Risk Of Oral Cancer In Patients Research Articles

Emerging Role of Decoy Receptor-2 as a Cancer Risk Predictor in Oral Potentially Malignant Disorders.

The aim of this study was to evaluate the expression of the senescence markers, Decoy Receptor 2 (DcR2) and Differentiated Embryo-Chondrocyte expressed gen 1 (DEC1), in oral potentially malignant disorders (OPMDs) to ascertain their possible association with oral cancer risk. The immunohistochemical analysis of DcR2 and DEC1 expression (along with p16 and Ki67 expression) was carried out in 60 patients with clinically diagnosed oral leukoplakia. Fifteen cases (25%) subsequently developed an invasive carcinoma. Correlations between protein marker expression, histological grade and oral cancer risk were assessed. DcR2, DEC1 and Ki67 protein expressions were found to correlate significantly with increased oral cancer risk, and also with an increased grade of dysplasia. Multivariate analysis demonstrated that DcR2 and Ki67 expression are independent predictors of oral cancer development. Our results evidence for the first time the potential of DcR2 as an early biomarker to assess oral cancer risk in patients with oral leukoplakia (HR = 59.7, p = 0.015), showing a superior predictive value to histology (HR = 4.225, p = 0.08). These findings reveal that the increased expression of DcR2 and DEC1 occurred frequently in OPMDs. In addition, DcR2 expression emerges as a powerful biomarker for oral cancer risk assessment in patients with oral leukoplakia.

Predicting oral cancer risk in patients with oral leukoplakia and oral lichenoid mucositis using machine learning

Oral cancer may arise from oral leukoplakia and oral lichenoid mucositis (oral lichen planus and oral lichenoid lesions) subtypes of oral potentially malignant disorders. As not all patients will develop oral cancer in their lifetime, the availability of malignant transformation predictive platforms would assist in the individualized treatment planning and formulation of optimal follow-up regimens for these patients. Therefore, this study aims to compare and select optimal machine learning (ML)-based models for stratifying the malignant transformation status of patients with oral leukoplakia and oral lichenoid mucositis. One thousand one hundred and eighty-seven patients with oral leukoplakia and oral lichenoid mucositis treated at three tertiary health institutions in Hong Kong, Newcastle UK, and Lagos Nigeria were included in the study. Demographic, clinical, pathological, and treatment-based factors obtained at diagnosis and during follow-up were used to populate and compare forty-six machine learning-based models. These were implemented as a set of twenty-six predictors for centers with substantial data quantity and fifteen predictors for centers with insufficient data. Two best models were selected according to the number of variables. We found that the optimal ML-based risk models with twenty-six and fifteen predictors achieved an accuracy of 97% and 94% respectively following model testing. Upon external validation, both models achieved a sensitivity, specificity, and F1-score of 1, 0.88, and 0.67 on consecutive patients treated after the construction of the models. Furthermore, the 15-predictor ML model for centers with reduced data achieved a higher sensitivity for identifying oral leukoplakia and oral lichenoid mucositis patients that developed malignancies in other treatment settings compared to the binary oral epithelial dysplasia system for risk stratification (0.96 vs 0.82). These findings suggest that machine learning-based models could be useful potentially to stratify patients with oral leukoplakia and oral lichenoid mucositis according to their risk of malignant transformation in different settings.

SOX2 Expression Is an Independent Predictor of Oral Cancer Progression.

Potentially malignant oral lesions, mainly leukoplakia, are common. Malignant transformation varies widely, even in the absence of histological features such as dysplasia. Hence, there is a need for novel biomarker-based systems to more accurately predict the risk of cancer progression. The pluripotency transcription factor SOX2 is frequently overexpressed in cancers, including oral squamous cell carcinoma (OSCC), thereby providing a link between malignancy and stemness. This study investigates the clinical relevance of SOX2 protein expression in early stages of oral carcinogenesis as a cancer risk biomarker, and also its impact on prognosis and disease outcome at late stages of OSCC progression. SOX2 expression was evaluated by immunohistochemistry in 55 patients with oral epithelial dysplasia, and in 125 patients with OSCC, and correlated with clinicopathological data and outcomes. Nuclear SOX2 expression was detected in four (7%) cases of oral epithelial dysplasia, using a cut-off of 10% stained nuclei, and in 16 (29%) cases when any positive nuclei was evaluated. Univariate analysis showed that SOX2 expression and histopathological grading were significantly associated with oral cancer risk; and both were found to be significant independent predictors in the multivariate analysis. Nuclear SOX2 expression was also found in 49 (39%) OSCC cases, was more frequent in early tumor stages and N0 cases, and was associated with a better survival. In conclusion, SOX2 expression emerges as an independent predictor of oral cancer risk in patients with oral leukoplakia. These findings underscore the relevant role of SOX2 in early oral tumorigenesis rather than in tumor progression.

The Emerging Role of NANOG as an Early Cancer Risk Biomarker in Patients with Oral Potentially Malignant Disorders.

NANOG, a key regulator of pluripotency and self-renewal in embryonic and adult stem cells, is frequently overexpressed in multiple cancers, including oral squamous cell carcinoma (OSCC). It has been frequently associated with poor outcomes in epithelial cancers, and recently implicated in laryngeal tumorigenesis. On this basis, we investigated the role of NANOG protein expression as an early cancer risk biomarker in oral potentially malignant disorders (OPMD), and the impact on prognosis and disease outcomes in OSCC patients. NANOG expression was evaluated by immunohistochemistry in 55 patients with oral epithelial dysplasia, and 125 OSCC patients. Correlations with clinical and follow-up data were assessed. Nuclear NANOG expression was detected in 2 (3.6%) and cytoplasmic NANOG expression in 9 (16.4%) oral dysplasias. NANOG expression increased with the grade of dysplasia. Cytoplasmic NANOG expression and the histopathological grading were significantly correlated with oral cancer risk, although dysplasia grading was the only significant independent predictor of oral cancer development in multivariate analyses. Cytoplasmic NANOG expression was also detected in 39 (31%) OSCC samples. Positive NANOG expression was significantly associated with tobacco and alcohol consumption, and was more frequent in pN0 tumors, early I-II stages. These data unveil the clinical relevance of NANOG in early stages of OSCC tumorigenesis rather than in advanced neoplastic disease. NANOG expression emerges as an early predictor of oral cancer risk in patients with OPMD.

Sitagliptin use may reduce oral cancer risk in patients with type 2 diabetes

Sitagliptin use may reduce oral cancer risk in patients with type 2 diabetes

Quantitative prediction of oral cancer risk in patients with oral leukoplakia.

Exfoliative cytology has been widely used for early diagnosis of oral squamous cell carcinoma. We have developed an oral cancer risk index using DNA index value to quantitatively assess cancer risk in patients with oral leukoplakia, but with limited success. In order to improve the performance of the risk index, we collected exfoliative cytology, histopathology, and clinical follow-up data from two independent cohorts of normal, leukoplakia and cancer subjects (training set and validation set). Peaks were defined on the basis of first derivatives with positives, and modern machine learning techniques were utilized to build statistical prediction models on the reconstructed data. Random forest was found to be the best model with high sensitivity (100%) and specificity (99.2%). Using the Peaks-Random Forest model, we constructed an index (OCRI2) as a quantitative measurement of cancer risk. Among 11 leukoplakia patients with an OCRI2 over 0.5, 4 (36.4%) developed cancer during follow-up (23 ± 20 months), whereas 3 (5.3%) of 57 leukoplakia patients with an OCRI2 less than 0.5 developed cancer (32 ± 31 months). OCRI2 is better than other methods in predicting oral squamous cell carcinoma during follow-up. In conclusion, we have developed an exfoliative cytology-based method for quantitative prediction of cancer risk in patients with oral leukoplakia.

TGF-β1 and IL-10 single nucleotide polymorphisms as risk factors for oral cancer in Taiwanese

Cytokine production capacity varies among individuals and depends on cytokine gene polymorphisms. Transforming growth factor-beta 1 (TGF-β1) plays a significant role in regulating the proliferation and apoptosis of epithelial cells. Interleukin 10 (IL-10) is an immunoregulatory cytokine with biological functions of anti-inflammation, immunosuppression, allergy, and anti-agenesis. The two cytokines are supposed to play an important role in carcinogenesis. The association between cytokine gene polymorphisms with oral cancer (OC) was investigated. We studied the association between the polymorphism in TGF-β1 (G to C polymorphism at codon 25 <+915>) and IL-10 (−1082 G/A, -819 C/T, and −592 C/A) and the risk of OC in patients (n = 162) and healthy controls (n = 118) in Taiwan. All genotyping experiments were performed using the polymerase chain reaction sequence-specific primer (PCR-SSP) method. It was found that the codon 25 GC genotype of TGF-β1 is significantly higher in frequency in patients with OC compared with a healthy control group (p < 0.0001). People with the GC genotype in codon 25 had an 11.09-fold increased risk of OC [odds ratio (OR) = 11.09; 95% confidence interval (CI) = 6.16–113.23]. IL-10 polymorphisms in −819 and −592 positions correlated with the risk of OC (p < 0.0001). The IL-10 -592 C allele-containing genotypes posed an increased risk of OC (OR = 1.79, 95% CI = 1.11–2.91). People with the CT genotype in IL-10 -819 had a 3.32-fold increased risk of OC (OR = 3.32; 95% CI = 1.64–6.94). The results suggest that polymorphisms in TGF-β1 and IL-10 may have a significant influence on the development of OC.

Pioglitazone and oral cancer risk in patients with type 2 diabetes

Pioglitazone has shown an inhibitory effect on the growth of cell lines derived from human salivary gland and human oral squamous cell carcinoma. However, whether this effect can be applied to patients with type 2 diabetes mellitus who use pioglitazone for glycemic control remains unanswered. The reimbursement records of all Taiwanese diabetic patients under treatment with oral anti-diabetic agents or insulin from 1996 to 2009 were retrieved from the National Health Insurance database. The entry date was set at 1 January 2006 and a total of 1,093,391 patients with type 2 diabetes were followed up for oral cancer incidence till the end of 2009. Incidences for ever-users, never-users and subgroups of pioglitazone dose-responsive exposure (using the parameters of time since starting pioglitazone, duration of therapy and cumulative dose) were calculated and hazard ratios estimated by Cox regression. There were 58,238 ever-users and 1,035,153 never-users, with respective numbers of incident oral cancer of 201 (0.35%) and 4168 (0.40%), and respective incidences of 94.26 and 114.24 per 100,000 person-years. The overall hazard ratios (95% confidence intervals) did show a significantly lower risk in unadjusted [0.832 (0.722-0.958)] and age-sex-adjusted [0.866 (0.752-0.998)] models. However, the multivariable-adjusted hazard ratio (95% confidence interval) was not significant: 0.992 (0.857-1.148). Although significant P-trends for the dose-response parameters could be observed in some of the unadjusted and age-sex-adjusted models, none was significant in the multivariable-adjusted models. Pioglitazone has a null association with oral cancer after adjustment for potential confounders.

Podoplanin expression in oral leukoplakia: Tumorigenic role

Recent studies have identified podoplanin, a mucin-type transmembrane glycoprotein, as a biomarker for oral cancer risk in patients with oral leukoplakia (OPL). The aim of this study was to investigate the potential association between podoplanin and the risk of malignant transformation of OPL with epithelial dysplasia. In this retrospective study, podoplanin immunoexpression was analyzed in 58 patients with oral leukoplakia that showed epithelial dysplasia. Lesions with podoplanin expression in the basal and suprabasal layers of oral epithelium at one area or showing suprabasal expression at two or more areas were considered as positive. Association between podoplanin expression and oral cancer development was analyzed. Twenty-two of the 58 lesions (38%) were classified as podoplanin-positive, and the remaining 36 (62%) lesions were considered podoplanin-negative. The expression of podoplanin was correlated with the grade of dysplasia (p<0.0005), and with the risk of progression to oral cancer (p<0.0005). In multivariate survival analysis, only premalignant oral lesions displaying positive podoplanin expression showed a significantly increased risk of developing an oral squamous cell carcinoma (hazard ratio=8.738, p=0.007). Podoplanin could be a valuable biomarker for risk assessment of malignant transformation in patients with OPL along with histological assessment.

Podoplanin: A Novel Marker for Oral Cancer Risk in Patients With Oral Premalignancy

Oral leukoplakia (OPL) is a heterogeneous oral lesion with an increased oral cancer risk. Current clinical parameters cannot predict the potential of malignant transformation in patients with OPL. We have shown that podoplanin, a lymphatic endothelial marker, is highly expressed in oral cancer and some oral premalignancies. The purpose of this study is to determine a role of podoplanin in predicting oral cancer development in patients with OPL. Podoplanin expression was determined in 150 OPL patients with long-term follow-up using immunohistochemistry. Association between the protein expression patterns and clinicopathologic parameters including oral cancer development during the follow-up were analyzed. Fifty-six (37%) of the 150 OPL patients exhibited podoplanin expression in the basal and suprabasal layers and were classified as podoplanin positive. Podoplanin positivity was more frequent in older patients (P = .016), females (P = .020), and dysplastic lesions (P = .040). Patients with OPL that was podoplanin positive had significantly higher incidence of oral cancer than did those whose OPL was podoplanin negative (P = .0002). In the multivariate analysis using histology and podoplanin as cofactors, podoplanin was the only independent factor for oral cancer development (hazard ratio = 3.087; 95% CI, 1.530 to 6.231; P = .002). Importantly, oral cancer risk can be further stratified by considering both histology and podoplanin information. Podoplanin is frequently expressed in OPL. Together with histology, podoplanin may serve as a powerful biomarker to predict the risk for oral cancer development in patients with OPL.