Transformation Of Oral Leukoplakia Research Articles

Induction of Peroxiredoxin 1 by Hypoxia Promotes Cellular Autophagy and Cell Proliferation in Oral Leukoplakia via HIF-1α/BNIP3 Pathway.

Hypoxia is a key trigger in the transformation of oral leukoplakia into oral cancer. However, it is still too early to determine the role of hypoxia in the development of oral leukoplakia. Prx1, an antioxidant protein, upregulated by hypoxia, regulates cellular autophagy in leukoplakia. This study aimed to understand the mechanisms by which hypoxia induces Prx1 expression during autophagy in oral leukoplakia. We used an experimental model of tongue epithelial hyperplasia induced by 4-nitroquinoline-1-oxide (4NQO) and dysplastic oral keratinocytes. Prx1 knockdown DOK cells, Leuk-1 cells and control cells were harvested, and cell proliferation was assayed using the Cell Counting Kit-8. Several hypoxia and autophagy-related proteins were examined using quantitative real-time polymerase chain reaction, immunohistochemistry, immunofluorescence, and western blotting in cells and mouse tongue tissues. In addition, the ultrastructure of the cells was observed by transmission electron microscopy. Hypoxia induces cell proliferation, autophagic vesicles and the expression of Prx1, BNIP3, LC3II/I and Beclin-1 in DOK and Leuk-1 cells. However, these effects were all attenuated by Prx1 knockdown. Histologically, 4NQO induced epithelial hyperplasia in the tongue mucosa. The expression of proliferation marker PCNA, autophagy-related proteins LC3B and Beclin-1, as well as HIF-1α/BNIP3 was significantly lower in the tongue tissues of Prx1flox/flox:Cre+ mice compared with Prx1flox/flox mice. In Prx1flox/flox:Cre+ mice, an increased expression of HIF-1α/BNIP3, LC3B and Beclin-1 was detected in epithelial hyperplasia tongue tissues compared to normal tissues. The current study suggests that Prx1 may promotes cell proliferation and autophagy in oral leukoplakia cells via the HIF-1α/BNIP3 pathway.

Development of a Pathomics-Based Model for the Prediction of Malignant Transformation in Oral Leukoplakia

Accurate prognostic stratification of oral leukoplakia (OLK) with risk of malignant transformation into oral squamous cell carcinoma is crucial. We developed an objective and powerful pathomics-based model for the prediction of malignant transformation in OLK using hematoxylin and eosin (H&E)-stained images. In total, 759 H&E-stained images from multicenter cohorts were included. A training set (n = 489), validation set (n = 196), and testing set (n = 74) were used for model development. Four deep learning methods were used to train and validate the model constructed using H&E-stained images. Pathomics features generated through deep learning combined with machine learning algorithms were used to develop a pathomics-based model. Immunohistochemical staining of Ki67, p53, and PD-L1 was used to interpret the black box of the model. Pathomics-based models predicted the malignant transformation of OLK (validation set area under curve [AUC], 0.899; testing set AUC, 0.813) and significantly identified high-risk and low-risk populations. The prediction performance of malignant transformation from dysplasia grading (validation set AUC, 0.743) was lower than that of the pathomics-based model. The expressions of Ki67, p53, and PD-L1 were correlated with various pathomics features. The pathomics-based model accurately predicted the malignant transformation of OLK and may be useful for the objective and rapid assessment of the prognosis of patients with OLK.

A Comparison of Podoplanin Expression in Oral Leukoplakia and Oral Squamous Cell Carcinoma: An Immunohistochemical Study.

Oral squamous cell carcinoma (OSCC) accounts for about 90% to 95% of all malignancies of the oral cavity.The majority of OSCCs are preceded by oral potentially malignant disorders (OPMDs). Podoplanin (PDPN) is a mucin-like small transmembrane glycoprotein. Alterations in PDPN immunoexpression have been reported in OPMDs and OSCCs. The objectives of this study were to evaluate the role of PDPN immunoexpression in oral leukoplakia (OL) and different histological grades of OSCC and to assess the role of PDPN as a potential biomarker for predicting the risk of malignant transformation. Immunohistochemical analysis for PDPN was performed in 45 histologically confirmed cases of formalin-fixed, paraffin-embedded specimens of different grades of OSCCs and 15 cases of OLs with 15 cases of the normal oral mucosa (NOM) as controls. The expression and distribution of this marker were analyzed in these lesions. The immunoexpression of PDPN showed a significant increase in the expression of the percentage of positive cells, staining intensity, location of staining in the epithelium, tumor islands, and within the cells, as well as the mean lymphatic micro vessel density between NOMs, OLs, and different grades of OSCCs. Upregulation of PDPN can be related to the malignant transformation of OLs and biological aggressiveness of OSCCs. The enhanced immunoexpression of PDPN signifies that this immunomarker can have a role in tumor cell differentiation and the neoplastic progression of OSCCs. Increased density of lymphatic vessels suggested an important role of lymphangiogenesis in tumor progression and also as a prognostic factor for lymph nodal metastasis.

EZH2 Expression Correlates With T-Cell Infiltration in Oral Leukoplakia and Predicts Cancer Transformation.

The EZH2 complex is involved in cellular proliferation and modulates the immune response in cancer. Less is known about the importance of EZH2 in precancerous lesions such as oral leukoplakia (OL). The aim of the study was to explore the association between EZH2 expression, immune activation, and cancer transformation in OL. Analyses were retrospectively performed on nine OL cases that had undergone transformation to oral squamous cell carcinoma (OSCC; OL-ca) and nine that had not undergone transformation (OL-non). EZH2-expressing cells, CD3+ and CD8+ T cells, and CD1a+ Langerhans cells were visualized with immunohistofluorescence and counted. A moderate positive correlation between CD3- and EZH2-expressing and CD8- and EZH2-expressing cells in the epithelium was found (r=0.57, p=0.01; r=0.59, p=0.01). The number of EZH2-expressing cells in the epithelium of OL-ca was significantly higher compared to OL-non (p=0.0002). Cancer-free survival rates differed significantly between patients with EZH2high compared to EZH2low expression (p=0.001). EZH2high expression in OL epithelium was associated with a 13-fold higher risk for developing OSCC (HR=12.8). EZH2 expression in oral epithelium predicts OSCC transformation of OL and correlates with the level of T-cell infiltration.

ASSOCIATION OF FOXP3 WITH CLINICAL AND HISTOPATHOLOGICAL ASPECTS OF MALIGNANT TRANSFORMATION OF THE ORAL LEUKOPLAKIA

<h3>Objectives</h3> Oral leukoplakia (OL) is the most common potentially malignant lesion of the oral mucosa. Several factors are associated with increased risk of malignant transformation. The aim was to evaluate the expression of Foxp3+ cells in OL samples and their relationship with clinical and pathologic factors associated with the malignant transformation of OL. <h3>Study Design</h3> Twenty-five samples from patients diagnosed with OL were selected. Clinical data such as age, sex, and location were obtained from archives. The histopathologic degree was obtained, and immunohistochemistry was performed using anti-Foxp3. Ten fields from each slide were obtained and Foxp3+ cells were counted. The mean density was compared between groups and statistical analysis was applied. Normal oral mucosa (NOM) samples were used as control. <h3>Results</h3> Foxp3+ cells were increased in samples of smokers when compared to NOM samples (<i>P</i> < .05). Foxp3+ cells were increased in females (<i>P</i> < .05) and in OL samples with severe epithelial dysplasia when compared with samples of moderate epithelial dysplasia (<i>P</i> < .05). <h3>Conclusions</h3> The study suggests that the number of cells associated with modulation of immune response may be affected by clinical and histopathologic characteristics associated with malignant transformation of OL.

Oral leukoplakia classification and staging system with incorporation of differentiated dysplasia.

A classification and staging system for oral leukoplakia (OL) was introduced to promote uniform reporting. In this system, size and the histopathologic diagnosis are assessed and combined in a staging system. The various stages could be predictive for malignant transformation of OL. Differentiated dysplasia (DD) was recently recognized as an important architectural pattern of dysplasia and is highly associated with malignant transformation (MT) of OL. In the present study, DD was incorporated in the OL-system. The aim of the present study was to test the adapted system on a cohort of patients with OL. The group consisted of 140 patients. The size, absence or presence and degree of classic dysplasia (CD) and DD were incorporated into the OL-system. In 31/140 patients, MT occurred. Size was not statistically significant with MT (p=0.422). The presence of dysplasia was predictive for MT (p=0.003), whereby severe CD and DD were highly statistically significant for MT (p=0.008). Stage IV was statistically significant for MT (p=0.011). The present study emphasizes the value of the slightly modified OL-system with incorporation of DD in uniform reporting of OL and the value in predicting MT.

Podoplanin Expression Independently and Jointly with Oral Epithelial Dysplasia Grade Acts as a Potential Biomarker of Malignant Transformation in Oral Leukoplakia.

Our aim was to evaluate the expression of biomarkers, CD44v6, CD147, EGFR, p53, p63, p73, p16, and podoplanin in oral leukoplakias (OL) and to assess their potential for prediction of malignant transformation (MT). We analyzed the expression of CD44v6, CD147, EGFR, p53, p63, p73, p16, and podoplanin by immunohistochemistry in 52 OL, comprised of 41 low-grade (LG) dysplasia and 11 high-grade (HG) cases. Twelve healthy normal tissues (NT) were also included. Univariate and multivariate analysis were performed to evaluate any association with MT. Variable expression among the studied markers was observed, with a significant increase of high expression from NT to LG and HG cases in CD44v6 (p = 0.002), P53 (p = 0.002), P73 (p = 0.043), and podoplanin (p < 0.001). In multivariate analysis, cases with high podoplanin score showed a significant increased risk of MT (HR of 10.148 (95% CI of 1.503–68.532; p = 0.017). Furthermore, podoplanin combined with binary dysplasia grade obtained a HR of 10.238 (95% CI of 2.06–50.889; p = 0.004). To conclude, CD44v6, p53, p73, and podoplanin showed an increasing expression along the natural history of oral carcinogenesis. Podoplanin expression independently or combined with dysplasia grade could be useful predictive markers of MT in OL.

Can tissue biomarkers be used to determine the prognosis of oral leukoplakia lesions with regards to malignant transformation?

Design Systematic review looking at published studies which aimed to identify human tissue biomarkers which could predict malignant transformation of oral leukoplakia (OL) lesions.Case/control selection Articles were identified from PubMed, EBSCO and Cochrane library databases using combinations of keywords. Randomised clinical trials, case-control studies and prospective and retrospective cohort studies were included. All studies had to include follow-up data. There were no restrictions regarding gender, age groups, geographic origin, or year of publication. The selection process involved two of the researchers independently analysing titles and abstracts to identify articles for full-text reading. The same authors then read the articles identified for full-text reading, applying the eligibility criteria. If there was a disagreement with regards to the selection, a discussion was had until a consensus was reached.Data analysis Qualitative data was presented as reported from the primary studies. Quantitative analysis was not carried out due to the high heterogeneity across the studies.Results Forty-six studies were included within the systematic review. These studies identified a total of 3,783 patients with OL, of which 1,047 went on to develop oral cancer, giving an average malignant transformation incidence of 27.6%. Forty-nine different tissue biomarkers were evaluated among the included studies, with the p53 and podoplanin proteins and loss of heterozygosity the most frequently discussed.Conclusions Of the biomarkers studied, podoplanin and chromosomal loci abnormalities (such as loss of heterozygosity) would appear the most promising in being able to predict malignant transformation of OL lesions; however, further research is required.

The expression and clinical significance of Bmi-1 gene in oral leukoplakia with different prognosis

Objective: To detect the expression of Bmi-1 in oral leukoplakia (OL) cells and tissues, and analyze its role and clinical significance in the malignant transformation of OL. Methods: Immunohistochemistry was used to evaluate Bmi-1 expression in OL samples from 109 patients (51 males, 58 females, age range: 18-74 years) who were treated in the Department of Stomatology, the Affiliated Wuxi People's Hospital of Nanjing Medical University and the Center of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, between 1996 and 2018. The correlation between Bmi-1 expression level and clinicopathological parameters and prognosis in patients with OL was analyzed. The mRNA and protein expression levels of Bmi-1 gene in normal oral mucosal epithelial cells, OL cells, oral squamous cell carcinoma (OSCC) cells, OL tissues and paired adjacent normal tissues were detected by real-time PCR and Western blotting. The effects of Bmi-1 on the proliferation, colony formation and apoptosis were investigated by silencing expression of Bmi-1 in OL cell lines Leuk-1. Results: The protein level of Bmi-1 in OL tissue with severe and mild dysplasia was statistically different (6 819±994 vs 4 713±372, P=0.017). The OSCC-free survival rate of OL patients with high Bmi-1 expression was 65.5% (36/55), which was lower than that of OL patients with low Bmi-1 expression (88.9%, 48/54, P=0.003). Multivariate Cox proportional analysis indicated that Bmi-1 expression was the independent predictor for malignant transformation of OL (HR=2.522, 95%CI: 1.128-5.640, P=0.024). The mRNA level of Bmi-1 in OL specimens was 0.455±0.120, which was higher than that in paired adjacent normal tissues (0.063±0.009, P=0.014). The Bmi-1 mRNA level in malignant transformed OL specimens was (1.405±0.397), which was higher than that in untransformed OL specimens (0.145±0.017, P<0.001). After transfection of Bmi-1-shNC and Bmi-1-shRNA2 adenovirus into OL cell line Leuk-1, there were significant differences in the number of clone formation (824±40 vs 414±38, P=0.002) and apoptosis rate (17.7%±2.3% vs 36.0%±2.0%, P=0.004). Conclusions: The up-regulation of Bmi-1 expression promotes the malignant biological behavior of OL cells. Bmi-1 expression can be used as a predictor for malignant transformation of OL.

Hsa_circ_0060927 Is a Novel Tumor Biomarker by Sponging miR-195-5p in the Malignant Transformation of OLK to OSCC.

ObjectiveTo investigate the clinical significance of differentially expressed circRNAs and candidate circRNAs in the transformation of oral leukoplakia (OLK) to oral squamous cell carcinoma (OSCC).MethodsWe performed high-throughput circRNA sequencing in six cases of normal oral mucosal (NOM) tissues, six cases of OLK tissues, and six cases of OSCC tissues. Ten circRNAs with significant differential expression were verified by qRT-PCR. Enzyme tolerance assay and Sanger sequencing were performed on the screened target circRNA hsa_circ_0060927, and a qRT-PCR assay of hsa_circ_0060927 was performed in three tissues (24 cases in each group); this was followed by an ROC analysis. The ceRNA network was predicted using TargetScan and miRanda. MiR-195-5p and TRIM14 were selected as the downstream research objects of hsa_circ_0060927. The sponge mechanism of hsa_circ_0060927 was detected by AGO2 RIP. The interaction between hsa_circ_0060927 and miR-195-5p was verified by RNA pull-down assay and dual luciferase reporter gene assay. The expressions of hsa_circ_0060927, miR-195-5p, and TRIM14 were verified by normal oral epithelial primary cells and cell lines of LEUK1, SCC9, and SCC25. The hsa_circ_0060927 overexpressed plasmid and miR-195-5p mimics were constructed to transfection LEUK1 to detect the changes in cell proliferation, apoptosis, and migration.ResultsThe results of qRT-PCR validation were consistent with the sequencing results. Hsa_circ_0060927 is a true circRNA with trans-splicing sites. The expression of hsa_circ_0060927 increased in NOM, OLK, and OSCC. Overexpression of hsa_circ_0060927 enhanced the ability of cell proliferation and migration, and decreased cell apoptosis capacity. The prediction of ceRNA network suggested that hsa_circ_0060927 could regulate the target gene TRIM14 through sponging miR-195-5p. AGO2 RIP indicated that hsa_circ_0060927 had a sponge mechanism. RNA pull-down and dual luciferase reporter gene assay suggested that hsa_circ_0060927 interacted with miR-195-5p. Hsa_circ_0060927 was positively correlated with the expression of TRIM14, and could relieve the inhibition of miR-195-5p on TRIM14 to regulate cell proliferation, apoptosis, and migration of LEUK1 cells.ConclusionHsa_circ_0060927 acted as a potential key ceRNA to sponge downstream miR-195-5p and promote OLK carcinogenesis by upregulating TRIM14. Hsa_circ_0060927 was expected to be a molecular marker for the prevention and treatment of OLK carcinogenesis through the hsa_circ_0060927/miR-195-5p/TRIM14 axis.

Deep Learning Predicts the Malignant-Transformation-Free Survival of Oral Potentially Malignant Disorders.

Simple SummaryMouth cancer is the most common malignancy in the head-and-neck region. Usually, these tumors develop from white lesions in the mouth that appear long before cancer diagnosis. However, platforms that can estimate the time-factored risk of cancer occurring from these diseases and guide treatment and monitoring approaches are elusive. To this end, our study presents time-to-event models that are based on machine learning for prediction of the risk of malignancy from oral white lesions following pathological diagnosis as a function of time. These models displayed very satisfactory discrimination and calibration after multiple tests. To facilitate their preliminary use in clinical practice and further validation, we created a website supporting the use of these models to aid decision making.Machine-intelligence platforms for the prediction of the probability of malignant transformation of oral potentially malignant disorders are required as adjunctive decision-making platforms in contemporary clinical practice. This study utilized time-to-event learning models to predict malignant transformation in oral leukoplakia and oral lichenoid lesions. A total of 1098 patients with oral white lesions from two institutions were included in this study. In all, 26 features available from electronic health records were used to train four learning algorithms—Cox-Time, DeepHit, DeepSurv, random survival forest (RSF)—and one standard statistical method—Cox proportional hazards model. Discriminatory performance, calibration of survival estimates, and model stability were assessed using a concordance index (c-index), integrated Brier score (IBS), and standard deviation of the averaged c-index and IBS following training cross-validation. This study found that DeepSurv (c-index: 0.95, IBS: 0.04) and RSF (c-index: 0.91, IBS: 0.03) were the two outperforming models based on discrimination and calibration following internal validation. However, DeepSurv was more stable than RSF upon cross-validation. External validation confirmed the utility of DeepSurv for discrimination (c-index—0.82 vs. 0.73) and RSF for individual survival estimates (0.18 vs. 0.03). We deployed the DeepSurv model to encourage incipient application in clinical practice. Overall, time-to-event models are successful in predicting the malignant transformation of oral leukoplakia and oral lichenoid lesions.

Malignant transformation of oral leukoplakia: Systematic review and meta-analysis of the last 5 years.

Oral leukoplakia (OL) is the most frequently encountered oral potentially malignant disorder. The aims of this systematic review are to estimate the overall malignant transformation of OL and to assess the risk factors associated with malignant transformation of OL published in the last 5years (2015-2020). We performed a bibliographic search in PubMed, Scopus, Web of Science, Embase, and Cochrane databases with keywords "oral leukoplakia", "oral cancer", "oral carcinoma" and "oral squamous cell carcinoma". Meta-analysis was conducted using a random-effects model. Twenty-four studies were selected, that reported a total of 16,604 patients. Malignant transformation proportion varied between 1.1% and 40.8%. Female gender, non-homogeneous clinical type, and presence of epithelial dysplasia were significantly related to MT. Other risk factors previously suggested did not show significant results. The pooled proportion of malignant transformation MT was 9.8% (95% CI: 7.9-11.7). It is necessary to continue to conduct well-designed prospective clinicopathological studies on OL, using a uniform definition for OL to reduce the risk of bias for evaluating various factors associated with the MT.

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia.

Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation. Material and Methods: PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined. Results: Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (pE = 0.001; pS = 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP (p = 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP (p = 0.007), but not in its subepithelial layers (p = 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years. Conclusion: Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions.

Tissue biomarkers for predicting the risk of oral cancer in patients diagnosed with oral leukoplakia: A systematic review.

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. 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. 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." 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.

An anatomical perspective on clinicopathological characteristics and treatment outcomes of dorsal and ventrolateral tongue leukoplakia after carbon dioxide laser surgery

BackgroundThe tongue has been identified as a high-risk site for malignant transformation of oral leukoplakia. The purpose of this study was to investigate the clinicopathological characteristics and treatment outcomes of the dorsal and ventrolateral tongue leukoplakia.MethodsDemographic data and pathological results of patients who underwent carbon dioxide laser surgery for tongue leukoplakia from 2002 to 2019 were retrospectively reviewed and analyzed statistically.ResultsOf the 111 patients enrolled, 80 were males and 31 females, with a mean age of 51.86 ± 11.84 years. The follow-up time was 3.74 ± 4.19 years. Fifteen patients had a postoperative recurrence (13.51%). Four (3.6%) patients developed malignant transformation. Annual transformation rate was 1.08%. There were no differences in the time to develop carcinoma (3.19 ± 1.94 vs. 3.51 ± 2.12 years, P = 0.83), overall cumulative malignant transformation rates (7.41% vs. 2.25%, P = 0.12), and annual transformation rates (2.32% vs. 0.64%, P = 0.099). The prevalence of the ventrolateral tongue leukoplakia was higher than that of the dorsal tongue leukoplakia (P < 0.001). The results of multivariate logistic regression analysis showed that the degree of pathology was the only independent prognostic factor related to postoperative malignant transformation (P = 0.045).ConclusionsDorsal tongue leukoplakia is not as frequently encountered clinically as ventrolateral tongue leukoplakia. The response of the dorsal tongue and ventrolateral tongue leukoplakia to laser therapy of are comparable in postoperative recurrence and postoperative malignant transformation. Clinicians should take a more aggressive attitude toward oral tongue leukoplakia with higher grade of dysplasia.

Laser excision of oral leukoplakia: Does it affect recurrence and malignant transformation? A systematic review and meta-analysis.

Oral leukoplakia (OL) is a white lesion with high potential of recurrence and malignant transformation. The variable clinical and histopathological features of OL may potentially impact both treatment and prognosis. Current literature shows that post treatment rates of recurrence and malignant transformation vary widely. The use of surgical lasers have been proposed with the objective of improving outcomes. We performed a systematic review and a comprehensive meta-analysis dedicated to pooling the rates of recurrence and malignant transformation of OL lesions treated using the main types of surgical lasers available. Scopus, MEDLINE/PubMed, and Embase were searched electronically. A total of 36 articles met the inclusion criteria. Selected studies included OL lesions that were treated by evaporation or excision using Nd:YAG laser, Er:YAG laser, CO2 laser, KTP laser, or diode laser. The results of this systematic review and meta-analysis suggest that surgical laser excision of OL may decrease recurrence rates but have no effect on the malignant transformation of OL when compared with conventional treatments.

World Workshop on Oral Medicine VII: Prognostic biomarkers in oral leukoplakia and proliferative verrucous leukoplakia-A systematic review of retrospective studies.

To systematically review retrospective studies examining prognostic potentials of candidate biomarkers to stratify malignant progression of oral leukoplakia (OL) and proliferative verrucous leukoplakia (PVL). A systematic literature search of PubMed, EMBASE, Evidence-Based Medicine and Web of Science databases targeted literature published through 29 March 2018. Inter-rater agreement was ascertained during title, abstract and full-text reviews. Eligibility evaluation and data abstraction from eligible studies were guided by predefined PICO questions and bias assessment by the Quality in Prognosis Studies tool. Reporting followed Preferred Reporting Items for Systematic Review and Meta-Analysis criteria. Biomarkers were stratified based on cancer hallmarks. Eligible studies (n=54/3,415) evaluated 109 unique biomarkers in tissue specimens from 2,762 cases (2,713 OL, 49 PVL). No biomarker achieved benchmarks for clinical application to detect malignant transformation. Inter-rater reliability was high, but 65% of included studies had high "Study Confounding" bias risk. There was no evidence to support translation of candidate biomarkers predictive of malignant transformation of OL and PVL. Systematically designed, large, optimally controlled, collaborative, prospective and longitudinal studies with a priori-specified methods to identify, recruit, prospectively follow and test for malignant transformation are needed to enhance feasibility of prognostic biomarkers predicting malignant OL or PVL transformation.

Malignant transformation of oral leukoplakia is associated with macrophage polarization

BackgroundMost oral squamous cell carcinomas (OSCC) occur on the basis of oral leukoplakias (OLP). The histologic degree of dysplasia is insufficient for the prediction of OLP malignant transformation. Immunologic parameters are gaining importance for prognostic assessment and therapy of cancer. M2 polarized macrophages were shown to be associated with OSCC progression and inferior prognosis. The current study aims to answer the question if OLP with malignant transformation into OSCC within 5 years differ from OLP without transformation regarding macrophage infiltration and polarization.Methods201 specimens (50 transforming OLP, 53 non-transforming OLP, 49 corresponding OSCC and 49 healthy oral mucosa controls) were processed for immunohistochemistry. Samples were stained for CD68, CD163 and CD11c expression, completely digitalized and computer-assisted cell counting was performed. Epithelial and subepithelial compartments were differentially assessed. Groups were statistically compared using the Mann–Whitney U-test. A cut-off point for the discrimination of transforming and non-transforming OLP was determined and the association between macrophage infiltration and malignant transformation was calculated using the Chi-square test (χ2 test).ResultsMacrophage infiltration and M2 polarization in OLP with malignant transformation within 5 years was significantly increased compared to OLP without malignant transformation (p < 0.05). OSCC samples showed the highest macrophage infiltration and strongest M2 polarization (p < 0.05). Additionally, transforming OLP revealed a significant shift of macrophage infiltration towards the epithelial compartment (p < 0.05). χ2 test revealed a significant association of increased macrophage infiltration with malignant transformation (p < 0.05).ConclusionImmunological changes precede malignant transformation of OLP. Increased macrophage infiltration and M2 polarization was associated with the development of oral cancer in OLP. Macrophage infiltration could serve as predictive marker for malignant transformation.

Oral leukoplakia and its malignant transformation as a diagnostic tool in oral squamous cell carcinoma: A retrospective clinicopathological study

Context: Oral leukoplakia is considered as potentially malignant disease and oral squamous cell carcinoma is one of the most common cancers in various countries. Aims: The aim of this study is to assess the rate of malignant transformation of oral leukoplakia in the diagnosis of oral squamous cell carcinoma. Settings and Design: A total of 165 patients were included in the study in 2-month duration. Subjects and Methods: Clinically and histopathologically confirmed cases of oral leukoplakia and other premalignant disorders were retrospectively studied. Statistical Analysis Used: Descriptive statistics included calculation of percentages. Data distribution was assessed for normality using Shapiro–Wilk test. Categorical data were compared using Chi-square test. Results: Among 165 cases, 55.46% of males were affected as compared to females and mostly patients of both sexes were of 40–50 years of age. A total of 140 oral leukoplakia cases were present with 59.28% of males and 40.71% of females, whereas only 25 other premalignant cases were reported with 44% of males and 56% of females. 69.28% and 52% of oral leukoplakia and other premalignant cases were involved in buccal mucosa. Histopathological analysis stated that out of 140 oral leukoplakia cases, 39.28% were present with malignant transformation and P value was 0.0007. Conclusions: Malignant changes of oral leukoplakia play an important role in the diagnosis of oral squamous cell carcinoma and males are more at risk to develop malignancy; therefore, close observation, early diagnosis, appropriate treatment plan, and prognosis are required to prevent malignant transformation.

An Easy Management of Gingival Leukoplakia Using Cotton-Swab Nitrogen: A Case Report

Oral leukoplakia (OL) is certainly the most relevant lesion that affects the oral mucosa, since it has an intrinsic potential for malignant transformation, specifically to squamous cell carcinoma (OSCC); and, besides, constitutes an important issue on clinical assessment. Thus far, no treatment (or management) can prevent the risk of malignant transformation of OL.