oral submucous fibrosis is a potentially malignant condition with strong links to chewing betel quid, and symptoms include a burning sensation in the oral mucosa, ulceration, blanching and fibrous bands forming on the buccal mucosa [109].

Dysplasia is typically classed as one of three grades [102]. Mild dysplasia is diagnosed when basal cells proliferate or are found above the basal layer, but that are restricted to the lower 33% of the epithelium [103]. In moderate dysplasia, basal cells are found and proliferate in the lower 66.7% of epithelium, and in severe dysplasia, basal cells can be found up to the upper third layer of epithelium [103], i.e. some basal cells have progressed through to the most superficial of the three epithelial layers [103]. Bouquot and colleagues state that oral cancers arising from dysplastic lesions normally arise within tw o to five years, but that attempts to remove dysplasias are complicated by the fact that 33% will recur [109]. There has been some debate as to w hether carcinoma in situ is a stage prior to malignancy or evidence of malignancy, however it is defined by cytological and architectural changes spanning the full thickness of the epithelium [102]. This is thought to be quite a rare occurrence in the oral cavity, as an intact keratin layer is evident even in the event of severe atypia [

102

The variability of dysplasia diagnosis from pathologist to pathologist, and the general difficulties in diagnosing what can be minor and subtle dysplastic changes, has been a subject of research. Abbey and colleagues investigated the extent to which six board-certified oral pathologists agreed with each others' findings for 120 oral biopsies, and the extent to which each pathologist agreed with their own findings for the same biopsies several months later [119]. In this study, each pathologist was given 120 numerically labelled microscope slides, which they were to class as mild, moderate, severe or no dysplasia [119]. After several months had passed, the six pathologists re-examined 60 of the original microscope slide which had since been re-numbered [119]. The authors found that the degree of

agreement for the diagnoses from the six pathologists and the pre-determined diagnoses was approximately 50.5%, though 85-94.2% of decisions were within one grade of the pre-determined diagnoses, and the examiners agreed on the presence of dysplasia found in the original diagnosis in 81.8% of cases [119]. The authors also found that intra-examiner agreement between first and second diagnosis was on average, 50.8%, and agreement to within one grade ranged from 88.3-100% [119]. Abbey and colleagues concluded that agreement on level of dysplasia was difficult to achieve, and is open to interpretation and therefore, variability [119].