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It has long been considered that the oral microbiome is tightly connected to oral health and that dysbiotic changes can be detrimental to the occurrence and progression of dysplastic oral mucosal lesions or oral cancer. Improved understanding of the concepts of microbial dysbiosis together with advances in high‐throughput molecular sequencing of these pathologies have charted in greater microbiological detail the nature of their clinical state. This review discusses the bacteriome and mycobiome associated with oral mucosal lesions, oral candidiasis, and oral squamous cell carcinoma, aiming to delineate the information available to date in pursuit of advancing diagnostic and prognostic utilities for oral medicine. [ABSTRACT FROM AUTHOR]

Objective: A few studies indicate that human papillomavirus (HPV) induces aberrant expression of microRNAs (miRNAs) and correlate this with p16INK4a in oral dysplasia (OD) and oral squamous cell carcinoma (OSCC). Therefore, this study aimed to evaluate the expression of miRNA-21, miRNA-22, and miRNA-224 by q-PCR and the p16INK4a by immunohistochemical (IHC) as markers for HPV-positive OSCC and OD in comparison to controls as miRNA expression can be altered by the HPV oncogenes and hence can be used as a biomarker for HPV positive cases. Material and Methods: Fifty-two specimens were collected from archived paraffin blocks for patients aged between 19 and 88 (31 males and 21 females) from various oral sites. They were examined by IHC using p16INK4a, by RT-PCR for the detection of HPV (6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 52, 53, 56), and by q-PCR for the expression of miRNA-21, miRNA-22, and miRNA-224 in positive specimens. Results: Out of the 15 OD, three were positive by both techniques. Meanwhile, 17 out of all OSCC specimens showed intense nuclear and cytoplasmic staining by p16INK4a, and only 16 were also positive by RT-PCR. However, all control specimens were negative. MiRNA-21, miRNA-22, and miRNA-224 were overexpressed in 3 specimens of OD and 16 of OSCC. Conclusion: MiRNA-21, miRNA-22, and miRNA-224, besides p16INK4a, could be used as indicators for HPV-associated OD and OSCC as their expression is attributed to the HPV oncoprotein. Further studies using follow-up data should be done to correlate it with miRNA overexpression.

Objective: A few studies indicate that human papillomavirus (HPV) induces aberrant expression of microRNAs (miRNAs) and correlate this with p16INK4a in oral dysplasia (OD) and oral squamous cell carcinoma (OSCC). Therefore, this study aimed to evaluate the expression of miRNA-21, miRNA-22, and miRNA-224 by q-PCR and the p16INK4a by immunohistochemical (IHC) as markers for HPV-positive OSCC and OD in comparison to controls as miRNA expression can be altered by the HPV oncogenes and hence can be used as a biomarker for HPV positive cases. Material and Methods: Fifty-two specimens were collected from archived paraffin blocks for patients aged between 19 and 88 (31 males and 21 females) from various oral sites. They were examined by IHC using p16INK4a, by RT-PCR for the detection of HPV (6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 52, 53, 56), and by q-PCR for the expression of miRNA-21, miRNA-22, and miRNA-224 in positive specimens. Results: Out of the 15 OD, three were positive by both techniques. Meanwhile, 17 out of all OSCC specimens showed intense nuclear and cytoplasmic staining by p16INK4a, and only 16 were also positive by RT-PCR. However, all control specimens were negative. MiRNA-21, miRNA-22, and miRNA-224 were overexpressed in 3 specimens of OD and 16 of OSCC. Conclusion: MiRNA-21, miRNA-22, and miRNA-224, besides p16INK4a, could be used as indicators for HPV-associated OD and OSCC as their expression is attributed to the HPV oncoprotein. Further studies using follow-up data should be done to correlate it with miRNA overexpression. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is a serious health disease that can lead to a reduced quality of life or even death. It ranks sixth in terms of cancer expansion. It is one of India's primary causes of natural death. In OSCC such potentially malignant Disorders (PMDs) are precancerous lesions with such a high risk of progression. Tumor angiogenesis is a one of the basic biomarkers that may influence the proliferation of a precancerous lesion into the cancerous lesion. Tropomyosin receptor kinase B (TrkB), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) also play important roles in carcinogenesis by promoting angiogenesis. The construction of new vessels of blood from existing vasculature is referred as angiogenesis. Aim of the Study: To get deep insights of immunohistochemistry expression of VEGF, BDNF, and TRKB in oral epithelial dysplasia (OED), verrucous carcinoma (VC), and OSCC. Material and Methods: The study included 100 formalin-fixed paraffin-embedded tissue blocks from 20 cases of OED, 20 cases of VC, and 60 cases of OSCC [20 cases of well-differentiated oral squamous cell carcinoma (WD-OSCC), 20 cases of moderately differentiated oral squamous cell carcinoma (MD-OSCC), and 20 cases of poorly differentiated oral squamous cell carcinoma (PD-OSCC). The staining intensity and distribution of VEGF, BNDF, and TrkB were examined and statistically analyzed using analysis of variance (ANOVA), post hoc Bonferroni test, independent t-test, Pearson's Chi-square test, and Pearson's correlation coefficient test. Results: The immunoexpression of VEGF, BDNF, and TrkB was found to be elevated in the order of OEDs, VC, and OSCC. The percentage of positive was highest in PD-OSCC, followed by MD-OSCC and WD-OSCC. Conclusion: Based on our findings, angiogenesis plays a significant role in tumor growth and metastasis. A substantial relationship was discovered between VEGF, BDNF, TrkB expression, and increases in vascularity throughout the transition from OEDs to VCs and OSCCs. [ABSTRACT FROM AUTHOR]

Nearly 90% of oral cancers are characterized as oral squamous cell carcinoma (OSCC), representing the sixth most common type of cancer. OSCC usually evolves from oral potentially malignant disorders that, in some cases, are histologically consistent with a oral dysplasia. The levels of 1α,25 dihydroxyvitamin D3 (1,25-(OH)2D3; calcitriol), the active form of vitamin D3, have been shown to be decreased in patients with oral dysplasia and OSCC. Moreover, treatment with 1,25-(OH)2D3 has been proven beneficial in OSCC by inhibiting the Wnt/β-catenin pathway, a signaling route that promotes cell migration, proliferation, and viability. However, whether this inhibition mechanism occurs in oral dysplasia is unknown. To approach this question, we used dysplastic oral keratinocyte cultures and oral explants (ex vivo model of oral dysplasia) treated with 1,25-(OH)2D3 for 48 h. Following treatment with 1,25-(OH)2D3, both in vitro and ex vivo models of oral dysplasia showed decreased levels of nuclear β-catenin by immunofluorescence (IF) and immunohistochemistry (IHC). Consistently, reduced protein and mRNA levels of the Wnt/β-catenin target gene survivin were observed after treatment with 1,25-(OH)2D3. Moreover, 1,25-(OH)2D3 promoted membranous localization of E-cadherin and nuclear localization of vitamin D receptor (VDR). Functionally, DOK cells treated with 1,25-(OH)2D3 displayed diminished cell migration and viability in vitro.

Oral cancer is a prevalent global health issue, with significant morbidity and mortality rates. Despite available preventive measures, it remains one of the most common cancers, emphasising the need for improved diagnostic and prognostic tools. This review focuses on oral potentially malignant disorders (OPMDs), precursors to oral cancer, specifically emphasising oral epithelial dysplasia (OED). The World Health Organisation (WHO) provides a three-tier grading system for OED, and recent updates have expanded the criteria to enhance diagnostic precision. In the prognostic evaluation of OED, histological grading is presently regarded as the gold standard; however, its subjectivity and unreliability in anticipating malignant transformation or recurrence pose notable limitations. The primary objective is to investigate whether specific immunohistochemical biomarkers can enhance OED grading assessment according to the WHO classification. Biomarkers exhibit significant potential for comprehensive cancer risk evaluation, early detection, diagnosis, prognosis, and treatment optimisation. Technological advancements, including sequencing and nanotechnology, have expanded detection capabilities. Some analysed biomarkers are most frequently chosen, such as p53, Ki-67, cadherins/catenins, and other proteins used to differentiate OED grades. However, further research is needed to confirm these findings and discover new potential biomarkers for precise dysplasia grading and minimally invasive assessment of the risk of malignant transformation. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with significant morbidity and mortality. Identifying potential premalignant lesions is crucial for early detection and effective management. Lichen planus (LP), a chronic inflammatory disorder has been associated with an increased risk of developing OSCC. This study aimed to assess the diagnostic importance of p16 and p53 expression in identifying LP as a potential premalignant lesion for OSCC. Materials and Methods: A retrospective analysis was conducted on archived tissue samples from patients diagnosed with LP (n = 80) and OSCC (n = 60) between 2017 and 2022. Immunohistochemistry was performed to evaluate p16 and p53 protein expression levels in both LP and OSCC tissues. Clinical data, including patient demographics and lesion characteristics, were collected and correlated with the immunohistochemical findings. Results and Discussion: The results revealed a significantly higher prevalence of p16 and p53 expression in LP tissues compared to normal oral mucosa (P < 0.001). Notably, p16 expression was observed in 70% of LP cases, while p53 was detected in 55% of LP cases. Furthermore, a significant association was established between p53 expression and the presence of dysplasia within LP lesions (P = 0.003). This indicates the potential of p53 as a predictive biomarker for malignant transformation in LP. The correlation between p16 and p53 expression levels in LP and OSCC tissues suggests a potential mechanistic link between LP and OSCC development. Conclusion: This study underscores the diagnostic importance of p16 and p53 expression as potential markers for identifying LP as a premalignant lesion in the context of OSCC. The elevated prevalence of these markers in LP tissues suggests a potential role in predicting malignant transformation. The findings contribute to a deeper understanding of the molecular pathways underlying OSCC development from LP and emphasize the need for regular monitoring and early intervention in patients diagnosed with LP. Further prospective studies are warranted to validate these findings and to explore the clinical utility of p16 and p53 as biomarkers for predicting OSCC risk in LP patients. [ABSTRACT FROM AUTHOR]

Copyright of Casos & Revisiones de Salud is the property of Victor Manuel Mendoza Nunez, Universidad Nacional Autonoma de Mexico and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Oral epithelial dysplasia associated with high-risk HPV infection has received different names since its initial description, such as oral Bowenoid lesions, HPV-associated intraepithelial neoplasia, and oral koilocytic dysplasia. Some features, identified in more or less quantity in some of the descriptions, like apoptotic keratinocytes, karyorrhexis, and mitosoid figures, are intricately connected to viral transcriptional status and, consequently, viral load. Since the variety in terminology has introduced diagnostic confusion within medical and research communities, establishing a uniform and standardized approach to diagnosing HPV-oral epithelial dysplasia is crucial for accurate and early diagnoses and holds significant implications for patient outcomes, particularly in high-risk individuals.

Objective: Oral leukoplakia is the most common oral potentially malignant disorder. Malignant transformation of oral leukoplakia occurs at an annual rate of 1%–7%. WHO‐defined classic epithelial dysplasia is an important predictor of malignant transformation of oral leukoplakia, but we have previously shown in a proof of concept study that prediction improves by incorporation of an architectural pattern of dysplasia, also coined as differentiated dysplasia. We aimed to analyze this finding in a larger cohort of patients. Method: For this retrospective study 176 oral leukoplakia patients were included. Biopsies for all patients were assessed for the presence of dysplasia and analyzed for cytokeratin 13 and 17 expression. Moreover, the inter‐observer agreement for the diagnosis of differentiated dysplasia was determined. Results: In total, 33 of 176 patients developed oral squamous cell carcinoma during follow‐up. Presence of classic epithelial dysplasia increased cancer risk two‐fold (HR = 2.18, p = 0.026). Lesions without classic epithelial dysplasia could be further risk‐stratified by the presence of differentiated dysplasia (HR = 7.36, p < 0.001). Combined classic epithelial and differentiated dysplasia imparted a seven‐fold increased risk of malignant transformation (7.34, p = 0.001). Inter‐observer agreement for the diagnosis of dysplasia, including differentiated dysplasia, was moderate (κ = 0.56, p < 0.001). Discussion: This study emphasizes the importance of the recognition of the architectural pattern of differentiated dysplasia as a separate entity for risk prediction of malignant transformation of oral leukoplakia. Presence of any pattern of dysplasia results in accurate prediction of malignant transformation risk of oral leukoplakia. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is amongst the most common cancers, with more than 377,000 new cases worldwide each year. OSCC prognosis remains poor, related to cancer presentation at a late stage, indicating the need for early detection to improve patient prognosis. OSCC is often preceded by a premalignant state known as oral epithelial dysplasia (OED), which is diagnosed and graded using subjective histological criteria leading to variability and prognostic unreliability. In this work, we propose a deep learning approach for the development of prognostic models for malignant transformation and their association with clinical outcomes in histology whole slide images (WSIs) of OED tissue sections. We train a weakly supervised method on OED cases (n = 137) with malignant transformation (n = 50) and mean malignant transformation time of 6.51 years (±5.35 SD). Stratified five‐fold cross‐validation achieved an average area under the receiver‐operator characteristic curve (AUROC) of 0.78 for predicting malignant transformation in OED. Hotspot analysis revealed various features of nuclei in the epithelium and peri‐epithelial tissue to be significant prognostic factors for malignant transformation, including the count of peri‐epithelial lymphocytes (PELs) (p < 0.05), epithelial layer nuclei count (NC) (p < 0.05), and basal layer NC (p < 0.05). Progression‐free survival (PFS) using the epithelial layer NC (p < 0.05, C‐index = 0.73), basal layer NC (p < 0.05, C‐index = 0.70), and PELs count (p < 0.05, C‐index = 0.73) all showed association of these features with a high risk of malignant transformation in our univariate analysis. Our work shows the application of deep learning for the prognostication and prediction of PFS of OED for the first time and offers potential to aid patient management. Further evaluation and testing on multi‐centre data is required for validation and translation to clinical practice. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: In the clinical practice, one of the most common suspicious lesions that may be potentially malignant is oral leukoplakia. Globally, the rate at which it turns malignant varies. This study examines the levels of markers CD138 and 43 in oral leukoplakia. Materials and Methods: Twenty archival blocks of confirmed epithelial dysplasia were taken from the Department of Oral Pathology. These were processed for the identification of markers CD138 and 43 through Immuno Histo Chemistry (IHC). The blocks were divided equally for both the markers. Results: There was a noticeable difference in staining intensity between dysplastic tissue and nondysplastic epithelium. However, CD138 expression was low or weak in dysplastic epithelium. CD43 expression was negative in all nonhematopoietic tissues. Conclusion: Genes that are cancer associated have been found to have incredibly different impacts in numerous tissues during the multistep process of oral carcinogenesis. In tissues undergoing dysplastic changes, CD138 expression was shown to be decreased, which could point out the malignant changes initiated in the epithelium of the oral tissues.

Head and neck squamous cell carcinoma (HNSCC) is the world's 6th most common malignancy. Oral cavity SCC (OCSCC) represents approximately one third of the HNSCC cases diagnosed annually in the United States. Despite therapeutic advances, OCSCC is frequently lethal, with a modest 5-year survival. Because OCSCC is often preceded by premalignant lesions, it is an ideal disease for screening initiatives. The conventional visual and tactile exam (CVTE), coupled with a tissue biopsy, remains the gold standard. However, CVTE alone cannot reliably differentiate between reactive/inflammatory and dysplastic lesions. Further, the histologic diagnosis of dysplasia is subjective in nature and a highly imperfect predictor of malignant transformation. This prognostic uncertainty creates a significant clinical management dilemma—watchful waiting with increased patient psychological and economic burdens versus unnecessary aggressive treatment. As such, the development and validation of novel diagnostic platforms such as Artificial Intelligence (AI) and prognostic molecular biomarkers may help address these critical unmet clinical needs. [ABSTRACT FROM AUTHOR]

Objective: To use large‐scale electronic health record (EHR) data to develop machine learning models predicting malignant transformation of oral lesions. Methods: A multi‐institutional health system database was used to identify a retrospective cohort of patients with biopsied oral lesions. The primary outcome was malignant transformation. Chart review and automated system database queries were used to identify a range of demographic, clinical, and pathologic variables. Machine learning was used to develop predictive models for progression to malignancy. Results: There were 2192 patients with a biopsied oral lesion, of whom 1232 had biopsy proven oral dysplasia. There was malignant transformation in 34% of patients in the oral lesions dataset, and in 54% of patients in the dysplasia subset. Multiple machine learning‐based models were trained on the data in two experiments, (a) including all patients with biopsied oral lesions and (b) including only patients with biopsy‐proven dysplasia. In the first experiment, the best machine learning models predicted malignant transformation among the biopsied oral lesions with an area under the curve (AUC) of 86%. In the second experiment, the random forest model predicted malignant transformation among lesions with dysplasia with an AUC of 0.75. The most influential features were dysplasia grade and the presence of multiple lesions, with smaller influences from other features including anemia, histopathologic description of atypia, and other prior cancer history. Conclusion: With diverse features from EHR data, machine learning approaches are feasible and allow for generation of models that predict which oral lesions are likely to progress to malignancy. Level of Evidence: 3 Laryngoscope, 133:1156–1162, 2023 [ABSTRACT FROM AUTHOR]

Oral cancer is a prevalent global health issue, with significant morbidity and mortality rates. Despite available preventive measures, it remains one of the most common cancers, emphasising the need for improved diagnostic and prognostic tools. This review focuses on oral potentially malignant disorders (OPMDs), precursors to oral cancer, specifically emphasising oral epithelial dysplasia (OED). The World Health Organisation (WHO) provides a three-tier grading system for OED, and recent updates have expanded the criteria to enhance diagnostic precision. In the prognostic evaluation of OED, histological grading is presently regarded as the gold standard; however, its subjectivity and unreliability in anticipating malignant transformation or recurrence pose notable limitations. The primary objective is to investigate whether specific immunohistochemical biomarkers can enhance OED grading assessment according to the WHO classification. Biomarkers exhibit significant potential for comprehensive cancer risk evaluation, early detection, diagnosis, prognosis, and treatment optimisation. Technological advancements, including sequencing and nanotechnology, have expanded detection capabilities. Some analysed biomarkers are most frequently chosen, such as p53, Ki-67, cadherins/catenins, and other proteins used to differentiate OED grades. However, further research is needed to confirm these findings and discover new potential biomarkers for precise dysplasia grading and minimally invasive assessment of the risk of malignant transformation.

Background: Early diagnosis and timely management of potentially malignant oral disorders may prevent malignant transformation and prompt diagnosis of frank malignancies favours better prognosis. The aim of this study was to evaluate the outcome of surgical management of oral potentially malignant disorders of the oral cavity and observe the prevalence of recurrence at the primary site and occurrence of another potentially malignant lesion in these patients. Methods: The study participants included patients who had undergone clinical oral examination, surgical excision of biopsy-proven cases of dysplastic oral potentially malignant disorders (leukoplakia, erythroplakia, non-healing ulcerative and erosive areas, etc.) who were on routine follow-up as per the standard guidelines. These patients were followed up closely during each monthly follow-up visit for the first year. The patients were then prospectively analysed for any recurrence of lesion. On follow-up visits, detailed clinical oral examination was done to note the prevalence of a new lesion in any oral cavity sub site other than the previous site. If a new lesion was detected, then biopsy followed by surgical excision was followed as per standard guidelines. The follow-up period after the second surgical intervention was 12 months. Results: Fifty patients with potentially malignant oral disorders underwent surgical excision. The majority of the study subjects were males (39/50) and 41 of them were below 65 years of age. Of 50 patients, 13 (26%) had second oral potentially malignant lesion other than the primary site. The rate of recurrence of the lesions at the primary site was 4% (2/50). Of these patients with recurrence, all had malignant transformation (2/2). Also, patients who were initially diagnosed with moderate dysplasia had a higher chance of recurrence. A second lesion at a site different from the primary lesion was seen in 26% of the cases. Conclusion: Surgical management of such lesions with one-centimetre oncological margins in all dimensions contrary to the routine five millimetre surgical margins reduces the chance of recurrence. [ABSTRACT FROM AUTHOR]

Background: Oral leukoplakia is a condition commonly associated with tobacco use. The literature also has documentation pertaining to likely cancerous transformation of leukoplakia. It is always a challenge to discover a therapeutic modality to prevent this transformation. Imiquimod is an immune response modifier possessing antiviral and anti-tumor activity which is being explored as an off label use in many cancerous conditions. Aim: To show any regression in oral leukoplakia and to test its safety and tolerability. Setting and Design: This is a randomized, open-label, single-centered clinical pilot study carried out with Imiquimod. Material and Methods: Two groups OPD of dental college with topical 5% Imiquimod and Topical Vitamin A (50,000 IU) were compared for their efficacy in the management of oral leukoplakia, pre- and post-treatment clinically and regression of oral dysplasia was observed histopathologically. Unit of improvement was noted for assessing the effectiveness of treatment. Statistical Analysis: Quantitative data were analyzed by Wilcoxon signed test. Results: Topical 5% Imiquimod application resulted in good clinical response +1, +2 unit of improvement with more regression of lesion noted in non-homogeneous leukoplakia and areas with less salivary contamination. Topical Imiquimod 5% is the best alternative to conservative management of moderate to severe dysplasia cases where we can offer more to the patient than just observation, and it is also better than a surgical option where surgery leads to more morbidity, in recurrent cases.

Introduction: Clinical management of oral potentially malignant disorders relies on accurate histopathological assessment of the presence and grade of oral epithelial dysplasia. While adjunctive laboratory tests have provided useful prognostic information, none are in widespread clinical use. This study was performed to assess the clinical utility of two contemporary oral epithelial dysplasia grading systems. Methods: Patients were identified from a clinical database. Oral epithelial dysplasia grading was performed by three oral and maxillofacial pathologists blinded to clinical outcome using the WHO 2017 system and a binary classification. The primary outcome measure was the development of oral squamous cell carcinoma, termed 'malignant transformation'. Results: One hundred thirty‐one cases satisfied the inclusion criteria, of which 23 underwent malignant transformation. There was substantial inter‐rater agreement between the study pathologists for both grading systems, measured using kappa statistics (κ = 0.753 – 0.784). However, there was only moderate agreement between the consensus WHO 2017 dysplasia grade for the study against the original grade assigned by a pool of six pathologists in the context of the clinical service (κ = 0.491). Higher grade categories correlated with an increased risk of developing cancer using both grading systems. Conclusion: This study demonstrates that the WHO 2017 and binary grading systems are reproducible between calibrated pathologists and that consensus reporting is likely to improve the consistency of grading. The WHO and binary systems were prognostically comparable. We recommend that institutions implement consensus oral epithelial dysplasia grading and prospectively audit the effectiveness of risk stratifying their patients with oral potentially malignant disorders. (249 words). [ABSTRACT FROM AUTHOR]

Introduction: Oral Leukoplakia is the second most common oral potentially malignant disorder encountered in day-to-day clinical practice, with an overall global prevalence of 4.11%. The rate of its malignant transformation varies worldwide. Aims & Objectives: The aim of the study was to assess CD 138 and CD43 immunoreactivity in oral epithelial dysplasia. Materials & Methods: Immunohistochemistry was performed on fifteen formalin-fixed oral epithelial dysplasia tissues for CD 43 (n=15) and CD 138 (n=15) which were obtained from archives at Oral cancer research and coordinating centre, Malaysia. Results: The expression of CD 43 in non-hematopoietic tissues was negative in all cases, but epithelium with dysplastic alterations had low or weak CD 138 expression between dysplastic tissue and non-dysplastic epithelium, there was a substantial difference in staining intensity. Conclusion: Oral carcinogenesis is a multistep process, and cancer driver genes have been shown to have vastly diverse effects in various tissues. CD 138 expression was shown to be lower in tissues undergoing dysplastic alterations, which could be a sign of oral epithelial dysplasia with a high risk of malignancy. [ABSTRACT FROM AUTHOR]

Grading of oral epithelial dysplasia (OED) can be challenging with considerable intraobserver and interobserver variability. Abnormal immunohistochemical staining patterns of the tumor suppressor protein, p53, have been recently shown to be potentially associated with progression in OED. We retrospectively identified 214 oral biopsies from 203 patients recruited in a longitudinal study between 2001 and 2008 with a diagnosis of reactive, nondysplastic lesions, low-grade lesions (mild OED and moderate OED) and high-grade lesions (HGLs; severe OED/carcinoma in situ). Tissue microarrays were constructed from the most representative area of the pathology. Three consecutive sections were sectioned and stained for hematoxylin and eosin, p53 immunohistochemistry, and p16 immunohistochemistry. The staining results were reviewed by 2 pathologists (Y.C.K.K., C.F.P.) blinded to clinical outcome. Samples were categorized into p53 abnormal OED (n = 46), p53 conventional OED (n = 118), and p53 human papillomavirus (HPV) OED (HPV associated) (n = 12) using a previously published pattern-based approach. All cases of p53 HPV OED (HPV associated) were identified in HGLs. In contrast, cases of p53 abnormal OED were observed in mild OED (9.5%), moderate OED (23%), and severe OED/carcinoma in situ (51%). None of the 27 reactive or nondysplastic lesions showed abnormal p53 staining patterns. Among the 135 low-grade lesions, 23 cases (17.0%; 2 mild OEDs and 21 moderate OEDs) progressed to HGL or squamous cell carcinoma, with 11 cases showing progression within the first 3 years. Remarkably, 82% (9/11) of these faster progressors showed abnormal p53 patterns. Survival analysis revealed that p53 abnormal OED had significantly poorer progression-free probability (P < .0001) with hazard ratio of 11.24 (95% CI, 4.26-29.66) compared with p53 conventional OED. Furthermore, p53 abnormal OED had poorer local recurrence-free survival compared with p53 wild-type OED (P = .03). The study supports that OED with p53 abnormal pattern is at high risk for progression and recurrence independent of the dysplasia grade., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Significance: Diagnosis of cancerous and pre-cancerous oral lesions at early stages is critical for the improvement of patient care, to increase survival rates and minimize the invasiveness of tumor resection surgery. Unfortunately, oral precancerous and early-stage cancerous lesions are often difficult to distinguish from oral benign lesions with the existing diagnostic tools used during standard clinical oral examination. In consequence, early diagnosis of oral cancer can be achieved in only about 30% of patients. Therefore, clinical diagnostic technologies for fast, minimally invasive, and accurate oral cancer screening are urgently needed., Aim: This study investigated the use of multispectral autofluorescence imaging endoscopy for the automated and noninvasive discrimination of cancerous and precancerous from benign oral epithelial lesions., Approach: In vivo multispectral autofluorescence endoscopic images of clinically suspicious oral lesions were acquired from 67 patients undergoing tissue biopsy examination. The imaged lesions were classified as precancerous ( n = 4), cancerous ( n = 29), and benign ( n = 34) lesions based on histopathology diagnosis. Multispectral autofluorescence intensity feature maps were generated for each oral lesion and used to train and optimize support vector machine (SVM) models for automated discrimination of cancerous and precancerous from benign oral lesions., Results: After a leave-one-patient-out cross-validation strategy, an optimized SVM model developed with four multispectral autofluorescence features yielded levels of sensitivity and specificity of 85% and 71%, respectively and overall accuracy of 78% in the discrimination of cancerous/precancerous versus benign oral lesions., Conclusion: This study demonstrates the potentials of a computer-assisted detection system based on multispectral autofluorescence imaging endoscopy for the early detection of cancerous and precancerous oral lesions., Competing Interests: Disclosures The authors declare no conflicts of interest.

Objectives: We performed a systematic review to evaluate the published biomarkers related to oral leukoplakia (OL), aiming to identify the biomarkers that indicate any future risk of cancer in patients with oral leukoplakia. Methods: A search strategy was developed for three main electronic databases: PubMed, Cochrane Library, and EBSCO, and also for Google Scholar, until February 28, 2020. The study selection was performed in a two‐phase process aiming at studies assessing tissue biomarkers for "malignant transformation of OL." Risk of bias analysis of included studies was performed using the Quality in Prognosis Studies Tool. Results: From 3,130 articles initially identified by searching databases, a total of 46 studies were included in this systematic review, with a combined sample of 3,783 patients, of whom 1,047 presented with malignant transformation of a previously diagnosed OL as reported by the authors. The cancer incidence in the whole group was 27.6% (range: 5.4% to 54.1%). The studies were derived from different geographic areas, including Asia (n = 21), Europe (n = 15), North America (n = 9), and Oceania (n = 1). There were 49 different molecular biomarkers evaluated in the 46 included studies: p53 and podoplanin proteins were the most frequently reported, followed by abnormalities at particular chromosomal loci (e.g., LOH). Risk of bias analysis revealed concerns associated with "measurement of prognostic factor," "study confounding" and "statistical analysis and reporting." Conclusions: Substantial heterogeneity and lack of standardized reporting of data among the studies were identified. The most promising biomarkers reported to have a significant association with the malignant transformation in OL included podoplanin and chromosomal loci abnormalities. A critical examination of the follow‐up studies on OL published so far indicated that tissue biomarkers that could predict the risk of oral cancer in patients with OL are still in a discovery phase. [ABSTRACT FROM AUTHOR]

Background: To analyse the clinical and histological characteristics from a series of oral leukoplakias, leukoerythroplakias, erythroplakias and actinic cheilitis diagnosed in a 14‐year period. Methods: The files were reviewed and all cases diagnosed as leukoplakia, leukoerythroplakia, erythroplakia and actinic cheilitis were selected. Clinical information was obtained from the biopsy submission forms, and histological review was performed in all cases. Results: Final sample included 953 lesions, mostly affecting females (534, 56%), and 87.5% of the patients were 41 to 80 years old. The most commonly affected regions were the lower lip (20.1%), tongue (18.1%) and buccal mucosa (16.9%). Leukoplakias, actinic cheilitis, leukoerythroplakias and erythroplakias represented, respectively, 74.6%, 15.2%, 9.3% and 0.8% of the sample. Most cases presented no dysplasia (42.1%) or mild dysplasia (33.5%). Lesions in the tongue, floor of mouth and lower lip, as well as lesions that presented hyperparakeratosis, showed higher frequencies of moderate dysplasia and severe dysplasia/carcinoma in situ. The most common histological criteria were the increase in number and size of nucleoli, loss of polarity of the basal cells and variations in cellular size and shape. Classification by the binary system showed that 7% were high‐risk lesions. Conclusion: All histological criteria for classification of oral epithelial dysplasia recommended by the World Health Organization showed increased frequency as grading increased. Additional criteria seem to be useful in grading oral epithelial dysplasia, such as the presence of normal and abnormal superficial mitotic figures and endophytic epithelial proliferation. [ABSTRACT FROM AUTHOR]

(1) Background: Several studies investigating the clinical outcomes of potentially premalignant oral epithelial lesions treated with CO2 lasers have been published over the last decades. (2) Methods: A systematic research review was performed for studies published between 2011 and 2021 in the PubMed, Science Direct, and Google Scholar databases. (3) Results: Initially, the search identified 52 relevant articles. The primary analysis of the titles and abstracts eliminated 22 articles, leaving 30 articles whose full texts were examined. A total of 22 articles met the inclusion criteria. The studies were classified into 3 categories. (4) Conclusions: After evaluating the results of all the studies included in this review, an initial general statement can be made, namely that CO2 lasers are a treatment option worth taking into consideration when approaching oral mucosal lesions. When compared to other types of lasers used in dental practice, the CO2 laser stands out due to its many advantages. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study was designed to examine the prevalence of Candida albicans alcohol dehydrogenase 1 (CaADH1) gene in oral dysplasia as well as oral squamous cell carcinoma (OSCC) with and without lymph node metastasis (LNM) using reverse transcription polymerase chain reaction (RT-PCR) in order to determine its role in initiation, propagation and metastasis of oral dysplasia and carcinoma. Formalin-fixed parafin-embedded specimens were grouped into four groups: 7 control, 16 oral dysplasia, 16 OSCC without LNM and 15 OSCC with LNM. All specimens were examined by periodic acid Schiff (PAS) stain to detect Candida hyphae, while CaADH1 gene was detected using RT-PCR. Candida hyphae were detected by PAS stain in one specimen of oral dysplasia group, 5 OSCC without LNM and 5 OSCC with LNM. CaADH1 gene was detected in 29 specimens (one case of sever dysplasia, 16 OSCC without LNM and 12 OSCC with LNM), with a highly statistically significant between the groups. CaADH1 gene is associated with OSCC with and without metastasis whereas in oral dysplasia it could not be estimated. Further studies with larger sample size are needed to confirm the role of CaADH1 in oral dysplasia and OSCC.

Nearly 90% of oral cancers are characterized as oral squamous cell carcinoma (OSCC), representing the sixth most common type of cancer. OSCC usually evolves from oral potentially malignant disorders that, in some cases, are histologically consistent with a oral dysplasia. The levels of 1α,25 dihydroxyvitamin D3 (1,25-(OH)2D3; calcitriol), the active form of vitamin D3, have been shown to be decreased in patients with oral dysplasia and OSCC. Moreover, treatment with 1,25-(OH)2D3 has been proven beneficial in OSCC by inhibiting the Wnt/β-catenin pathway, a signaling route that promotes cell migration, proliferation, and viability. However, whether this inhibition mechanism occurs in oral dysplasia is unknown. To approach this question, we used dysplastic oral keratinocyte cultures and oral explants (ex vivo model of oral dysplasia) treated with 1,25-(OH)2D3 for 48 h. Following treatment with 1,25-(OH)2D3, both in vitro and ex vivo models of oral dysplasia showed decreased levels of nuclear β-catenin by immunofluorescence (IF) and immunohistochemistry (IHC). Consistently, reduced protein and mRNA levels of the Wnt/β-catenin target gene survivin were observed after treatment with 1,25-(OH)2D3. Moreover, 1,25-(OH)2D3 promoted membranous localization of E-cadherin and nuclear localization of vitamin D receptor (VDR). Functionally, DOK cells treated with 1,25-(OH)2D3 displayed diminished cell migration and viability in vitro.

The purpose of this systematic review and meta‐analysis was to estimate the overall and type‐specific prevalence of human papillomavirus (HPV) DNA in oral epithelial dysplasia and assess p16INK4a overexpression in relation to HPV‐status. A systematic literature search identified 31 eligible studies (832 cases) evaluating the presence of HPV DNA in oral epithelial dysplasia cases by PCR. Of these, six studies evaluated p16INK4a overexpression in relation to HPV‐status. The overall pooled prevalence of HPV DNA in oral epithelial dysplasia was 27.2% (95% CI: 17.6‐38.1). We observed substantial interstudy heterogeneity, which could not be explained by differences in continent, tissue type, or severity of epithelial dysplasia. HPV16 was the predominant genotype detected. Moreover, 62.2% of HPV positive and 17.8% of HPV negative oral epithelial dysplasia samples stained intensively positive for p16INK4a. This meta‐analysis found that 27% of oral epithelial dysplasia harbor HPV DNA. Whether this represents a transient infection or has a carcinogenic role is unknown. [ABSTRACT FROM AUTHOR]

Aim: The COVID‐19 pandemic has resulted in society experiencing unprecedented challenges for health care practitioners and facilities serving at the frontlines of this pandemic. With regard to oral cancer, there is a complete absence of literature regarding the long‐term impact of pandemics on patients with oral potentially malignant disorders (OPMDs). The objective of this article is to put forth an institutional multidisciplinary approach for the evaluation and management of OPMDs. Methods: A multidisciplinary approach was put formalized within our institution to risk stratify patients based on need for in‐person assessment vs telehealth assessment during the COVID‐19 pandemic. Results: With judicious risk stratification of patients based on clinical features of their OPMD and with consideration of ongoing mitigation efforts and regional pandemic impact, providers are able to safely care for their patients. Conclusions: The COVID‐19 pandemic has required health care practitioners to make novel decisions that are new to us with development of creative pathways of care that focused on patient safety, mitigation efforts, and clinical management of disease processes. The care of patients with OPMDs requires special considerations especially as patients at high risk for severe COVID‐19 illness are also higher risk for the development of OPMDs. [ABSTRACT FROM AUTHOR]

Background: Oral potentially malignant disorders have a risk for malignant transformation but are difficult to reliably identify and predict which patients are at the risk for malignant transformation. OCT4 has been hypothesized to play a key oncogenic driver in a variety of solid tumors. A deeper understanding of the aberrant molecular pathways which lead to carcinogenesis needs to be identified by the potential markers. Aims: To assess the OCT4 stemness factor in oral leukoplakia for its potential risk to malignant transformation. Settings and Design: 20 cases of oral leukoplakia were obtained from archives at Oral Cancer Research & Coordinating center (OCRCC) Malaysia Subjects and Methods: 20 cases of oral leukoplakia were assessed by OCT4 immunohistochemically. Oral squamous cell carcinoma was used as a control. Result: no expression of OCT 4 was observed in any cases of oral leukoplakia. Conclusion: The molecular mechanisms of Oct4 regulation and in particular of its switch on and off in tissues depends upon its microenvironment, which makes it challenging in fundamental and applied research fields of regenerative medicine and cancer therapy. It's better that patients should undergo multiple biopsies for the early detection of malignant transformation with close follow-up during the first two to three years, a large amount of work remains to be done with multi-marker panel investigation, as cure rates have remained constant over three decades. [ABSTRACT FROM AUTHOR]

Aim: To develop nanomedicines for immuno-therapy of oral dysplasia and oral squamous cell carcinoma. Materials & methods: All-trans retinoic acid (ATRA)-poly(lactide-co-glycolide acid) (PLGA)-poly(ethylene glycol) (PEG)-programmed death-ligand 1 (PD-L1) nanomedicines were fabricated by loading ATRA into PLGA-PEG nanocarriers and modification using an anti-PD-L1 antibody. Results: ATRA-PLGA-PEG-PD-L1 nanoparticles showed fast cellular uptake, significantly inhibited proliferation and induced apoptosis in DOK and CAL27 cells. Moreover, in C3H tumor-bearing mice, ATRA-PLGA-PEG-PD-L1 nanoparticles more specifically targeted tumor cells, enhanced anticancer activity and reduced side effects when compared with free ATRA. Furthermore, CD8+ T cells were activated around PD-L1 positive cells in the tumor microenvironment after treatment. Conclusion: ATRA-PLGA-PEG-PD-L1 nanoparticles had low toxicity, high biocompatibility and specifically targeted oral dysplasia and squamous carcinoma cells both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Potentially malignant lesions, commonly referred to as dysplasia, are associated with malignant transformation by mechanisms that remain unclear. We recently reported that increased Wnt secretion promotes the nuclear accumulation of β‐catenin and expression of target genes in oral dysplasia. However, the mechanisms accounting for nuclear re‐localization of β‐catenin in oral dysplasia remain unclear. In this study, we show that endosomal sequestration of the β‐catenin destruction complex allows nuclear accumulation of β‐catenin in oral dysplasia, and that these events depended on the endocytic protein Rab5. Tissue immunofluorescence analysis showed aberrant accumulation of enlarged early endosomes in oral dysplasia biopsies, when compared with healthy oral mucosa. These observations were confirmed in cell culture models, by comparing dysplastic oral keratinocytes (DOK) and non‐dysplastic oral keratinocytes (OKF6). Intriguingly, DOK depicted higher levels of active Rab5, a critical regulator of early endosomes, when compared with OKF6. Increased Rab5 activity in DOK was necessary for nuclear localization of β‐catenin and Tcf/Lef‐dependent transcription, as shown by expression of dominant negative and constitutively active mutants of Rab5, along with immunofluorescence, subcellular fractionation, transcription, and protease protection assays. Mechanistically, elevated Rab5 activity in DOK accounted for endosomal sequestration of components of the destruction complex, including GSK3β, Axin, and adenomatous polyposis coli (APC), as observed in Rab5 dominant negative experiments. In agreement with these in vitro observations, tissue immunofluorescence analysis showed increased co‐localization of GSK3β, APC, and Axin, with early endosome antigen 1‐ and Rab5‐positive early endosomes in clinical samples of oral dysplasia. Collectively, these data indicate that increased Rab5 activity and endosomal sequestration of the β‐catenin destruction complex leads to stabilization and nuclear accumulation of β‐catenin in oral dysplasia. [ABSTRACT FROM AUTHOR]

BackgroundIn vivo, non-invasive optical coherence tomography (OCT) permits high-resolution imaging of tissue surfaces and subsurfaces, with the potential capability for detection and mapping of epithelial pathologies.PurposeTo evaluate the clinical capability of non-invasive in vivo OCT for diagnosing oral dysplasia and malignancy.Experimental designIn 50 patients with oral lesions, conventional clinical examination was followed by OCT imaging, then standard biopsy and histopathology. Two blinded, pre-standardized investigators separately diagnosed each lesion based on (1) OCT and (2) histopathology.ResultsIntra- and inter-observer agreement between diagnoses based on histopathology and imaging data was excellent, with lambda values between 0.844 and 0.896. Sensitivity and specificity were also very good.ConclusionsThese data demonstrate the excellent capability of in vivo OCT for detecting and diagnosing oral premalignancy and malignancy in human subjects.

(1) Background: Several studies investigating the clinical outcomes of potentially premalignant oral epithelial lesions treated with CO2 lasers have been published over the last decades. (2) Methods: A systematic research review was performed for studies published between 2011 and 2021 in the PubMed, Science Direct, and Google Scholar databases. (3) Results: Initially, the search identified 52 relevant articles. The primary analysis of the titles and abstracts eliminated 22 articles, leaving 30 articles whose full texts were examined. A total of 22 articles met the inclusion criteria. The studies were classified into 3 categories. (4) Conclusions: After evaluating the results of all the studies included in this review, an initial general statement can be made, namely that CO2 lasers are a treatment option worth taking into consideration when approaching oral mucosal lesions. When compared to other types of lasers used in dental practice, the CO2 laser stands out due to its many advantages.

Abstract Background Head and neck cancers include malignancies of the mouth, larynx and oropharynx. Tobacco use and alcohol consumption are associated with increased risks of developing and dying from head and neck cancer. The aim of this review is to examine the effectiveness of smoking and alcohol cessation interventions on disease-related outcomes, quality of life and behavioural change in adults with head and neck cancer and oral dysplasia. Methods The Cochrane library, CINAHL, Embase, MEDLINE, PsycINFO and Web of Science databases will be searched for randomised controlled trials investigating the effects of smoking or alcohol interventions on patients with either head and neck cancer or oral dysplasia. The primary outcomes are disease-free survival and, for participants with oral dysplasia, malignant transformation to cancer. Secondary outcomes are disease recurrence and progression, quality of life and behavioural change. The quality of included studies will be assessed using the ‘Cochrane Collaborations tool for assessing risk of bias’. A qualitative synthesis of the results will be reported, and a meta-analysis of the outcome data conducted, where appropriate. Discussion This systematic review will identify the extent of the current research on smoking and alcohol cessation interventions in patients with head and neck cancer and oral epithelial dysplasia. The findings have the potential to inform which interventions have been successful and how future behavioural change interventions should be conducted within these populations. Systematic review registration PROSPERO CRD42016038237

Oral epithelial dysplasia associated with high-risk HPV infection has received different names since its initial description, such as oral Bowenoid lesions, HPV-associated intraepithelial neoplasia, and oral koilocytic dysplasia. Some features, identified in more or less quantity in some of the descriptions, like apoptotic keratinocytes, karyorrhexis, and mitosoid figures, are intricately connected to viral transcriptional status and, consequently, viral load. Since the variety in terminology has introduced diagnostic confusion within medical and research communities, establishing a uniform and standardized approach to diagnosing HPV-oral epithelial dysplasia is crucial for accurate and early diagnoses and holds significant implications for patient outcomes, particularly in high-risk individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Anaya-Saavedra and Vázquez-Garduño.)

Background: The prognosis of human cancer depends on the deregulations of many molecular patterns. In recent years, a great interest in the intracellular signaling mechanisms related to nitric oxide (NO)-induced carcinogenesis has appeared, as one of the most preeminent prognostic markers for many types of neoplasms. In this study, we identify the levels of iNOS and nitrotyrosine in the sample of normal oral mucosa (NOM), oral leukoplakia (OL), and oral squamous cell carcinoma (OSCC).Methods: Quantitative polymerase chain reactions (qPCRs) were utilized to detect the NOS2 levels in fresh-frozen tissue samples of NOM (n = 6), OL (n = 20), and OSCC (n = 15). Moreover, the immunohistochemical method was used to examine the levels of iNOS and nitrotyrosine in 85 cases of OSCC (39 cases without metastases and 46 with metastases), 42 cases of OL, and 16 cases of NOM.Results: There are rising tendencies in the iNOS mRNA and protein levels during human oral carcinogenesis. Similar findings were obtained in the nitrotyrosine staining. Furthermore, iNOS and nitrotyrosine immunostaining are associated with several clinical-pathological features of OSCC (site, presence of metastasis, staging, recidivism, and survival).Conclusions: The NO-signaling pathway plays a vital role in the development and progression of human oral dysplastic and neoplastic diseases. Nitrotyrosine was a significant marker for the discrimination of OSCC prognosis and survival. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC), which may arise from oral dysplasia, is one of the most prevalent cancers around the world. In recent years, all-trans retinoic acid (ATRA) has shown great potential in cancer treatment. However, the molecular mechanism for the anti-tumor effects of ATRA remains unclear.Materials and Methods: After treated with ATRA, inhibition of cell proliferation of OSCC and oral dysplasia cell lines, CAL27 and DOK, respectively, was analyzed by a Cell Counting Kit-8 (CCK8) assay. The cell cycle arrest, cell apoptosis induction, and PD-L1 expression level were measured by flow cytometry. A small molecular inhibitor was utilized to block STAT3 pathway, and the related proteins expression was measured by Western Blot.Results: The present study demonstrated that ATRA inhibited cell proliferation at 5-75 μmol/L, arrested cell cycle at S and G2-phase, induced apoptosis effect in OSCC, and oral dysplasia cell line, CAL27 and DOK, respectively. ATRA led to inhibition of p-STAT3, p-JAK2, increased the level of p-ERK, and significantly decreased the PD-L1 expression. Moreover, targeting STAT3 signaling increased (P < .001) the level of cleaved caspase-3 and effectively (P < .001) decreased the expression of cyclin A2 and PD-L1. The effect of ATRA on cell growth inhibition, apoptosis induction, and PD-L1 expression decrease was significantly (P < .05) enhanced after the STAT3 signaling blockade.Conclusion: These findings suggested that ATRA-induced anti-tumor effects and downregulated PD-L1 expression via STAT3 signaling inhibition in both OSCC and oral dysplasia. [ABSTRACT FROM AUTHOR]

It is believed that the majority of oral cancers develop from oral potentially malignant lesions (OPML). Though they can be easily detected during screening, risk stratification is difficult. During screening clinicians often find it difficult to distinguish OPMLs from benign lesions, and predicting OPML at risk of malignant transformation is particularly challenging. DNA aneuploidy has been known to be a marker of malignancy in a number of sites including the oral cavity. We performed a systematic review to evaluate the effectiveness of DNA-ICM using brushings in differentiating OPMLs from benign/inflammatory lesions during screening and in predicting malignant transformation. MEDLINE, Pubmed, EMBASE electronic databases were systematically searched using a combination of keywords and subject headings. A total of 11 articles satisfied our inclusion criteria. These studies reported a wide range of sensitivity (16-96.4%) and specificity (90-100%) due to the differences in study design, definitions of high risk or low risk lesions and DNA-ICM protocol used. No long-term longitudinal studies were identified to assess the role of DNA-ICM using brushings in predicting malignant transformation. No studies evaluated the role of DNA-ICM in community screening settings. A number of studies combined DNA-ICM with other techniques like cytology or argyrophilic nucleolar organizer region counts leading to improved test results. In spite of DNA aneuploidy being accepted as a marker of malignancy, there is limited evidence of DNA-ICM using brushings being successful as an adjunct oral cancer screening tool. Longitudinal studies and large community screening studies need to be undertaken to draw stronger conclusion. [ABSTRACT FROM AUTHOR]

Objectives: To map the genomic pathways of patients with oral leukoplakia (OLK) which transformed to cancer (progressive) and those which did not (non-progressive), and to compare their exomic profiles.Materials and Methods: Whole exome sequencing was performed on 42 sequential samples from five progressive and eight non-progressive patients. Association of genomic variant frequencies with progression or lesion severity were analysed by non-parametric tests (Kruskal-Wallis and Mann-Whitney-Wilcoxon) and multivariate sparse partial least squares discriminant analysis (sPLS-DA). Enrichment analysis was used to characterise the effect of mutations upon biological pathways. Confirmatory studies used qPCR and immunohistochemistry.Results: Using sPLS-DA, the variant frequency of a small number of genes could be used to classify the samples based on lesion severity or progressive status. Enrichment analysis showed that DNA damage repair gene related pathways were highly impacted in lesions which progressed to cancer. Multivariate analysis of a set of 148 DNA damage repair genes could be used to classify progressive lesions using mutation frequency. BRCA1, BRCA2 and other double strand break (DSB) repair Fanconi anaemia (FA)/BRCA pathway genes were prominent contributors to this classification.Conclusion: Patients with progressive and non-progressive OLK can be differentiated using the frequency of exomic variants, particularly in DNA damage repair pathway genes. To our knowledge, this is the first report of FA/BRCA (DSB) pathway involvement in malignant transformation of OLK to oral squamous cell carcinoma (OSCC). [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the localization of β-catenin in oral dysplastic cells, the expression of target genes upregulated in oral dysplasia, and the role of Wnt ligands in these events.Materials and Methods: Subcellular localization of total and non-phosphorylated (transcriptionally active) β-catenin was evaluated by immunofluorescence and biochemical fractionation in dysplastic oral keratinocytes (DOK), non-dysplastic oral keratinocytes (OKF6), oral squamous carcinoma cells (CAL27) and primary oral keratinocytes. Tcf/Lef-dependent transcription was measured by luciferase reporter assays. Expression of target genes, survivin and cyclin D1, was evaluated by RT-qPCR and Western blotting. Wnt secretion was inhibited with the inhibitor of porcupine, C59. Wnt3a and β-catenin were evaluated in biopsies by tissue immunofluorescence.Results: Immunofluorescence and fractionation experiments showed augmented nuclear β-catenin (total and transcriptionally active) in DOK, when compared with OKF6 and CAL27 cells. Intriguingly, conditioned medium from DOK promoted nuclear accumulation of β-catenin and Tcf/Lef-dependent transcription in OKF6 and primary oral keratinocytes, suggesting the participation of secreted factors. Treatment of DOK with C59 decreased Wnt3a secretion, nuclear β-catenin and the expression of survivin and cyclin D1 at both mRNA and protein levels. Accordingly, DOK secreted higher Wnt3a levels than OKF6, and inhibition of Wnt3a secretion prevented DOK-induced Tcf/Lef-dependent transcription in OKF6. These observations were confirmed in clinical samples, since tissue immunofluorescence analysis showed simultaneous expression of Wnt3a and nuclear β-catenin in oral dysplasia, but not in healthy mucosa biopsies.Conclusion: These data indicate that secretion of Wnt ligands is critical for β-catenin nuclear localization and expression of target genes in oral dysplasia. [ABSTRACT FROM AUTHOR]

This study was designed to examine the prevalence of Candida albicans alcohol dehydrogenase 1 (CaADH1) gene in oral dysplasia as well as oral squamous cell carcinoma (OSCC) with and without lymph node metastasis (LNM) using reverse transcription polymerase chain reaction (RT-PCR) in order to determine its role in initiation, propagation and metastasis of oral dysplasia and carcinoma. Formalin- fixed parafin-embedded specimens were grouped into four groups: 7 control, 16 oral dysplasia, 16 OSCC without LNM and 15 OSCC with LNM. All specimens were examined by periodic acid Schiff (PAS) stain to detect Candida hyphae, while CaADH1 gene was detected using RT-PCR. Candida hyphae were detected by PAS stain in one specimen of oral dysplasia group, 5 OSCC without LNM and 5 OSCC with LNM. CaADH1 gene was detected in 29 specimens (one case of sever dysplasia, 16 OSCC without LNM and 12 OSCC with LNM), with a highly statistically significant between the groups. CaADH1 gene is associated with OSCC with and without metastasis whereas in oral dysplasia it could not be estimated. Further studies with larger sample size are needed to confirm the role of CaADH1 in oral dysplasia and OSCC. [ABSTRACT FROM AUTHOR]

Highlights • First and comprehensive systematic review of photodynamic therapy in the treatment of oral leukoplakia. • Effectiveness and advantages of photodynamic therapy are indicated after statistical analysis. • Influencing factors of photodynamic therapy in oral leukoplakia are analyzed and recommended parameters are proposed. Abstract Objective The aim of the present study was to systematically review the efficacy of photodynamic therapy (PDT) in the management of oral leukoplakia (OLK). Methods This systematic review aimed to address the following focused question: "Is photodynamic therapy effective in the management of oral leukoplakia?" PubMed/Medline, EMBASE, ISI Web of Knowledge, OVID, CNKI, and WANFANG DATA were searched up to and including June 2018 using different combinations of the following keywords: photodynamic therapy, leukoplakia, oral dysplasia, oral precancers, and oral premalignant lesions. Results Sixteen studies were included in the present study. A total of 352 patients was included in this review, with age ranging from 20 to 79 years. Photosensitizers used were aminolevulinic acid, Photofrin, methylene blue, and chlorine-e6. Laser wavelength, duration of irradiation, and power density were 420–660 nm, 60–1000 s, and 100–150 mW/cm2, respectively. On the whole, the rates of complete response and partial response were 32.9% and 43.2%, and the sum was 76.1%. The follow-up period ranged from 1 month to 119 months. The recurrence rate of OLK was 0–60%. Conclusion PDT appears to be a useful therapeutic strategy in the management of oral leukoplakia as a non-surgical treatment. Further RCTs with long follow-up period, standardized PDT parameters, and comparing efficacy of PDT with various other therapies are needed to acquire definite conclusions. [ABSTRACT FROM AUTHOR]

A series of studies are dedicated to research the clinical outcomes of oral leukoplakia (OLK) treated with carbon dioxide laser (CO2 laser); however, the results vary from studies especially related to recurrence and malignant transformation. Hence, we performed this meta-analysis to precisely evaluate the malignant transformation of OLK dealt with CO2 laser and investigate the association between its malignant transformation and kinds of related risk factors, such as gender, clinical classification, long duration of leukoplakia, and degree of epithelial dysplasia and lesion regions. We performed a systematic search of the Cochrane Library, EMBASE, Pubmed, Web of Science, and SCOPUS. Single-arm rate of the overall risk of malignant transformation in OLK treated with CO2 laser was calculated using the Der-Simonian Liard method. We applied subgroup analysis to compare the risk of malignant transformation according to the degree of epithelial dysplasia, clinical type, and region of OLK. Moreover, a pooled odds ratio (OR) is calculated, along with its 95% confidence interval (CI), to compare the risk of malignant transformation according to patients' gender, tobacco, and alcohol consumption. We used the meta package of R software for quantitative data synthesis and analysis. The rate of malignant transformation of OLK treated with carbon dioxide laser ranged from 0 to 15.38% in included studies. The overall rate of malignant transformation of OLK treated with CO2 laser is 4.50% under the random effect model [95% CI 0.0305-0.0659]. A systematic review of observational studies of OLK reported that the estimated overall (mean) malignant transformation rate was 3.5%, with a wide range between 0.13 and 34.0%. Interestingly, our result revealed that it was the male, homogeneous type, no tobacco consumption, and without alcohol-use who had a higher tendency of malignancy after laser surgery. However, this result lack statistically significant data. Generally speaking, whether oral leukoplakia patients underwent laser surgical treatment or not, it may have little effect on malignant transformation. In addition, we strongly advise that it had better not to perform CO2 laser intervention on OLK patients with the following clinical characteristics: homogeneous type, male, no tobacco consumption, and without alcohol-use. Evidence is still lacking in terms of relationship between malignant transformation and risk factors among OLK patients managed with CO2 laser. Thus, these associations should be further investigated. [ABSTRACT FROM AUTHOR]