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OBJECTIVES: To update the current evidence on the malignant transformation of oral leukoplakia (OL), including all studies published worldwide on the subject, selected with the maximum rigor regarding eligibility. MATERIALS AND METHODS: MEDLINE, Embase, Web of Science and Scopus were searched for studies published before June-2024, with no lower date limit. The risk of bias was analyzed using the Joanna Briggs Institute tool for meta-analyses of proportions. We carried out meta-analyses, explored heterogeneity across subgroups and identified risk factors with potential prognostic value. RESULTS: Fifty-five studies (41,231 with OL) were included. The pooled malignant transformation proportion for OL was 6.64% (95% CI = 5.21-8.21). The malignant transformation did not significantly vary by time periods (p = 0.75), 5.35% prior to 1978, 7.06% from 1979 to 2007 and 6.97% during more recent times. The risk factors that significantly had a higher impact on malignant transformation were the non-homogeneous leukoplakias (RR = 4.23, 95% CI = 3.31-5.39, p < 0.001), the larger size (RR = 2.08, 1.45-2.96, p < 0.001), leukoplakia located on the lateral border of tongue (malignant transformation = 12.71%; RR = 2.09, 95% CI = 1.48-2.95, p < 0.001), smoking (RR = 1.64, 95% CI = 1.25-2.15, p < 0.001), and the presence of epithelial dysplasia (RR = 2.75, 95% CI = 2.26-3.35, p < 0.001). CONCLUSIONS: OL presents a considerable malignant transformation probability that is especially increased in large non-homogeneous lesions in smokers, located on the lateral border of the tongue, with epithelial dysplasia.

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Different efforts have been made to find better and less invasive methods for the diagnosis and prediction of oral cancer, such as the study of saliva as a source of biomarkers. The aim of this study was to perform a scoping review about salivary molecules that have been assessed as possible biomarkers for the diagnosis of oral squamous cell carcinoma (OSCC). A search was conducted using EBSCO, PubMed (MEDLINE), Scopus, and Web of Science. The research question was as follows: which molecules present in saliva have utility to be used as biomarkers for the early detection of oral cancer? Sixty-two studies were included. Over 100 molecules were assessed. Most of the markers were oriented towards the early diagnosis of OSCC and were classified based on their ability for detecting OSCC and oral potentially malignant disorders (OPMDs), OSCC outcome prediction, and the prediction of the malignant transformation of OPMDs. TNF-α, IL-1ß, IL-6 IL-8, LDH, and MMP-9 were the most studied, with almost all studies reporting high sensitivity and specificity values. TNF-α, IL-1ß, IL-6 IL-8, LDH, and MMP-9 are the most promising salivary biomarkers. However, more studies with larger cohorts are needed before translating the use of these biomarkers to clinical settings.

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The gradual accumulation and inadequate renewal of senescent cells over time drive organismal aging. Senescent cells undergo altered gene expression and release inflammatory mediators collectively termed the senescence-associated secretory phenotype (SASP), which significantly contributes to a spectrum of age-related disorders, including cancer. In the context of carcinogenesis, the SASP produced by senescent cells has been implicated in the promotion of epithelial cancers, including oral squamous cell carcinoma (OSCC), the most common form of oral cancer. Senescent cells within the tumor microenvironment release factors that amplify the growth and invasiveness of neighboring cancer cells. Senotherapeutics, including senolytics and senomorphics, emerge as promising modalities to target senescent cells and their associated inflammatory factors, thereby opening novel avenues for augmenting the efficacy of cancer treatments. Here, we review the general aspects of cellular senescence, focusing on the relation between senescence-related inflammation with cancer development. We also analyze the available evidence linking cellular senescence with OSCC, highlighting possible clinical applications.

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OBJECTIVE: To identify the teaching-learning process characteristics of Oral Pathology and Medicine (OP&M) related to oral potentially malignant disorders (OPMDs) and oral cancer (OC), in the dental schools' curricula in Mexico, to analyze the approach given to this topic worldwide, and to provide the possible solution strategies. MATERIALS AND METHODS: Questionnaires were sent to OP&M deans and professors from public Mexican Universities to explore the curriculum and academic profile of the dental schools. The recommendations gathered from a workshop with expert professors on the challenges in OPMD/OC teaching were reported. RESULTS: Twenty-two dental schools participated (22 deans, 30 professors). The most widely used strategies were clinical-case resolving (86%) and presentations (73%). Although 77.3% of the programs included maxillofacial lesions, only 40.9% contemplated OPMD/OC. Only 45% of the programs developed community activities for early OC detection. The workshop recommendations were (i) multidisciplinary approach to OPMD/OC teaching, involving OP&M professors in other dental and nondental courses; (ii) implementation of the most effective teaching techniques (currently, problem-based learning and clinical-case presentation) in OP&M curricula; (iii) education of OP&M professors on teaching-learning processes. CONCLUSIONS: These recommendations from the Mexican context, integrated with similar experiences from other countries could contribute to develop a unique, internationally acknowledged OP&M curriculum.

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An important rat model using the chemical carcinogen 4-nitroquinoline-1-oxide (4NQO) has been described for the study of the process of oral carcinogenesis. This model replicates the gradual progression seen in oral carcinoma patients. However, due to its high level of toxicity, its use in fundamental research is challenging. Here, we propose a secure and efficient modified protocol based on a lower dose of 4NQO concentration as well as an increased water supply and hypercaloric diet, in order to reduce the damage caused to the animals during the process of oral carcinogenesis. Twenty-two male Wistar rats were exposed to 4NQO, evaluated clinically once a week and euthanized at 12 and 20 weeks for histopathological analysis. The protocol involves a staggered dose of 4NQO up to a concentration of 25 ppm, associated with two days of pure water, a 5% glucose solution once a week and a hypercaloric diet. This modified protocol prevents the immediate consequences of the carcinogen. At week 7, all animals displayed clinically evident tongue lesions. From a histological perspective, after 12 weeks of 4NQO exposure, 72.7% of the animals developed epithelial dysplasia and 27.3% developed in situ carcinoma. In the group exposed for 20 weeks, epithelial dysplasia and in situ carcinoma were diagnosed in one case each, whereas invasive carcinoma was diagnosed in 81.8% of the cases. Nonsignificant modification of animal's behavior and weight was observed. This new proposed 4NQO protocol was secure and effective for studying oral carcinogenesis and can be used to conduct lengthy investigations.

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BACKGROUND: This study summarized the available evidence about the use of photodynamic therapy (PDT) for the management of oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC). METHODS: An overview of systematic reviews was undertaken based on the 2020 PRISMA statement. Electronic searches were performed in five databases. Studies published up to November 2022 were included. Risk of bias was assessed with the AMSTAR 2 tool. RESULTS: A total of 30 studies enrolling 9,245 individuals with OPMD (n = 7,487) or OSCC (n = 1,758) met the selection criteria. All studies examined the efficacy and/or safety of PDT. OPMD were investigated individually in 82.8% of the studies, the most common being oral lichen planus and actinic cheilitis. OSCC was addressed separately in 10.3% of the studies, while only 6.9% evaluated both OPMD and OSCC. Fourteen different types of photosensitizers were described. PDT was used according to the following setting parameters: 417-670 nm, 10-500 mW/cm2, 1.5-200 J/cm2, and 0.5-143 min. Regarding OPMD, leukoerythroplakia showed the best response rates, while oral lichen planus presented a partial or no response in nearly 75% of documented cases. A complete response was observed in 85.9% of OSCC cases, while 14.1% had no resolution. CONCLUSION: Overall, the response to PDT depended on the type of OPMD/OSCC and the parameters used. Although PDT is an emerging candidate for the treatment of OPMD and OSCC, there is heterogeneity of the methodologies used and the clinical data obtained, particularly regarding the follow-up period.

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Oral potentially malignant disorders represent precursor lesions that may undergo malignant transformation to oral cancer. There are many known risk factors associated with the development of oral potentially malignant disorders, and contribute to the risk of malignant transformation. Although many advances have been reported to understand the biological behavior of oral potentially malignant disorders, their clinical features that indicate the characteristics of malignant transformation are not well established. Early diagnosis of malignancy is the most important factor to improve patients' prognosis. The integration of machine learning into routine diagnosis has recently emerged as an adjunct to aid clinical examination. Increased performances of artificial intelligence AI-assisted medical devices are claimed to exceed the human capability in the clinical detection of early cancer. Therefore, the aim of this narrative review is to introduce artificial intelligence terminology, concepts, and models currently used in oncology to familiarize oral medicine scientists with the language skills, best research practices, and knowledge for developing machine learning models applied to the clinical detection of oral potentially malignant disorders.

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To evaluate the possible involvement of epigenetic modulation by HPV16-p16INK4a in oral potentially malignant disorder (OPMD). We generated DNA-methylation profiles, according to p16INK4a expression and HPV16 genotype (positive or negative), of OPMD samples and p16INK4a-HPV16 negative samples (used as control), using reduced-representation bisulphite sequencing (RRBS-Seq- Illumina) technology. Twelve samples, four for each group, as follows: 1) p16INK4a+ HPV16+; 2) p16INK4a+ HPV16-; 3) p16INK4a- HPV16-, were analysed in triplicate for DNA-methylation profiles. Fifty-four per cent of DMRs were hypermethylated and 46% were hypomethylated. An increase in methylation of loci in OPMD was independent of the presence of HPV. The hypermethylated genes in HPV+ samples were associated with signalling pathways such as NICD traffics to nucleus, signalling by NOTCH1 (p = 0.008), Interferon-gamma (p = 0.008) and Interleukin-6 signalling (p = 0.027). The hypomethylated genes in HPV infection were associated with TRAF3-dependent IRF activation pathway (p = 0.002), RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways (p = 0.005), TRAF6 mediated IRF7 activation (p = 0.009), TRIF-mediated TLR3/TLR4 signalling (p = 0.011) and MyD88-independent cascade release of apoptotic factors (p = 0.011). Protein association analysis of DMRs in OPMD revealed 19 genes involved in the cell cycle regulation, immune system, and focal adhesion. Aberrantly methylated loci in OPMD were observed in p16INK4a positive samples which suggests that a shift in global methylation status may be important for cancer progression. The results suggest that HPV infection in OPMD induces modulation of genes related to the immune system and regulation of the cellular cycle.

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Oral leukoplakia (OL) is the most common oral potentially malignant disorder, with a global prevalence of 2%-3%, variable malignant transformation rate and incompletely understood aetiology. Considering the subjectivity in oral dysplasia grading, other evaluation methods have been tested as predictors of malignant transformation. DNA ploidy status and loss of heterozygosity signatures have been shown to be good predictive markers of malignant transformation. However, effective markers to predict which lesions will progress to invasive carcinoma and by which mechanisms remain unclear. Recent evidence suggests that dysplasia progression to carcinoma occurs through neutral clonal evolution (i.e. randomly). We focus on the genetic basis of OL, encompassing the gross chromosomal alterations and single-gene mutations, and discuss such alterations in the context of aetiology, clinical presentation and progression. The deeper we understand the genetic basis of OL, the more we approach a better comprehension of the complex and poorly understood process of oral carcinogenesis.

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In oral cancer, acquisition of α-smooth muscle actin (α-SMA)-positive fibroblasts, known as myofibroblasts or carcinoma-associated fibroblasts (CAF), is an important event for progression and metastasis. However, the contribution of myofibroblasts in oral potentially malignant disorders (OPMD) remains controversial. This systematic review provides evidence that immunodetection of myofibroblasts may identify oral submucous fibrosis (OSMF) with high risk of malignant transformation, but does not represent an auxiliary tool to predict the malignant potential of leukoplakia and erythroplakia, the most common OPMD.

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