1.Department of Oral Pathology, Surgery, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Some alterations of the oral mucosa can mimic OL, and these lesions must be considered as OL differential diagnosis. So, for the establishment of a correct diagnosis of OL, such lesions must be excluded (Warnakulasuriya et al., 2007; van der Waal, 2009):1. Frictional lesion2. Candidiasis3. Linea alba4. Leukoedema5. Chemical injuries6. Hairy leukoplakia7. Nicotinic stomatitis
Once a provisional clinical diagnosis of OL was made, a biopsy must be performed in order to obtain the histopathological features. This is of paramount importance because it is believed that the presence and degree of epithelial dysplasia is a great indicator of evolution and prognosis (see below) (Warnakulasuriya et al., 2008).
Architectural features:- Irregular epithelial stratification- Loss of polarity of basal cells- Drop-shaped rete ridges- Increased number of mitotic figures- Abnormally superficial mitoses- Premature keratinisation in single cells (dyskeratosis)
Cytological alterations- Nuclear pleomorphism: abnormal variation in nuclear shape- Cellular pleomorphism: abnormal variation in cell shape- Anisonucleosis: abnormal variation in nuclear size- Anisocytosis: abnormal variation in cell size- Increased nuclear size- Increased nuclear-cytoplasm ratio- Atypical mitotic figures- Increased number and size of nucleoli
Considering the epithelium divided into "thirds", lesions are classified into five categories:1. Hyperplasia: increase in cell number in the spinous layer and/or in the basal/parabasal cell layers. There is regular stratification and no cellular atypia (Figure 4).2. Mild dysplasia: architectural disturbance only in the lower third of the epithelium with cytological atypia (Figure 5).3. Moderate dysplasia: architectural disturbance extending into the middle third of the epithelium is the initial criteria, but the degree of cytological atypia may require upgrading it to "severe" (Figure 6).4. Severe dysplasia: architectural disturbance affecting greater than two thirds of the epithelium, with cytological atypia (Figure 7).5. Carcinoma "in situ": theorically, indicates that malignant transformation has occurred but invasion has not. Full or almost full thickness architectural disturbance is present in viable cellular layers with pronounced cellular atypia. Atypical mitotic figures and abnormal superficial mitoses are common.
Concerning the microscopic classification schemes for OL, a new binary system was proposed (Kujan et al., 2006). Accoding to it, pathologists would observe the same morphological criteria used in the WHO classification, but lesions would be classified as low-risk OL (former "no/mild/questionable" dysplasia) or as high-risk OL (former "moderate/severe" dysplasia). Shorten the degrees of dysplasia from five, i.e. no, mild, moderate, and severe, to two - low-risk and high-risk - would provide a more feasible and reproducible classification system. Also, it could offer a more reliable criteria upon which to rely for the selection of patient treatment. Accordingly, OL classified as "high-risk" would be more prone to develop into cancer and, thus, should be removed. On the other hand, low-risk OL could be clinically followed up as they are less expected to evolve (Kujan et al., 2006; Warnakulasuriya et al., 2008; van der Waal, 2009). In a study with 218 patients with OL, the authors reported that high-risk OL was associated with a 4.57-fold increased risk for malignant transformation, compared with low-risk OL (Liu et al., 2010). Moreover, in another research with 138 patients with histologically confirmed oral dysplasia, 115 had OL and 23 had lichen planus. From these 138 lesions, 37 (26.8%) developed into cancer and the "high-risk" degree of dysplasia was an independent risk factor for transformation (Liu et al., 2011). The authors then suggest the utilization of high-risk dysplasia as a significant indicator for evaluating malignant transformation risk in patients with potentially malignant lesions. In a recently published paper, our research group showed statistically significant differences for hMLH1 - a DNA repair protein - , p53 - a tumor supressor protein - , and AgNOR - an indicative of cell proliferation - indexes between low- and high-risk OL. This suggests that the biological processes linked to the impairment of those proteins remain enhancing from low-risk OL to high-risk OL. Thus, the use of the binary system would give support to a more reliable clinical approach involving the removal of high-risk OL (Caldeira et al., 2012).
Briefly, some information about the most frequent genetic alterations of OL are shown below. A complete and detailed revision on this topic was published by Mithani et al. (2007).p53 alterations: The p53 protein can induce DNA repair, cell cycle arrest, cell death or senescence, showing a pivotal role in tumor avoidance (Joerger and Fersht, 2008). Its alteration is a common finding in human cancers, including those of oral mucosa (Kurokawa et al., 2003). Investigations demonstrated that the normal oral mucosa presents negative or low indexes of p53 immunoexpression (Kurokawa et al., 2003; Fan et al., 2006; Caldeira et al., 2011b). Likewise, p53 immunopositive cells were identified in OL with mild dysplasia, with increasing indexes from hyperplasia, to dysplastic lesions (Figure 8) and to oral squamous cell carcinoma, with immunopositivity found in superficial layers of moderate and severe dysplasias (Kerdpon et al., 1997; Cruz et al., 2002; Kurokawa et al., 2003; Caldeira et al., 2011b). The detection of p53 in oral dysplastic lesions prompted many investigators to suggest that its abnormalities may constitute an early event in carcinogenesis. Loss of heterozygosity (LOH): describes the elimination of a genetic loci containing tumor suppressor genes. In OL, LOH of the chromosome arms 3p and 9p seem to be related to a higher risk of malignant transformation. Fifty percent of OL contains allelic loss of either the 3p or 9p chromosome arms (Mithani et al., 2007).Microsatellite instability (MSI) and the mammalian mismatch repair system (MMR): Microsatellites are DNA regions in which multiple repeated sequencies of nucleotides are found. These regions are prone to the occurence of mismatched DNA, developing the MSI phenotype (Jascur and Boland, 2006; Jiricny, 2006). MSI was detected in many OL and there is a trend toward an increased prevalence of MSI in more aggressive histologic OL lesions (Ha et al., 2002). The MMR is responsible for maintaining genomic stability during repeated duplication, and microsatellites regions are hypersensitive to MMR dysfunction. The immunoexpression of hMLH1 - one of the main MMR protein - was shown to decrease in OL with more severe grades of dysplasia (Figure 9) (Caldeira et al., 2011a). Taken together, these results may suggest that the altered function of MMR and the occurence of MSI could be early events in the carcinogenic process, but these findings still need more investigation.Methylation / hypermethylation: is an epigenetic alteration which can inactivate genes. In OL, it was described to occur in RAR-b2, p16, hMLH1, hMSH2, and MGMT (Ha et al., 2002; López et al., 2003; Youssef et al., 2004; Sengupta et al., 2007).AgNOR number: AgNOR staining technique is used to assess cellular proliferation, and normal oral epithelium showed lower AgNOR number than dysplastic OL (Figure 10), which in turn presents lower indexes than oral squamous cell carcinoma (Chattopadhyay et al., 1994; Caldeira et al., 2011b). It was suggested that mean AgNOR number would be useful in distinguishing OL with mild and moderate dysplasia (Chattopadhyay and Ray, 2008).Telomerase activity: these are the enzymes that degradate telomers, which are a sequence of nucleotides that prevents DNA to undergo degradation and fusion. The telomerase activity was detected in OL.
Patrícia Carlos Caldeira ; Maria Auxiliadora Vieira do Carmo
Head and Neck: Oral leukoplakia
Atlas Genet Cytogenet Oncol Haematol. 2012-11-01
Online version: http://atlasgeneticsoncology.org/solid-tumor/5937/head-and-neck-oral-leukoplakia