Objectives Oral leukoplakia is a potentially malignant disorder of the oral mucosa. The aim of this retrospective study was to identify the factors that possibly predict malignant transformation in a well‐defined cohort of patients with a long‐term follow‐up. All leukoplakias were staged according to a clinicopathological classification and staging system. Furthermore, a certainty factor has been used with which the diagnosis has been established. Material and methods The group consisted of 144 patients. The size, presence and degree of epithelial dysplasia were incorporated into a clinicopathological classification and staging system. Initial management consisted of surgical excision, CO2 laser vaporisation or observation only. The mean follow‐up period was 51.2 months (s.d. = 39.33, range 12–179 months). Results In 16 of 144 patients (11%), malignant transformation occurred between 20 and 94 months (mean 57.0 months) after the first visit, the annual malignant transformation rate being approximately 2.6%. A large size of the lesion (≥ 4 cm) showed to be the only statistically significant predictor of malignant transformation (P = 0.034). Conclusion A size of ≥ 4 cm showed to be the only significant predicting factor of malignant transformation in oral leukoplakia. No other epidemiological, aetiological, clinical or histopathological parameters were of statistical significance.

The aim of the present study was to evaluate the definition of oral leukoplakia, proposed by the WHO in 2005 and taking into account a previously reported classification and staging system, including the use of a Certainty factor of four levels with which the diagnosis of leukoplakia can be established. In the period 1997-2012 a hospital-based population of 275 consecutive patients with a provisional diagnosis of oral leukoplakia has been examined. In only 176 patients of these 275 patients a firm diagnosis of leukoplakia has been established based on strict clinicopathological criteria. The 176 patients have subsequently been staged using a classification and staging system based on size and histopathologic features. For use in epidemiological studies it seems acceptable to accept a diagnosis of leukoplakia based on a single oral examination (Certainty level 1). For studies on management and malignant transformation rate the recommendation is made to include the requirement of histopathologic examination of an incisional or excisional biopsy, representing Certainty level 3 and 4, respectively. This recommendation results in the following definition of oral leukoplakia: “A predominantly white lesion or plaque of questionable behaviour having excluded, clinically and histopathologically, any other definable white disease or disorder”. Furthermore, we recommend the use of strict diagnostic criteria for predominantly white lesions for which a causative factor has been identified, e.g. smokers’ lesion, frictional lesion and dental restoration associated lesion. Key words:Oral epithelial dysplasia, oral leukoplakia, potentially malignant oral disorders.

The results in the present study are worse than those reported in the literature, perhaps owing to the use of different diagnostic criteria for OL, differences in the employed laser technique and assessment of possible recurrences by an independent clinician.

Since its introduction in the literature in 1985, the term proliferative verrucous leukoplakia (PVL) has been the subject of an ongoing discussion with regard to its definition. Widespread or multifocal occurrence of oral leukoplakia is not just synonymous to PVL. In the present treatise the proposal is made to require the involvement of more than two oral oral subsites, a total added seizeof the leukoplakic areas of at least 3 centimeters, and a well documented period of at least five years of disease evolution being characterized by spreading and the occurrence of one or more recurrences in a previously treated area. Key words:Oral premalignant lesions, leukoplakia, verrucous leukoplakia.

Oral leukoplakia is the most common oral potentially malignant disorder with a malignant transformation rate into oral squamous cell carcinoma of 1-3% annually. The presence and grade of World Health Organization defined dysplasia is an important histological marker to assess the risk for malignant transformation, but is not sufficiently accurate to personalize treatment and surveillance. Differentiated dysplasia, known from differentiated vulvar intraepithelial neoplasia, is hitherto not used in oral dysplasia grading. We hypothesized that assessing differentiated dysplasia besides World Health Organization defined (classic) dysplasia will improve risk assessment of malignant transformation of oral leukoplakia. We investigated a retrospective cohort consisting of 84 oral leukoplakia patients. Biopsies were assessed for dysplasia presence and grade, and the expression of keratins 13 (CK13) and 17, known to be dysregulated in dysplastic vulvar mucosa. In dysplastic oral lesions, differentiated dysplasia is as common as classic dysplasia. In 25 out of 84 (30%) patients, squamous cell carcinoma of the upper aerodigestive tract developed during follow-up. Considering only classic dysplasia, 11 out of 56 (20%) patients with nondysplastic lesions progressed. With the incorporation of differentiated dysplasia, only 2 out of 30 (7%) patients with nondysplastic lesions progressed. The risk of progression increased from 3.26 (Hazard ratio, p = 0.002) when only classic dysplasia is considered to 7.43 (Hazard ratio, p = 0.001) when classic and differentiated dysplasia are combined. Loss of CK13, combined with presence of dysplasia, is associated with greater risk of malignant progression (p = 0.006). This study demonstrates that differentiated dysplasia should be recognized as a separate type of dysplasia in the oral mucosa and that its distinction from classic dysplasia is of pathological and clinical significance since it is a strong (co) prognostic histopathological marker for oral malignant transformation. In oral lesions without dysplasia and retained CK13 staining the risk for progression is very low.

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The estimated prevalence of oral leukoplakia is worldwide approximately 2%, with an annual malignant transformation rate of approximately 1%. The aim of the present study was to evaluate the possible contribution of ploidy measurement to the prediction of the clinical course, in a well defined cohort of patients with oral leukoplakia. Ploidy was measured by both flow cytometry (FCM-DNA) and image cytometry (ICM-DNA) and we focussed on the comparison of the two different techniques to determine ploidy. A total of 41 patients have been included, with a mean age of 59 years (range 36-78 years). With FCM-DNA, three lesions were aneuploid, with ICM-DNA, 19 lesions were aneuploid. DNA ploidy was compared with clinicopathological and patients parameters. There were no statistically significant differences between DNA ploidy and any patient factor with both FCM-DNA and ICM-DNA. Using FCM-DNA, DNA aneuploid lesions showed statistically significant more dysplasia (p=0.04) than diploid lesions. Furthermore, DNA aneuploid lesions were more frequently encountered at high-risk locations (p=0.03) as being determined with FCM-DNA. These relations were not found when DNA ploidy was determined with ICM-DNA.

Purpose: Oral leukoplakia is the most common oral potentially malignant disorder with an annual malignant transformation rate of 1-5%. Consequently, oral leukoplakia patients have a 30-50% lifetime risk to develop oral squamous cell carcinoma. Although risk factors for malignant transformation of oral leukoplakia have been investigated, no definitive risk stratification model has been proposed. Next generation sequencing can elucidate the genetic landscape of oral leukoplakia which may be used to predict the risk for malignant transformation. Experimental Design: We investigated a retrospective cohort of 89 oral leukoplakia patients, and analyzed their oral leukoplakia lesions for the presence of genomic copy number alterations and mutations in genes associated with oral squamous cell carcinoma. Results: In 25 of 89 (28%) patients, oral squamous cell carcinoma developed during follow-up. Seventy-nine of 89 (89%) oral leukoplakias harbored at least one genetic event. Copy number alterations were present in 61 of 89 (69%) oral leukoplakias, most commonly gains of chromosome regions 8q24 (46%) and 20p11 (20%) and loss of 13q12 (19%). Mutations were present in 59 of 89 (66%) oral leukoplakias, most commonly in TP53 (28%), FAT1 (20%) and NOTCH1 (13%). Genetic data was combined with the presence of dysplasia to generate a prediction model, identifying three groups with a distinct risk for malignant transformation. Conclusions: We provide an extensive description of genetic alterations in oral leukoplakia and its relation to malignant transformation. Based on our data we provide a model for the prediction of malignant transformation of oral leukoplakia using dysplasia and genetic markers.