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Objectives: Our main purpose and research question were to analyze and quantify whether there were significant differences in the time to develop cancer among patients with oral leukoplakia (OL), comparing the more susceptible cases to those with the least susceptibility to malignancy. Materials and methods: We followed 224 cases of OL after surgical or CO2 laser treatment for a mean time of 6.4 years. A Bayesian mixture cure model based on the Weibull distribution was used to model the relationship between our variables and cancer risk. In this model type, the population is considered a mixture of individuals who are susceptible or non-susceptible to developing cancer. The statistical model estimates the probability of cure (incidence model) and then infers the time to malignancy. The model was adjusted using the R-package INLA using default priors. Results: Histology type (moderate or severe dysplasia) and tongue location showed hazard ratios (HR) of 3.19 (95% CI [1.05–8.59]) and 4.78 (95% CI [1.6–16.61]), respectively. Both variables increased the risk of malignant transformation, thus identifying a susceptible subpopulation with reduced time required to develop cancer, as with non-homogeneous leukoplakias. The median time for cancer development was 4 years and 5 months, with a minimum of 9 months after the diagnosis of OL and a maximum of 15 years and 2 months. Conclusions: Susceptible patients with non-homogeneous leukoplakia, dysplasia, or leukoplakia in the tongue develop cancer earlier than those with homogeneous OL and those without dysplasia. Clinical relevance: The novel contribution of this research is that, until now, the time it took for oral leukoplakias to develop cancer based on whether they were homogeneous or non-homogeneous, and if they have or not epithelial dysplasia, had not been comparatively described and quantified. As a final result, the time to malignant transformation in non-homogeneous and dysplastic leukoplakias is significantly shorter. [ABSTRACT FROM AUTHOR]

Objectives: To study the association of Candida and antifungal therapy with pro-inflammatory cytokines (PIC) in oral leukoplakia (OL). Materials and methods: A prospective observational study where immunocompetent adult subjects with OL (30 homogenous (HL), 30 non-homogenous (NHL)) and 30 age and sex-matched healthy controls (C) with no predisposing factors for oral Candida infection were recruited. Sterile cotton swabs and ophthalmic sponges were used to sample the lesion surface in OL and buccal mucosa in C, for direct microscopy and culture for Candida and to determine levels of PIC (IL-6, IL-8. IL-17, TNF-α) by ELISA, respectively. Sampling for PIC was repeated at same sites in OL, 2 weeks after antifungal therapy. Results: Candida was associated with 55.3% of NHL, 23.3% of HL and 13.3% of C. The oral secretary levels of PIC were raised in NHL as compared to HL and C. The levels of IL-6, IL-8, TNF-α (p<0.001) and IL-17 (p<0.01) were significantly raised in Candida positive NHL while IL-6 (p<0.05) and TNF-α (p<0.01) were significantly raised in Candida positive HL before antifungal treatment. After antifungal treatment, there was significant reduction in PIC in Candida positive NHL and HL. Conclusions: Candida infection contributes to the inflammatory milieu in Candida associated OL which increases the risk of carcinogenesis. Antifungal therapy reduces the PIC in Candida associated OL. Clinical relevance: Identification and elimination of predisposing factors for Candida infection, like cessation of harmful habits, maintenance of oral/denture hygiene, surveillance for Candida and antifungal therapy at intervals, are recommended in OL. Clinical trial registration: ClinicalTrials.gov Identifier: NCT04712929 [ABSTRACT FROM AUTHOR]

Objectives: The aim of this systematic review was to examine the evidence of the binary histologic grading system capacity for predicting malignant transformation and to compare it with that of the WHO systems. Material and methods: A systematic review was conducted, using PubMed, EMBASE, LILACS, Web of Science, Scopus, and LIVIVO databases without any language or timeframe restrictions. Studies were included if they compared the binary and the WHO histologic grading systems in the prediction of malignant transformation of oral epithelial dysplasia (OED). Results: The capacity of the WHO and binary grading systems to predict malignant transformation ranged from 16 to 80% and from 5 to 80%, respectively. The pooled malignant transformation rate of lesions classified as severe dysplasia or carcinoma in situ by the WHO grading was 40% (95% confidence interval (CI), 0.02–0.87; I2 = 92%; P = 0.00), while the corresponding value for lesions classified as high-risk by the binary grading system was 31% (95% CI, 0.00–0.84; I2 = 97%; P = 0.00). Overall, there was no significant difference in prognostication accuracy between the WHO and the binary systems (odds ratio = 2.02; 95% CI, 0.88–4.64). Conclusions: Although some studies suggest that the binary system is associated with lower inter-rater variability when grading OED, the evidence remains inconclusive on whether this system is superior to that of the WHO at predicting malignant transformation. Clinical relevance: The reproducibility of the binary system has the potential to be better for prognostic purposes. However, there is no high-quality evidence to confirm if this advantage may assist clinicians in decision-making. [ABSTRACT FROM AUTHOR]

Objectives: The tongue is identified as a high-risk site for oral leukoplakia and malignant transformation. The purpose of this study is to investigate the clinicopathological characteristics and treatment outcomes of tongue leukoplakia and assess the factors related to recurrence and malignant transformation. Materials and methods: One hundred and forty-four patients who received carbon dioxide laser surgery for tongue leukoplakia from 2002 to 2019 were analyzed statistically. Results: The follow-up period was 54.90 ± 54.41 months. Thirty patients showed postoperative recurrence (20.83%), and 12 patients developed malignant transformation (8.33%). The annual transformation rate was 2.28%. Univariate analysis showed that a history of head and neck cancer, size of lesion area, clinical appearance, and pathology were significant factors for both recurrence and malignant transformation. In the multivariate logistic regression, a history of head and neck cancer and size of lesion area were independent prognostic factors for recurrence, and a history of head and neck cancer was the only independent factor for postoperative malignant change. Conclusions: Clinicians should adopt more aggressive strategies for tongue leukoplakia patients with a history of head and neck cancer. Clinical relevance: These results may help clinicians gain a better understanding of oral tongue leukoplakia. [ABSTRACT FROM AUTHOR]

Objective: To perform an epidemiological survey comparing the cell proliferative activity of 107 cases of oral leukoplakia with their clinical and histopathological characteristics. Materials and methods: A cross-sectional, observational, and histological-histochemical study. The cases came from the Histopathological Diagnostic Service of UPF/RS and the School of Dentistry of Araçatuba FOA/UNESP/SP (1986–2016). The histopathological sections were stained using the silver staining (AgNOR) technique and the nuclei of 100 epithelial cells selected randomly were recorded to count the number of nucleolar organizer regions (NORs). The mean NORs per lesion were correlated to clinical and histological characteristics using ANOVA, at 5% significance. Results: Most of the cases included men (62.62%), white (64.49%), and with an average age of 53.94 years. The most probable etiological factors were smoking (44.7%) and alcohol consumption (9.85%). The evolution time of most lesions was fast (33.65%), manifesting mainly in the form of plaques (70.37%) and without symptoms (58.88%). They were located mainly in the cheek mucosa (26.62%) and presented white color (66.35%), well-defined edges (59.81%), firm consistency (47.5%), and keratinized surface (49.53%). Etiological factor (p = 0.003), evolution time (p = 0.006), symptoms (p = 0.029), location (p = 0.020), consistency (p = 0.047), histopathological characteristics (p = 0.004), and superficial keratinization (p = 0.001) were statistically significant regarding the mean NORs of the leukoplakias studied. Clinical relevance: Oral leukoplakias caused by alcohol consumption and/or tobacco use, considering an evolution time of fewer than 12 months, asymptomatic, located in the lower lip or tongue, and with a firm consistency and increased superficial keratinization should be treated more aggressively by the clinician to avoid cancerization. [ABSTRACT FROM AUTHOR]

Objective: The main objective of the study was to identify the determinants that contribute to the malignant transformation of oral leukoplakia in a group of patients managed in secondary care. A secondary objective was to compare two dysplasia grading systems to determine their utility in assessing the prognosis. Material and methods: The cohort consisted of 93 patients diagnosed during the period 2009–2013. The variables recorded and analysed included age and sex, clinical presentation (colour) and severity of oral epithelial dysplasia (OED) scored by the WHO (2005) and the binary grading systems. The planned management included excision of high-grade dysplasia and observation of low-grade dysplasia lesions based on the WHO grading system. Patient factors were transcribed from the pathology records and updated using a questionnaire sent out to the whole group of patients. Data were analysed using χ2 test and Kaplan-Meier analysis (P < 0.05). Results: Complete follow-up data were available for 93 patients. Malignant transformation occurred in 7 patients (7.5%) during a mean follow-up period of 30 months. Among the surgically excised group (n = 51), a recurrence of oral leukoplakia was noted in 16 patients (31%). WHO OED grading (P = 0.02) and the presence of red areas (P = 0.012) were useful in predicting malignant transformation with severe epithelial dysplastic lesions and red and white mixed lesions showing higher rates. Conclusion: Leukoplakias (7.5%) transformed over a mean follow-up period of 30 months. Dysplasia grading and the clinical appearance by colour (mixed white and red) were significant predictors of malignant transformation Clinical significance: Patients with erythroleukoplakia and those diagnosed with moderate or severe epithelial dysplasia require more intensive interventions as such lesions have a higher risk of developing a malignancy. [ABSTRACT FROM AUTHOR]

The I Candida i positivity in homogenous gingival leukoplakia in the Japanese cohort was also found to be less than other sites, but non-homogenous gingival leukoplakia had frequent I Candida i colonization and higher malignant transformation rates. Clinical trial registration ClinicalTrials.gov Identifier: NCT04712929 Date of registration: 19/1/2021 Dear Editor, We thank the author Jianqiu Jin for his interest in our article "The association of Candida and antifungal therapy with pro-inflammatory cytokines in oral leukoplakia". Genotyping Candida albicans from Candida leukoplakia and non-Candida leukoplakia shows no enrichment of multilocus sequence typing clades but enrichment of ABC genotype C in Candida leukoplakia. [Extracted from the article]

Aim: The aim of the present study was to evaluate the prevalence of HPV infection in oral leukoplakia, specifying the HPV genotypes eventually involved. We also compared the micro-biopsy and brushing HPV detecting efficacy. Materials and methods: Consecutive patients with a presumptive diagnosis of oral leukoplakia were enrolled. Demographical, behavioral data (smoking, alcohol) and lesion features were recorded. Each patient underwent a brushing procedure, performed with a cytobrush rubbed on the lesion, and then a biopsy was performed. The brushing and micro-biopsy specimens were both analyzed with the HPV 28 Anyplex II Seegene RT-PCR. The prevalence of HPV infection was calculated considering the two methods' outcomes separately and then combining both. Cohen's k coefficient was used to assess the agreement between the two methods. Results: Sixty-five patients were enrolled with a mean age of 60 years. The HPV infection prevalence was 17%, decreasing to 5% considering the brushing outcomes alone. The most frequently detected genotypes were 6 (12%), 11 (3%), 42 (3%), and 16 (3%). No statistically significant correlation was found between HPV infection and the variables analyzed, except for smoking and the type of mucosa (p < 0.05). The strength of agreement between cytobrush and micro-biopsy was "fair" (k = 0.384). Conclusions: The present study showed a low prevalence of HPV infection in oral leukoplakia. The micro-biopsy appeared to be more reliable than brushing in detecting HPV DNA in oral leukoplakia, but the method invasiveness discourages its employ as a screening tool. The importance of HPV in the etiopathogenesis of oral potentially malignant lesions remains unclear; further studies are needed to establish the HPV role in oral leukoplakia. Clinical relevance: HPV involvement in oral leukoplakia and an effective and appropriate detecting technique are still a debated issue. From this study, the restricted use of brushing did not appear sufficient to assess the presence of HPV infection with PCR techniques in samples obtained from oral leukoplakia. [ABSTRACT FROM AUTHOR]

Objective: Smads are the keys of transforming growth factor β (TGFβ) signaling cascade and play a crucial role in many cancers. Once TGFβ receptors are activated, Smad2 and Smad3 are phosphorylated and form complexes with Smad4. These complexes translocate from the cytoplasm to the nucleus where they regulate the target genes. The subcellular localization of phosphorylated Smad3 (p-Smad3) in oral carcinogenesis has never been reported. This study investigated the subcellular distribution of p-Smad3 in oral squamous cell carcinoma (OSCC) and oral leukoplakia (OL) with and without dysplasia. Materials and methods: Expression of p-Smad3 was immunohistochemically examined in 150 samples including OSCC, OL with and without dysplasia, and normal mucosa (NM). Cytoplasmic and nuclear positive cells were counted separately. The results were present as the frequency of positive cases. Results: Cytoplasmic and/or nuclear staining for p-Smad3 was detected. The frequency of cytoplasmic expression in OL with dysplasia was significantly higher than that in NM. The numbers of cytoplasmic expression and cytoplasmic plus nuclear expression in OSCC were significantly higher than those in NM and OL with and without dysplasia. Conclusions: The overexpression of cytoplasmic p-Smad3 in OL with dysplasia and in OSCC suggests that p-Smad3 is in the nonfunctional state. Thus, the growth inhibitory effect of p-Smad3 is diminished during oral carcinogenesis. The cytoplasmic plus nuclear staining of p-Smad3 was aberrant in OSCC. Clinical relevance: The cytoplasmic staining of p-Smad3 may serve as a marker for oral premalignant lesions whereas the cytoplasmic plus nuclear staining of p-Smad3 may serve as a marker for OSCC. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate gene/protein expression alterations of intercellular connections' components in oral leukoplakia (OLs) and squamous-cell carcinoma (OSCCs). Materials and methods: Expression of desmogleins-2,3 (Dsg2/Dsg3), E-cadherin, and their cytoplasmic ligand, β/γ-catenins were quantitatively assessed in HSC-3 cells growing as monolayer cultures (ML)/multicellular aggregates (MCAs), using RT-PCR/Western blot, whereas their localization was detected by immunofluorescence. Furthermore, their expression was semi-quantitatively investigated in tissues from 25 OLs/25 OSCCs, using automated immunohistochemistry. Results: The steady-state levels of Dsg3 RNA transcripts increased as HSC-3 cells enter their exponential phase of growth, before a dramatic decrease to be observed as cells reached their plateau phase especially in MCAs. Upon the same period of time, Dsg2 levels have been increased. The expression of γ-catenin but not that of β-catenin was increased after 48 h in both MLs and MCAs. In clinical samples, Dsg3, Ε-cadherin, β/γ-catenin down-regulation was observed to be associated with the grade of OLs-dysplasia and OSCCs. Importantly, a membrane-to-cytoplasmic switch of expression and strong perinuclear aggregation of Dsg3/γ-catenin was seen in both HSC-3 cells and OLs/OSCCs. Conclusions: The altered expression of Dsg3/γ-catenin and E-cadherin/β-catenin, in vitro and in ODs/OSCC imply their involvement in growth regulation and phenotype of dysplastic/malignant oral epithelial cells, contributing to the better understanding of epithelial dysplasia and OSCCs. Clinical relevance: The observed alterations of their expression suggest a role of Dsg3 and γ-catenin (additionally to E-cadherin/β-catenin) as biomarkers of malignant transformation risk of oral dysplasia and the biological behavior (aggressiveness) of oral cancer, respectively. [ABSTRACT FROM AUTHOR]

The development of oral cancer proceeds through discrete molecular changes that are acquired from loss of genomic integrity after continued exposure to environmental risk factors. It is preceded in the majority of cases by clinically evident oral potentially malignant disorders, the most common of which is leukoplakia. Early detection of these oral lesions by screening methods using suitable markers is critical as it mirrors molecular alterations, long before cancer phenotypes are manifested. Assessment of salivary interleukin-6 (IL-6) as a marker of malignant progression was undertaken in patients with leukoplakia having coexisting periodontitis ( n = 20), periodontitis patients without leukoplakia ( n = 20), and healthy controls ( n = 20) by competitive enzyme-linked immunosorbent assay. Results showed elevation of IL-6 levels in leukoplakia with coexisting periodontitis and in periodontitis patients when compared to healthy control ( P < 0.001). Within the leukoplakia group, IL-6 level was found to be increased with increase in the severity of dysplasia. The use of tobacco was seen to play a significant role in the elevation of salivary IL-6.The importance of IL-6 as a specific marker for leukoplakia with dysplasia and the role of tobacco as an independent risk factor has been highlighted. [ABSTRACT FROM AUTHOR]

The objectives of the study are to evaluate the relationship between common HIV-related oral lesions and absolute CD4+ count, age, gender, and medication used and to assess the sensitivity, specificity, positive and negative predictive value of oral manifestations for low absolute CD4+ counts. HIV-positive patients, 200, from south India were selected, whose absolute CD4+ counts were determined within 2 weeks of oral examination. Sociodemographic data was obtained using a structured questionnaire. Oral manifestations were diagnosed according to presumptive criteria of EEC-clearinghouse classification (1993). Four or more concurrent oral lesions were statistically significant with low CD4+ counts <200 cells/mm3 ( P = 0.005). The highest and lowest mean CD4+ cell counts were seen in individuals with linear gingival erythema (LGE; 172.5 cells/mm3) and pseudomembranous candidiasis (PC; 87 cells/mm3), respectively. Smoking, age (<35 years), and males had a positive association with oral hairy leukoplakia (OHL; P < 0.05). Patients with CD4+ counts < 200 cells/mm3 were associated with 15 times greater risk of PC and four times at greater risk for occurrence of any oral manifestation. Concurrent oral manifestations (≥4) were good predictors (80–100%) of severe immune suppression. In most resource poor countries where facilities for undertaking CD4+ counts are not available, the presence of concurrent oral manifestations may be used as an indicator of deteriorating immune status. [ABSTRACT FROM AUTHOR]