Progression Of Oral Epithelial Dysplasia Research Articles

A fully automated and explainable algorithm for predicting malignant transformation in oral epithelial dysplasia

Oral epithelial dysplasia (OED) is a premalignant histopathological diagnosis given to lesions of the oral cavity. Its grading suffers from significant inter-/intra-observer variability, and does not reliably predict malignancy progression, potentially leading to suboptimal treatment decisions. To address this, we developed an artificial intelligence (AI) algorithm, that assigns an Oral Malignant Transformation (OMT) risk score based on the Haematoxylin and Eosin (H&E) stained whole slide images (WSIs). Our AI pipeline leverages an in-house segmentation model to detect and segment both nuclei and epithelium. Subsequently, a shallow neural network utilises interpretable morphological and spatial features, emulating histological markers, to predict progression. We conducted internal cross-validation on our development cohort (Sheffield; n = 193 cases) and independent validation on two external cohorts (Birmingham and Belfast; n = 89 cases). On external validation, the proposed OMTscore achieved an AUROC = 0.75 (Recall = 0.92) in predicting OED progression, outperforming other grading systems (Binary: AUROC = 0.72, Recall = 0.85). Survival analyses showed the prognostic value of our OMTscore (C-index = 0.60, p = 0.02), compared to WHO (C-index = 0.64, p = 0.003) and binary grades (C-index = 0.65, p < 0.001). Nuclear analyses elucidated the presence of peri-epithelial and intra-epithelial lymphocytes in highly predictive patches of transforming cases (p < 0.001). This is the first study to propose a completely automated, explainable, and externally validated algorithm for predicting OED transformation. Our algorithm shows comparable-to-human-level performance, offering a promising solution to the challenges of grading OED in routine clinical practice.

Expression of PD-L1 and p-RPS6 in epithelial dysplasia and squamous cell carcinoma of the oral cavity.

Oral squamous cell carcinoma (OSCC) is often preceded by oral epithelial dysplasia (OED). The role of ribosomal protein S6 (RPS6) and programmed cell death ligand-1 (PD-L1) in the progression of OED to OSCC remains unclear. This study aimed to investigate the expression of phosphorylated RPS6 (p-RPS6) and PD-L1 in OSCC and OED and to examine its relationship with clinicopathological features. Fifty-two OSCC and 48 OED cases were recruited for immunohistochemical analysis of p-RPS6 and PD-L1 expression. The expression of markers was correlated with clinicopathological features of OSCC and OED. We found p-RPS6 expression in all cases of OSCC and OED, whereas PD-L1 was expressed in 42/48 (87%) OED and in 28/52 (53%) OSCC. The patients with mild OED presented higher expression level of PD-L1 and p-RPS6 significantly, when compared to moderate-differentiated OSCC patients (p < 0.05). Moreover, we found a significant positive correlation between PD-L1 and p-RPS6 expression in OED and OSCC patients (p < 0.01). The PD-L1 expression was significantly related to more than 2 cm tumor size in OSCC patients (p = 0.007). Our findings suggest the upregulation of PD-L1 may be related with activation of the mTOR pathway in the early events of tumor progression and the pathogenesis of OSCC.

EVALUATION OF THE ROLE OF ANGIOGENESIS IN THE DEVELOPMENT AND PROGRESSION OF ORAL CANCER

Objective To evaluate the microvascular density (MVD) associated to the progression of oral epithelial dysplasia (OED) towards oral squamous cell carcinoma (OSCC) using immunostaining with alpha-smooth muscle actin (α-SMA). Study Design Eighty cases of OED were selected, in which 41 were low-risk epithelial dysplasia (LRED), and 39 were high-risk epithelial dysplasia (HRED). The group of non-neoplastic epithelium (NNE) consisted of 34 cases of inflammatory fibrous hyperplasia, while the group of neoplastic epithelium contained 36 cases of OSCC. All cases were submitted to immunohistochemical reaction with anti-α-SMA antibody. The MVD in the connective tissue was determined by the average number of immunostained vessels. Results The MVD values for the NNE group (14.07±4.79) were statistically lower (Kruskal-Wallis/Dunn´s Test, P≤0.05) than for OED (18.67±8.25) and OSCC (29.78±23.08) cases. No statistical difference was observed between HRED and LRED cases (Mann-Whitney Test). Conclusion The increase in MVD present in malignant and pre-malignant lesions suggests a possible role of angiogenesis in the progression of these lesions. To evaluate the microvascular density (MVD) associated to the progression of oral epithelial dysplasia (OED) towards oral squamous cell carcinoma (OSCC) using immunostaining with alpha-smooth muscle actin (α-SMA). Eighty cases of OED were selected, in which 41 were low-risk epithelial dysplasia (LRED), and 39 were high-risk epithelial dysplasia (HRED). The group of non-neoplastic epithelium (NNE) consisted of 34 cases of inflammatory fibrous hyperplasia, while the group of neoplastic epithelium contained 36 cases of OSCC. All cases were submitted to immunohistochemical reaction with anti-α-SMA antibody. The MVD in the connective tissue was determined by the average number of immunostained vessels. The MVD values for the NNE group (14.07±4.79) were statistically lower (Kruskal-Wallis/Dunn´s Test, P≤0.05) than for OED (18.67±8.25) and OSCC (29.78±23.08) cases. No statistical difference was observed between HRED and LRED cases (Mann-Whitney Test). The increase in MVD present in malignant and pre-malignant lesions suggests a possible role of angiogenesis in the progression of these lesions.

The Expression of Methyltransferase-Like 3 in Oral Precancerous Lesions and Oral Squamous Cell Carcinoma.

N6-methyladenosine is the most frequent mRNA modification in eukaryotic cells. It is catalyzed by the methyltransferase complex, methyltransferase-like 3 (METTL3). Previous studies have revealed that METTL3 plays a role in various cancers. However, there is limited information about the roles of METTL3 in oral epithelial dysplasia (OED). This study determined METTL3 expression in normal oral mucosa (NOM), OED, and oral squamous cell carcinoma (OSCC) by immunohistochemistry. Twenty formalin-fixed paraffin embedded specimens each of NOM, OED, and OSCC were included. The expression pattern, the number of positive cells, the staining intensity, and the histochemical score (H-score) of METTL3 were investigated. The data were analyzed by using one-way analysis of variance, chi-squared test, and a Kruskal-Wallis test. A p-value < 0.05 indicated statistically significant. The METTL3 expression in NOM was observed in the basal, parabasal, and lower layers of epithelium. In low-grade OED, METTL3 was expressed in the lower epithelial layers and partially presented in the spinous layer. However, in high-grade OED, METTL3 expression was observed in the lower layers, spinous layers, and upper layers of dysplastic epithelium. For OSCC, METTL3 immunostaining was presented in both the peripheral and central cells of the tumor islands. All NOM samples showed weak-to-moderate METTL3 staining intensity, while the moderate-to-strong METTL3 staining intensity was observed in 95% of both OED and OSCC specimens (p < 0.05). The percentage of METTL3 positive cells and H-score was highest in OSCC, followed by OED and NOM, respectively (p < 0.05). Interestingly, H-score was greater in high-grade OED (209.8 ± 18.61) when compared with low-grade OED (162.1 ± 38.93) (p < 0.05). METTL3 expression in OED and OSCC was more outstanding than in NOM, suggesting possible roles for OED and OSCC pathogenesis. Additionally, METTL3 expression may be an indicator for OED progression to OSCC.

Immunohistochemical Evaluation of CD10 Expression in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma: A Cross-sectional Study

bjectives: The objective of the study is to evaluate the expression of CD10 in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC) and to determine its role as a potential biomarker in OSCC. Methods: Immunohistochemical evaluation of 40 archival paraffin-embedded tissue specimens grouped into oral epithelial dysplasia and early invasive, well-differentiated, and moderately differentiated OSCC was conducted to determine and compare the CD10 expression among the groups. Stromal positivity of the CD10 expression was calculated and statistically analyzed at p<0.05. Results: The results of the study showed that there was a statistically significant increase in the mean CD10 expression among the four groups. Intergroup comparison showed a statistically significant difference between oral epithelial dysplasia and OSCC while statistical significance was not observed in the various grades of OSCC. Conclusion: CD10 expression could be used as an important biomarker for determining the progression of oral epithelial dysplasia and the overall prognosis of OSCC. Keywords: Biomarker, CD10, oral epithelial dysplasia, oral cancer, immunohistochemistry

Role of Mast Cells in Progression of Oral Epithelial Dysplasia

Role of Mast Cells in Progression of Oral Epithelial Dysplasia

Outcomes of Oral Epithelial Dysplasia Managed by Observation versus Excision at a Canadian Tertiary Centre

BackgroundThere is a lack of consensus in the management of oral epithelial dysplasia (OED). The purpose of this study is: 1) to evaluate whether surgical excision with histologically negative margins impacts the 5-year malignant transformation rate of OED, and 2) to compare the disease-specific survival outcome of patients diagnosed with oral squamous cell carcinoma (OSCC) that progressed from OED to those presenting with OSCC on initial biopsy. MethodsIn this retrospective study, the electronic health records of all patients diagnosed with OED or OSCC between years 2009 and 2015 were reviewed. Patient age, gender, presence of risk factors, biopsy location, grade of dysplasia, and oncologic staging were collected. Of the OED cases, patients were divided into observational and excisional groups. Histopathologic reports of excisional biopsies were reviewed for margin status. Oncologic management and survival outcome details for cases progressing to OSCC were collected. All cases of OSCC at initial biopsy were also reviewed for oncologic management and survival outcome details available until January 2021. ResultsIn total, 115 patients diagnosed with OED between 2009 and 2015 met the inclusion criteria; 58 were managed by observation, while 57 had surgical excision. The overall malignant transformation rate was 26%. Surgical excision with histologically negative margins did not significantly reduce malignant transformation rate. Of the 30 cases of OED that progressed to OSCC, 5 (17%) died of disease; 66 patients were diagnosed with OSCC on initial biopsy, 19 (29%) of which died of disease. The difference in disease-specific survival was significantly different between the groups. ConclusionSurgical excision with negative margins does not reduce the rate of malignant progression of OED. However, lower oncologic staging and improved disease-specific survival was observed in cases of OSCC arising from previously biopsied OED compared to those presenting with OSCC on initial biopsy. These observations support the role of surgical excision as purely diagnostic rather than curative in the management of OED.

Detection of deletions in 1q25, 1p36 and 1pTEL and chromosome 17 aneuploidy in oral epithelial dysplasia and oral squamous cell carcinoma by fluorescence in situ hybridization (FISH)

ObjectiveTo identify chromosome deletions in 1q25, 1p36 and 1pTEL, and chromosome 17 ploidy status in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). Material and methodsSamples from 57 OED and 63 OSCC were selected. FISH was performed using centromeric probes 17 and n LSIR 1p36/LSI 1q25 Dual Color Probe. ResultsIn OED, deletions were found only in 1pTEL region (29.8%). In OSCC, there was a higher frequency of deletion in 1pTEL (79.4%), followed by 1p36 (73.0%), and 1q25 (20.6%). Advanced TNM clinical stages (III/IV) showed all the deletions studied; at early clinical stages (I/II) of OSCC, deletions were observed only in 1pTEL. The frequency of deletion in 1p36 was 17.0 times higher in OSCC at advanced clinical stages (PR: 17.00). The median number of cell nuclei with chromosome 17 aneuploidy was higher in OSCC than in OED (P < 0.001). Early clinical stages of OSCC showed lower median number nuclei with aneuploidy when compared to advanced tumors (P < 0.05). Tumors harboring deletions in 1p36, 1q25 and 1pTEL revealed higher median numbers of trisomic/polysomic nuclei when compared to lesions exhibiting no abnormalities in chromosome 1 (P < 0.05). ConclusionA higher prevalence of chromosomal abnormalities was found in OSCC than in OED, while in OSCC, higher abnormalities were present in lesions with higher TNM staging. 1pTEL deletion and monosomy of chromosome 17 are possible markers for progression of OED to OSCC. 1p36 deletion and trisomy/polysomy of chromosome 17 could be markers of worse prognosis of OSCC.

UK consensus recommendations on the management of oral epithelial dysplasia during COVID-19 pandemic outbreaks.

Oral Epithelial Dysplasia (OED) is associated with an increased risk of oral cancer development. The SARS-CoV-2 pandemic is necessitating the suspension or dramatic reduction of face-to-face non-urgent elective services, including OED clinics. Little is known regarding the potential impact of elective services suspension upon the risk of OED progression, and whether alternative strategies (e.g. remote consultations) may be introduced to ensure OED surveillance. The aim of this paper is to provide expert-opinion consensus recommendations for the management of OED during the current and future pandemic outbreaks. A working group of nine UK-based senior clinicians and academics in Oral and Maxillofacial Surgery and Oral Medicine was created and twelve consensus statements were developed using a modified-Delphi process. Greater than 80% agreement was considered a consensus. Consensus was achieved for all twelve statements (89-100% agreement). The group agreed that, during the temporary suspension of elective services associated with COVID-19 pandemic outbreaks, patients with OED can be risk stratified to determine the length of accepted delay in face-to-face consultation. Remote consultations with patient-provided clinical photographs may be a useful way of maintaining a level of surveillance in this group of patients. Using an expert working group methodology, we have developed consensus recommendations for the monitoring of individuals with OED during pandemic outbreaks associated with temporary suspension of elective services. This has identified areas of future research and highlighted the need for a stronger evidence base to inform the set-up and delivery of surveillance regimens for patients with OED.

CD146 expression in oral lichen planus and oral cancer.

To examine the CD146/METCAM expression on keratinocytes in normal oral mucosa (NOM), oral lichen planus (OLP), oral epithelial dysplasia (OED), and oral squamous cell carcinoma (OSCC). Immunohistochemical examination of CD146 was performed on 80 specimens, divided into 20 cases from each group. The number of CD146+ keratinocytes was quantitatively assessed together with the staining intensity. The mean percentage of CD146+ keratinocytes was 19.04±15.32, 59.40±24.48, 60.04±28.87, and 22.13±21.03 in NOM, OLP, OED, and OSCC, respectively. The mean percentages of CD146+ keratinocytes in OLP and OED were significantly higher than those of NOM and OSCC (p≤0.001). Most OED (55%) and OLP (60%) showed strong and moderate staining intensity, respectively, while NOM (50%) and OSCC (45%) predominantly expressed CD146 at mild intensity. This is the first study to examine CD146 expression in OLP and OED. CD146 is upregulated in OLP and OED but downregulated in OSCC. The alteration in CD146 may be involved in the immunoregulatory response of OLP and the early event of oral carcinogenesis. The loss of this protein may underlie the progression of OED into invasive OSCC. Overexpression of CD146 protein may play a role in the pathophysiology of OLP and OED.

Similar Effect of P16 Hydroxymethylation and True Methylation on Prediction of Malignant Transformation of Oral Epithelial Dysplasia: A Prospective Study

Background: Total P16 methylation (P16M), including P16 hydroxymethylation (P16H) and true-P16M, correlates with malignant transformation of oral epithelial dysplasia (OED). Both true-P16M and P16H are early events in carcinogenesis. Aim: The aim of this study is to prospectively determine if discrimination of true-P16M from P16H similarly is necessary for prediction of cancer development from OEDs. Methods: Patients (n = 265) with mild or moderate OED were recruited into the double-blind 2-center cohort. Total-P16M and P16H were analyzed using the 115-bp MethyLight, TET-assistant bisulfite (TAB) methylation-specific PCR (MSP), and TAB-sequencing. Total-P16M-positive and P16H-negative samples were defined as true-P16M-positive. Progression of OEDs was monitored for a minimum 24 months follow-up period. Results: P16H was detected in 23 of 73 (31.5%) total-P16M-positive OEDs. Follow-up information was obtained from 247 patients with an ultimate compliance of 93.2%. OED-derived squamous cell carcinomas were observed in 13.0% (32/247) patients during the follow-up (median, 41.0 months). The cancer progression rate for total-P16M-positive patients was significantly increased when compared with total-P16M-negative patients (23.3% vs 8.6%; adjusted odds ratio = 2.67 [95% CI: 1.19-5.99]). However, the cancer progression rate was similar between P16H- and true-P16M-positive OEDs (26.1% [6/23] vs 22.0% [11/50]; odds ratio = 0.80 [95% CI: 0.22-2.92]). The progression-free survival was also similar for these patients. Conclusion: P16H and true-P16M are similar biomarkers for determining malignant potential of OEDs. Discrimination of P16H from true-P16M, at least in OED, may be not necessary in clinical applications.

A similar effect of P16 hydroxymethylation and true-methylation on the prediction of malignant transformation of oral epithelial dysplasia: observation from a prospective study

BackgroundTotal P16 methylation (P16M), including P16 hydroxymethylation (P16H) and true-P16M, correlates with malignant transformation of oral epithelial dysplasia (OED). Both true-P16M and P16H are early events in carcinogenesis. The aim of this study is to prospectively determine if discrimination of true-P16M from P16H is necessary for prediction of cancer development from OEDs.MethodsPatients (n = 265) with mild or moderate OED were recruited into the double blind two-center cohort. Total-P16M and P16H were analyzed using the 115-bp MethyLight, TET-assisted bisulfite (TAB) methylation-specific PCR (MSP), and TAB-sequencing. Total-P16M-positive and P16H-negative samples were defined as true-P16M-positive. Progression of OEDs was monitored for a minimum 24 months follow-up period.ResultsP16H was detected in 23 of 73 (31.5%) total-P16M-positive OEDs. Follow-up information was obtained from 247 patients with an ultimate compliance rate of 93.2%. OED-derived squamous cell carcinomas were observed in 13.0% (32/247) patients during follow-up (median, 41.0 months). The cancer progression rate for total-P16M-positive patients was significantly increased when compared to total-P16M-negative patients [23.3% vs 8.6%; adjusted odds ratio = 2.67 (95% CI: 1.19–5.99)]. However, the cancer progression rates were similar between P16H- and true-P16M-positive OEDs [26.1% (6/23) vs 22.0% (11/50); odds ratio = 0.80 (95% CI: 0.22–2.92)]. The cancer-free survival was also similar for these patients.ConclusionP16H and true-P16M are similar biomarkers for determining malignant potential of OEDs. Discrimination of P16H from true-P16M, at least in OED, may be not necessary in clinical applications.Trial registrationThis study is registered prospectively in the U.S. National Institutes of Health Clinical Trials Protocol Registration System (trial number NCT02967120, available at https://ClinicalTrials.gov/ct2/show/NCT02967120).

Loss of heterozygosity as a marker to predict progression of oral epithelial dysplasia to oral squamous cell carcinoma.

Loss of heterozygosity as a marker to predict progression of oral epithelial dysplasia to oral squamous cell carcinoma.

Immuno-Histochemical and Quantitative Study of Melanocytes and Melanin Granules in Oral Epithelial Dysplasia.

Oral Epithelial dysplasia (OED) is a potentially malignant disorder that is characterized by the presence of architectural and cytological changes. One of the prime factors responsible for the development of these lesions is the usage of tobacco. A variety of factors provide protective mechanism in order to prevent the effects of chemotoxic agents including tobacco products of which, melanin pigmentation is one of the vital elements. Role of melanocytes in progression of OED has remained unclear, so the present study was done to evaluate density of melanocyte and melanin granules in different grades of epithelial dysplasia and to correlate both findings with different grades of epithelial dysplasia. The study included 60 OED cases, of which three histopathogical sections were prepared from each block. The sections were stained with Hematoxylin and Eosin, Masson Fontana and Human Melanoma Black (HMB-45), an immunohistochemical stain. Quantification of melanin granules was evaluated under 40X magnification using arbitrary scale with micrometer square as, 0= Absence of melanin granules, 1= Rare and scattered melanin granules, 2= Dense but not aggregated melanin granules, 3= Dense and aggregated melanin granules. Density of melanocytes was evaluated under 10X magnification. Five consecutive fields were evaluated for melanocytes and melanin granules starting from the field of highest density. There was an insignificant increase in number of melanocytes and melanin granules in mild and moderate dysplasia compared to normal but significant reduction was observed in severe dysplasia. The decrease in number of melanocytes and melanin granules was proportional to severity of epithelial dysplasia. This could be due to chronic irritation by chemical products leading to death of melanocytes.

P16 Methylation as an Early Predictor for Cancer Development From Oral Epithelial Dysplasia: A Double-blind Multicentre Prospective Study

BackgroundSilencing of P16 through methylation and locus deletion is the most frequent early events in carcinogenesis. The aim of this study is to prospectively determine if early P16 methylation is a predictor for oral cancer development. MethodsPatients (n=181) with mild or moderate oral epithelial dysplasia (OED) were recruited into the double blind multicentre cohort. P16 methylation was analyzed using the MethyLight assay. Progression of OEDs was monitored for a minimum 3year follow-up period. FindingsP16 methylation-informative cases (n=152) were enrolled in the prospective multicenter cohorts with an ultimate compliance of 96.7%. OED-derived squamous cell carcinomas were observed in 21 patients (14.3%) during the follow-up (median, 41.0months). The cancer progression rate from the P16 methylation-positive patients was significantly increased when compared to P16 methylation-negative patients [27.1% vs 8.1%; adjusted odds ratio=4.6; P=0.006]. When the P16 methylation-positive criteria were used as a biomarker for early prediction of cancer development from OEDs, sensitivity and specificity of 62% and 76% were obtained, respectively. InterpretationP16 methylation is unequivocally a marker for determining the malignant potential of OED and there is no need for further research regarding this aspect. FundingNational Basic Research Programs of China (2011CB504201 and 2015CB553902), Beijing Science and Technology Commission (Z090507017709016), and Beijing Municipal Administration of Hospital (XM201303) to Dajun Deng. The funding agencies have no role in the actual experimental design, patient recruitment, data collection, analysis, interpretation, or writing of this manuscript.

Immunohistochemical expression of TLR4 and TLR9 in various grades of oral epithelial dysplasia and squamous cell carcinoma, and their roles in tumor progression: a pilot study

Toll-like receptors (TLRs) play an essential role in the activation of innate immunity. TLRs are expressed in B-lymphocytes, monocytes, dendritic cells and epithelial cells. We examined the immunohistochemical expressions of TLR4 and TLR9 in various grades of oral epithelial dysplasia (OED), oral squamous cell carcinoma (OSCC) and normal oral mucosa (NOM) to determine the association between TLR4 and TLR9 in the progression of lesions from dysplasia to carcinoma. Expressions of TLR4 and TLR9 were assessed using immunohistochemistry (IHC) on paraffin embedded tissue blocks of various grades of OED (28 cases), OSCC (27 cases) and NOM (10 cases). Expression of TLR4 was high in all grades of OED and OSCC. Expression of TLR9 was high in well differentiated squamous cell carcinoma and moderately differentiated squamous cell carcinomas, and moderate to low in poorly differentiated squamous cell carcinomas. Although expression was high in case of TLR4, it was not statistically significant. Expression of TLR9 was statistically significant. In OED, expression of TLR9 was less than that of TLR4. Our results indicated that the pattern of expression of TLR4 and TLR9 increased significantly from mild to severe dysplasia compared to controls. Expression of TLR4 and TLR9 reflects progression of OED to OSCC, which suggests that TLR may play a role in tumorigenesis and that it could be used as a target for OSCC prevention and therapy in the future.

Heparanase and cyclooxygenase-2 gene and protein expressions during progression of oral epithelial dysplasia to carcinoma

Heparanase and cyclooxygenase-2 (COX-2) are 2 key enzymes that modulate diverse physiological processes during embryonic development and in adult life. Their deregulations have been implicated in the growth and progression of many cancer types. To date, comparatively little is known about the roles of these molecules during oral carcinogenesis. The aim of this study was to investigate the expression patterns of heparanase and COX-2 during progression of oral epithelial dysplasia (OED) to carcinoma. In situ hybridization and immunohistochemistry were performed on 5 cases of normal mucosa, 15 cases of OED, 5 cases of carcinoma in situ and/or microinvasive carcinoma, and 40 cases of oral squamous cell carcinoma (OSCC). Results demonstrated that heparanase and COX-2 messenger RNA and protein were absent in normal oral mucosa but were coexpressed in increasing intensity as OED progressed to OSCC. Concomitant heparanase- and COX-2-positive staining in the stromal cells suggests that OED/OSCC progression may be modulated by stromal-cancer cell interactions. Diffuse intense staining of poorly differentiated OSCC compared with staining localized to tumor nest periphery in well- and moderately differentiated OSCC suggests that heparanase and COX-2 overexpressions correlated with tumor grade. Strong expression of these enzymes in tumor cells at the advancing front suggests a role in local tumor spread. These results, taken together, suggest that heparanase and COX-2 might play complementary roles in the stepwise progression of OED to carcinoma.

Methylation of p16 CpG Island Associated with Malignant Progression of Oral Epithelial Dysplasia: A Prospective Cohort Study

Inactivation of p16 gene by CpG methylation is a frequent event in oral epithelial dysplasia. To investigate the predictive value of p16 methylation on malignant potential in oral epithelial dysplasia, we carried out the prospective cohort study. One hundred one patients with histologically confirmed mild or moderate oral epithelial dysplasia were included in the present cohort study. p16 Methylation status of the oral epithelial dysplasia lesions from 93 cases was obtained by methylation-specific PCR. Progression of the oral epithelial dysplasia lesions was examined in 78 cases histologically during a 45.8 months follow-up period. The association between p16 methylation and progression of oral epithelial dysplasia was analyzed. Of the 93 enrolled cases, 15 cases were lost during the follow-up because of changes of contact information, with a compliance of 83.9%. p16 Methylation was detectable in oral epithelial dysplasia lesions from 32 (41.0%) of 78 enrolled patients. Oral epithelial dysplasia-related squamous cell carcinomas were observed in 22 patients (28.2%) during the follow-up. Rate of progression to oral cancer in patients with the p16-methylated oral epithelial dysplasia was significantly higher than that with the p16-unmethylated oral epithelial dysplasia (43.8% versus 17.4%; adjusted odds ratio, 3.7; P = 0.013), especially for patients at the baseline age of > or = 60 years (adjusted odds ratio, 12.0; P = 0.003) and patients with moderate oral epithelial dysplasia (adjusted odds ratio, 15.6; P = 0.022). The overall sensitivity and specificity of prediction of malignant transformation of oral epithelial dysplasia by p16 methylation were 63.6% and 67.9%, respectively. p16 Methylation was correlated with malignant transformation of oral epithelial dysplasia and is a potential biomarker for prediction of prognosis of mild or moderate oral epithelial dysplasia.