Malignant Transformation Of Oral Epithelial Dysplasia Research Articles

Artificial Intelligence Applications in Oral Cancer and Oral Dysplasia.

Oral squamous cell carcinoma (OSCC) is a highly unpredictable disease with devastating mortality rates that have not changed over the past decades, in the face of advancements in treatments and biomarkers, which have improved survival for other cancers. Delays in diagnosis are frequent, leading to more disfiguring treatments and poor outcomes for patients. The clinical challenge lies in identifying those patients at the highest risk of developing OSCC. Oral epithelial dysplasia (OED) is a precursor of OSCC with highly variable behavior across patients. There is no reliable clinical, pathological, histological, or molecular biomarker to determine individual risk in OED patients. Similarly, there are no robust biomarkers to predict treatment outcomes or mortality in OSCC patients. This review aims to highlight advancements in artificial intelligence (AI)-based methods to develop predictive biomarkers of OED transformation to OSCC or predictive biomarkers of OSCC mortality and treatment response. Biomarkers such as S100A7 demonstrate promising appraisal for the risk of malignant transformation of OED. Machine learning-enhanced multiplex immunohistochemistry workflows examine immune cell patterns and organization within the tumor immune microenvironment to generate outcome predictions in immunotherapy. Deep learning (DL) is an AI-based method using an extended neural network or related architecture with multiple "hidden" layers of simulated neurons to combine simple visual features into complex patterns. DL-based digital pathology is currently being developed to assess OED and OSCC outcomes. The integration of machine learning in epigenomics aims to examine the epigenetic modification of diseases and improve our ability to detect, classify, and predict outcomes associated with epigenetic marks. Collectively, these tools showcase promising advancements in discovery and technology, which may provide a potential solution to addressing the current limitations in predicting OED transformation and OSCC behavior, both of which are clinical challenges that must be addressed in order to improve OSCC survival.

A digital score of peri-epithelial lymphocytic activity predicts malignant transformation in oral epithelial dysplasia.

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.

A study of RNA m6A demethylases in oral epithelial dysplasia and oral squamous cell carcinoma.

N6-Methyladenosine (m6A) modification is involved in the tumorigenesis of various cancers. However, the roles of RNA m6A demethylases, fat mass and obesity-associated protein (FTO), and AlkB homolog 5 (ALKBH5) in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) remain unclear. This study focuses on FTO and ALKBH5 expression by using immunohistochemistry. Twenty specimens each of OED, OSCC, and normal oral mucosa (NOM) were included. The expression pattern, the number of positive cells, the cell-staining intensity, and the histochemical scoring (H-score) were examined and analyzed. In all the OED and OSCC specimens, FTO and ALKBH5 were mainly expressed with moderate to strong staining intensity in the nuclei of the abnormal epithelial cells, respectively. Regarding the NOM, both RNA demethylases showed mild cell staining intensity and was present in 50-60% of the specimens. Interestingly, the percentage of cell positivity, the cell-staining intensity, and the H-score of the FTO and ALKBH5 in NOM, OED, and OSCC were increased, respectively (p<0.001). There was also a positive correlation between the FTO and ALKBH5 expressions in OSCC (r=0.62, p=0.003), but not in the NOM and OED. These results suggest a possible prognostic role of FTO and ALKBH5 expression in the malignant transformation of OED and tumor progression. Further studies are needed to elucidate the mechanisms underlying the roles of FTO and ALKBH5 in carcinogenesis.

Histopathological findings of oral epithelial dysplasias and their relation to malignant transformation

Objectives: Oral squamous cell carcinomas (OSCCs) are often diagnosed late. This study aimed to determine how frequently oral epithelial dysplasia (OED) transforms to OSCC and to identify histological features that could influence the rate of malignant transformation.Materials and methods: The study was a retrospective analysis of OED over 29 years at the Institute of Dentistry, University of Turku, Finland. OEDs with co-existing carcinomas were excluded from the data (5.8%). OED patients who developed carcinoma were identified from the Finnish Cancer Registry database.Results: Altogether 681 OED patients had a mean age of 59.0 years, and the male:female ratio was 0.67. Of all OED samples, 21.8% were on the tongue, followed by lining mucosa (21.3%), lip (5.3%), and masticatory mucosa (4.85%). In addition, 46.7% had no location cited. The prevalence of mild dysplasia was 62.4%, moderate dysplasia 29.1%, and severe dysplasia 3.2%. Of the patients, 94.7% had an additional histological diagnosis alongside OED. Candidiasis, lichenoid inflammation, and ulcer were found in 18.2%, 0.0%, and 22.7% of severe dysplasias, in 12.1%, 12.2%, and 22.7% of moderate dysplasias, and in 6.6%, 12.2%, and 15.8% of mild dysplasias, respectively. An additional histopathological diagnosis did not increase the risk for OED to transform to OSCC. In a mean time of 5.2 (range 0.7-29.0) years, 7.5% of OED patients developed OSCC.Conclusions: Location on the tongue and the more severe OED grades increased the risk of malignant transformation of OED. These patients may benefit from an intensified follow-up schedule to ensure early diagnosis of OSCC.

Immunohistochemical expression of putative cancer stem cell markers aldehyde dehydrogenase 1, SOX2, CD44 and OCT4 in different grades of oral epithelial dysplasia.

The hypothesized existence of cancer stem cells (CSC) and its markers aldehyde dehydrogenase 1 (ALDH1), CD44, SOX2 and OCT4 in oral dysplastic tissues provides the potential for a more reliable assessment of malignant transformation of oral epithelial dysplasia (OED). Thus, the present study is intended to evaluate the immunohistochemical expression of four different CSC markers ALDH1, CD44, SOX2 and OCT4 in different grades of OED and to investigate the co-expression of these putative stem cell markers in OED. A total of 35 samples of varying grades of OED which included 7 mild, 11 moderate and 17 severe dysplasia samples and 10 samples of normal oral mucosa without dysplasia were used. Four sections each from all 45 samples were stained with ALDH1, CD44, SOX2 and OCT4, respectively, by immunohistochemistry. The acquired data were analyzed and evaluated using the Chi-square test and unpaired t-test and the P < 0.05 was taken significant. ALDH1 and SOX2 expression percentages showed statistically significant differences among study groups (P < 0.05). Statistical comparison of percentage expression of CD44 and OCT4 between OED and normal was nonsignificant (P > 0.05). Co-expression of all four markers was found in 15 cases of OED with none of the normal cases showing co-expression. The expression of CSC markers in OED and normal mucosa differs significantly with co-expression of all four markers located only in dysplastic tissues. Until now, no single protein marker has been able to unequivocally identify the CSCs. Thus, a panel of putative CSC markers will help in identifying the patients with high risk for malignant transformation in OED.

Prediction of malignant transformation in oral epithelial dysplasia using infrared absorbance spectra.

Oral epithelial dysplasia (OED) is a histopathologically-defined, potentially premalignant condition of the oral cavity. The rate of transformation to frank carcinoma is relatively low (12% within 2 years) and prediction based on histopathological grade is unreliable, leading to both over- and under-treatment. Alternative approaches include infrared (IR) spectroscopy, which is able to classify cancerous and non-cancerous tissue in a number of cancers, including oral. The aim of this study was to explore the capability of FTIR (Fourier-transform IR) microscopy and machine learning as a means of predicting malignant transformation of OED. Supervised, retrospective analysis of longitudinally-collected OED biopsy samples from 17 patients with high risk OED lesions: 10 lesions transformed and 7 did not over a follow-up period of more than 3 years. FTIR spectra were collected from routine, unstained histopathological sections and machine learning used to predict malignant transformation, irrespective of OED classification. PCA-LDA (principal component analysis followed by linear discriminant analysis) provided evidence that the subsequent transforming status of these 17 lesions could be predicted from FTIR data with a sensitivity of 79 ± 5% and a specificity of 76 ± 5%. Six key wavenumbers were identified as most important in this classification. Although this pilot study used a small cohort, the strict inclusion criteria and classification based on known outcome, rather than OED grade, make this a novel study in the field of FTIR in oral cancer and support the clinical potential of this technology in the surveillance of OED.

Loss of FANCD2 and related proteins may predict malignant transformation in oral epithelial dysplasia

Predicting malignant transformation (MT) in oral epithelial dysplasia (OED) is challenging. The higher rate of MT reported in nonsmokers suggests an endogenous etiology in oncogenesis. We hypothesize that loss of FANCD2 and associated proteins could influence genomic instability and MT in the absence of environmental carcinogens. Longitudinal archival samples were obtained from 40 individuals with OED: from diagnosis to the most recent review in 23 patients with stable OED or until excision of the squamous cell carcinoma in 17 patients with unstable OED undergoing MT. Histopathological reassessment, immunohistochemistry for FANCD2, and Western blotting for phosphorylation/monoubiquitylation status of ATR, CHK1, FANCD2, and FANCG were undertaken on each tissue sample. Decreased expression of FANCD2 was observed in the diagnostic biopsies of OED lesions that later underwent MT. Combining the FANCD2 expression scores with histologic grading more accurately predicted MT (P=.005) than histology alone, and it correctly predicted MT in 10 of 17 initial biopsies. Significantly reduced expression of total FANCD2, pFANCD2, pATR, pCHK-1, and pFANCG was observed in unstable OED. There is preliminary evidence that defects in the DNA damage sensing/signaling/repair cascade are associated with MT in OED. Loss of expression of FANCD2 protein in association with a higher histologic grade of dysplasia offered better prediction of MT than clinicopathologic parameters alone.

Evaluation of glucose transporter-1 expression in oral epithelial dysplasia and oral squamous cell carcinoma: An immunohistochemical study

Introduction:Oral squamous cell carcinoma (OSCC) is the most common malignancy of oral cavity and is commonly preceded by oral potentially malignant disorders. Glucose transporter-1 (GLUT-1) protein expression is upregulated in malignant cells that show increased glucose uptake. Alterations in GLUT-1 expression have been reported in several potentially malignant and malignant lesions.Aims and Objectives:The aims and objectives of this study were to analyze and assess the role of GLUT-1 immunomarker in oral epithelial dysplasia (OED) and OSCC, to demonstrate and analyze the presence, location and intensity of GLUT-1 immunomarker in low-risk and high-risk OEDs and in different grades of OSCC and to correlate the expression of GLUT-1 immunomarker between normal oral mucosa (NOM), OED and different grades of OSCC.Materials and Methodology:A total of ninety paraffin-embedded tissue blocks, 15 each of NOM; low-risk and high-risk OED and well, moderately and poorly differentiated OSCC were stained with the immunomarker GLUT-1.Results and Observation:GLUT-1 immunoexpression was statistically significant in terms of number of positive cells, staining intensity, IRS score and level of staining within the epithelium and also within the cell between NOM, OED and OSCC.Conclusion:Increased GLUT-1 expression has a consistent role in the malignant transformation of OED and aggressiveness of OSCC.

Coalition of E-cadherin and vascular endothelial growth factor expression in predicting malignant transformation in common oral potentially malignant disorders.

Background:Reduced E-cadherin expression and increased VEGF expression is known to be involved in tissue growth and transformation of Oral Potentially Malignant Disorders (OPMDs) and has been correlated with their differing histological grades in numerous studies.Aim:To evaluate Immunohistochemical (IHC) expression of both E-cadherin and VEGF in predicting the malignant transformation potential of common OPMDs.Materials and Methods:Ten cases each of Normal Oral mucosa (NOM), Mild Oral Epithelial Dysplasia (OED), Moderate OED, Severe OED, Oral Submucous Fibrosis, (OSMF) and Oral Squamous Cell Carcinoma (OSCC) were stained and evaluated for the expression of Ecadherin and VEGF. Quick score (QS) for expression intensity in all epithelial layers was calculated for both markers and results statistically analysed using Kruskal –Wallis ANOVA and Mann-Whitney “U” test.Results:E-cadherin expression was continuous and membranous in all the layers of NOM and reduced with progressing grades of OED to OSCC. In OSMF, expression was intermediate between moderate and severe OED. VEGF expression increased as the disease progressed from normal to increasing grades of OED to malignancy. In OSMF, expression was similar to that in mild OED. VEGF, E-cadherin expression for basal and parabasilar cells showed a strong statistically significant negative correlation in NOM. A very strong statistically significant positive correlation with perfect monotonic relation was noted in superficial cells in severe OED group and OSCC group.Conclusion:E-Cadherin and VEGF could be used as combination markers to predict the potential risk for malignant transformation in OEDs.

The clinical determinants of malignant transformation in oral epithelial dysplasia

While the size and clinical appearance are known risk factors for malignant transformation of potentially malignant oral the importance of site, grade of dysplasia and exposure to environmental carcinogens remains controversial. We aim to report the clinical determinants of malignant progression in a series of patients with histopathologically graded oral epithelial dysplasia (OED). We recruited patients with a histopathological diagnosis of OED to a longitudinal observational study in a tertiary oral dysplasia clinic. Clinical, histopathological and risk factor data were recorded at baseline. One of three clinical endpoints were determined: malignant transformation, progression of dysplasia grade, remission/stable dysplasia grade. Ninety-one patients meeting the criteria gave consent for inclusion to the cohort, with outcomes reported after a median follow up of 48 months. An estimated 22% (SE 6%) of patients underwent malignant transformation within 5 years, with significant predictors being: non-smoking status (χ(2)=15.1, p=0.001), site (χ(2)=15.3, p=0.002), non-homogeneous appearance (χ(2)=8.2, p=0.004), size of lesion >200 mm(2) (χ(2)=4.7, p=0.03) and, of borderline significance, high grade (χ(2)=5.8, p=0.06). Gender, age, number of lesions and alcohol history did not predict for malignant transformation. Although a number of these clinical determinants have previously been associated with higher malignant transformation in OED, the high-risk nature of lesions in non-smokers is of particular note and requires a greater emphasis and recognition amongst clinicians dealing with OED. It suggests that those non-smokers with OED, have an inherited or acquired predisposition and should be treated more aggressively; these should form the focus for further investigation.