Oral cancers preceded by proliferative verrucous leukoplakia exhibit distinctive molecular features.

OBJECTIVE: Proliferative verrucous leukoplakia (PVL) has high rates of malignant transformation into oral squamous cell carcinoma (OSCC), but the clinical and evolutionary pattern of OSCC from PVL (PVL-OSCC) is more favorable than that of OSCC not preceded by PVL (OSCC). Here, we aimed to explore the pathophysiologic differences between PVL-OSCC and OSCC through transcriptomic and DNA methylation analyses. MATERIALS AND METHODS: In this case-control study, oral biopsies from 8 PVL-OSCC and 10 OSCC patients were obtained for global sequencing using RNAseq and a genome-wide DNA methylation analysis via the Infinium EPIC Platform (graphical abstract). RESULTS: One hundred and thirty-three differentially expressed genes (DEGs) were detected, 94 of them upregulated in OSCC. Most of these genes were previously described in cancer and associated with prognosis. The integrative analysis revealed 26 DEGs, corresponding to 37 CpGs, whose promoters were regulated by DNA methylation. Twenty-nine of the CpGs were found as hypermethylated in PVL-OSCC. Only 5 of the genes that were aberrantly methylated and differentially expressed were upregulated in PVL-OSCC patients, whereas 21 were underexpressed. CONCLUSIONS: PVL-OSCC patients presented lower expression of cancer-related genes. Hypermethylation of the promoter region of many genes was also noticed, indicating that DNA methylation could be a regulatory mechanism.

On the Oral Microbiome of Oral Potentially Malignant and Malignant Disorders: Dysbiosis, Loss of Diversity, and Pathogens Enrichment.

The role of dysbiosis in the development and progression of oral potentially malignant disorders (OPMDs) remains largely unknown. Here, we aim to characterize and compare the oral microbiome of homogeneous leucoplakia (HL), proliferative verrucous leukoplakia (PVL), oral squamous cell carcinoma (OSCC), and OSCC preceded by PVL (PVL-OSCC). Fifty oral biopsies from HL (n = 9), PVL (n = 12), OSCC (n = 10), PVL-OSCC (n = 8), and healthy (n = 11) donors were obtained. The sequence of the V3-V4 region of the 16S rRNA gene was used to analyze the composition and diversity of bacterial populations. In the cancer patients, the number of observed amplicon sequence variants (ASVs) was lower and Fusobacteriota constituted more than 30% of the microbiome. PVL and PVL-OSCC patients had a higher abundance of Campilobacterota and lower Proteobacteria than any other group analyzed. A penalized regression was performed to determine which species were able to distinguish groups. HL is enriched in Streptococcus parasanguinis, Streptococcus salivarius, Fusobacterium periodonticum, Prevotella histicola, Porphyromonas pasteri, and Megasphaera micronuciformis; PVL is enriched in Prevotella salivae, Campylobacter concisus, Dialister pneumosintes, and Schaalia odontolytica; OSCC is enriched in Capnocytophaga leadbetteri, Capnocytophaga sputigena, Capnocytophaga gingivalis, Campylobacter showae, Metamycoplasma salivarium, and Prevotella nanceiensis; and PVL-OSCC is enriched in Lachnospiraceae bacterium, Selenomonas sputigena, and Prevotella shahii. There is differential dysbiosis in patients suffering from OPMDs and cancer. To the best of our knowledge, this is the first study comparing the oral microbiome alterations in these groups; thus, additional studies are needed.

Quantitative proteomics in medication-related osteonecrosis of the jaw: A proof-of-concept study.

OBJECTIVE: Medication-related osteonecrosis of the jaw (MRONJ) is a paradoxical effect associated with bone-modifying agents (BMAs) and other drugs. Currently, no valuable diagnostic or prognosis biomarkers exist. The goal of this research was to study MRONJ-related salivary proteome. MATERIALS AND METHODS: This case-control aimed to study salivary proteome in MRONJ versus control groups (i) formed from BMAs consumers and (ii) healthy individuals to unravel biomarkers. Thirty-eight samples of unstimulated whole saliva (18 MRONJ patients, 10 BMA consumers, and 10 healthy controls) were collected. Proteomic analysis by SWATH-MS coupled with bioinformatics analysis was executed. RESULTS: A total of 586 proteins were identified, 175 proteins showed significant differences among MRONJ versus controls. SWATH-MS revealed differentially expressed proteins among three groups, which have never been isolated. These proteins had distinct roles including cell envelope organization, positive regulation of vesicle fusion, positive regulation of receptor binding, or regulation of low-density lipoprotein particle clearance. Integrative analysis prioritized 3 proteins (MMP9, AACT, and HBD). Under receiver-operating characteristic analysis, this panel discriminated MRONJ with a sensitivity of 90% and a specificity of 78.9%. CONCLUSION: These findings may inform a novel biomarker panel for MRONJ prediction or diagnosis. Nonetheless, further research is needed to validate this panel.

Oral leukoplakia diagnosis and treatment in Europe and Australia: Oral Medicine Practitioners' attitudes and practice.

The management of oral potentially malignant disorders (OPMD) including oral leukoplakia (OL) is not currently structured according to agreed guidelines. The current report presents survey data gathered from Oral Medicine Practitioners (OMPs) in Europe and Australia and is aimed to investigate attitudes and practice in the diagnosis, risk stratification and treatment of OL. In the presence of a clinical provisional diagnosis of OL, respondents reported always undertaking biopsy in 83% of cases, with most OMPs also relying on diagnostic adjuncts. The potential for malignant transformation is almost invariably assessed through epithelial dysplasia status, with other biomarkers described in the literature used less often. Active treatment of OL was considered mandatory by 20% of OMPs, while others reserve treatment for selected cases only. OMPs are mostly driven to active treatment by lesion-related features which are frequently jointly considered including lesion site, clinical appearance and dysplasia status. Inconsistent assessment was observed regarding mild dysplasia, lesion size, presence of unavoidable trauma, exposure to tobacco and patient age. Frequently observed geographical variations were seldom statistically significant. In agreement with previous surveys, a lack of consensus around the management of OL was observed, supporting claims from learned academies and societies for treatment guidelines aiming to reduce inter-practitioner variability.

Prediction of the risk of cancer and the grade of dysplasia in leukoplakia lesions using deep learning.

OBJECTIVES: To estimate the probability of malignancy of an oral leukoplakia lesion using Deep Learning, in terms of evolution to cancer and high-risk dysplasia. MATERIALS AND METHODS: A total of 261 oral leukoplakia lesions with a mean of 5.5 years follow-up were analysed from standard digital photographs. A deep learning pipeline composed by a U-Net based segmentation of the lesion followed by a multi-task CNN classifier was used to predict the malignant transformation and the risk of dysplasia of the lesion. An explainability heatmap is constructed using LIME in order to interpret the decision of the model for each output. RESULTS: A Dice coefficient of 0.561 was achieved on the segmentation task. For the prediction of a malignant transformation, the model provided a sensitivity of 1 with a specificity of 0.692. For the prediction of high-risk dysplasia, the model achieved a specificity of 0.740 and a sensitivity of 0.928. CONCLUSION: The proposed model using deep learning can be a helpful tool for predicting the possible malignant evolution of oral leukoplakias. The generated heatmap provides a high confidence on the output of the model and enables its interpretability.

Effect of clinical and histologic features on time to malignancy in 224 cases of oral leukoplakia treated by surgery.

OBJECTIVES: Our main purpose and research question were to analyze and quantify whether there were significant differences in the time to develop cancer among patients with oral leukoplakia (OL), comparing the more susceptible cases to those with the least susceptibility to malignancy. MATERIALS AND METHODS: We followed 224 cases of OL after surgical or CO2 laser treatment for a mean time of 6.4 years. A Bayesian mixture cure model based on the Weibull distribution was used to model the relationship between our variables and cancer risk. In this model type, the population is considered a mixture of individuals who are susceptible or non-susceptible to developing cancer. The statistical model estimates the probability of cure (incidence model) and then infers the time to malignancy. The model was adjusted using the R-package INLA using default priors. RESULTS: Histology type (moderate or severe dysplasia) and tongue location showed hazard ratios (HR) of 3.19 (95% CI [1.05-8.59]) and 4.78 (95% CI [1.6-16.61]), respectively. Both variables increased the risk of malignant transformation, thus identifying a susceptible subpopulation with reduced time required to develop cancer, as with non-homogeneous leukoplakias. The median time for cancer development was 4 years and 5 months, with a minimum of 9 months after the diagnosis of OL and a maximum of 15 years and 2 months. CONCLUSIONS: Susceptible patients with non-homogeneous leukoplakia, dysplasia, or leukoplakia in the tongue develop cancer earlier than those with homogeneous OL and those without dysplasia. CLINICAL RELEVANCE: The novel contribution of this research is that, until now, the time it took for oral leukoplakias to develop cancer based on whether they were homogeneous or non-homogeneous, and if they have or not epithelial dysplasia, had not been comparatively described and quantified. As a final result, the time to malignant transformation in non-homogeneous and dysplastic leukoplakias is significantly shorter.

Oral medicine practice in Europe and Australia: Identifying practitioner characteristics and their clinical activity.

Oral Medicine is a young dental specialty born almost a century ago and deals with orofacial conditions not directly attributable to the most prevalent tooth pathologies such as dental caries or periodontal diseases. Presentations may reflect local disease or orofacial manifestations of more widespread pathology affecting other parts of the body. Due to its recency as a distinct discipline and to heterogeneous global settings, Oral Medicine has not yet achieved a shared scope and definition, as well as a recognized status across the globe. The current report presents survey data gathered from Oral Medicine practitioners in Europe and Australia and aimed to identify practitioner characteristics including demographics, training, clinical and research activity. As expected, Oral Medicine clinical practice commonly deals with conditions such as immune-mediated disorders, potentially malignant disorders, oral mucosal infections and chronic pain disorders, but geographical heterogeneities are observed. The present data, representative of current clinical practice, are valuable in order to understand the evolution of Oral Medicine as a distinct discipline and should be taken into consideration in order to create or update postgraduate training curricula able to meet the needs of future practitioners and the communities they serve.

Salivary IL-8 as a putative predictive biomarker of radiotherapy response in head and neck cancer patients.

OBJECTIVES: Ionizing radiation increases the expression of a number of salivary proteins involved in immunoregulatory networks related to infection, injury, inflammation, and cancer. Our main objective was to analyze whether there are significant differences in salivary cytokines before and after radiotherapy and whether any of them are associated to better outcomes after radiotherapy serving as a potential predictive biomarker of response to the treatment. MATERIALS AND METHODS: We analyzed a panel of eight salivary markers (IL-4, IL-6, IL-8, and IL-10; MCP-1; TNF-α; VEGF; and EGF) in a group of HNC patients (N = 30), before and after irradiation treatment pre- and post-RT. We also compared these results with a group of healthy controls (N = 37). In both groups, we used stimulated saliva and we performed immunoassays based on multi-analyte profiling technology (Luminex xMAP). RESULTS: In our group of 30 HNC patients, 24 of them showed a good clinical response after radiotherapy treatment while 6 cases did not respond to radiotherapy. The data revealed a post-treatment increase in multiple cytokines in the stimulated saliva of HNC patients; the increases in IL-8 and MCP-1 were statistically significant (p ≤ 0.001 and p ≤ 0.0001, respectively). Analysis of receiver operating characteristic curves indicated the strong potential of IL-8 as a predictive biomarker of RT good outcomes (area under the curve = 0.84; p = 0.018). CONCLUSIONS: After analyzing the panel of salivary cytokines, IL-8 showed the best association to the response to radiotherapy; in this sense, low IL-8 levels in the saliva of HNC patients before receiving irradiation therapy are associated with positive RT outcomes. CLINICAL RELEVANCE: Salivary IL-8 expression in HNC patients undergoing RT may serve as a potential predictive biomarker of response to the treatment.

Medication-Related Osteonecrosis of the Jaw: A Critical Narrative Review.

BACKGROUND: Nearly two decades have passed since a paradoxical reaction in the orofacial region to some bone modifying agents and other drugs was recognized, namely medication-related osteonecrosis of the jaw (MRONJ). PURPOSE: The aim of this manuscript was to critically review published data on MRONJ to provide an update on key terminology, concepts, and current trends in terms of prevention and diagnosis. In addition, our objective was to examine and evaluate the therapeutic options available for MRONJ. METHODS: The authors perused the most relevant literature relating to MRONJ through a search in textbooks and published articles included in several databases for the years 2003-2021. RESULTS AND CONCLUSIONS: A comprehensive update of the current understanding of these matters was elaborated, addressing these topics and identifying relevant gaps of knowledge. This review describes our updated view of the previous thematic blocks, highlights our current clinical directions, and emphasizes controversial aspects and barriers that may lead to extending the accumulating body of evidence related to this severe treatment sequela.

Oral microbiome in Proliferative Verrucous Leukoplakia exhibits loss of diversity and enrichment of pathogens.

OBJECTIVES: Oral microbiome plays an important role in oral diseases. Among them, proliferative verrucous leucoplakia (PVL) is an uncommon form of progressive multifocal leukoplakia with a worryingly rate of malignant transformation. Here, we aimed to characterize the oral microbiome of PVL patients and compare it with those of healthy controls. MATERIAL AND METHODS: Oral biopsies from ten PVL patients and five healthy individuals were obtained and used to compare their microbial communities. The sequence of the V3-V4 region of 16S rRNA gene was used as the taxonomic basis to estimate and analyze the composition and diversity of bacterial populations present in the samples. RESULTS: Our results show that the oral microbial composition and diversity are significantly different among PVL patients and healthy donors. The average number of observed operational taxonomic units (OTUs) was higher for healthy donors than for PVL, proving a loss of diversity in PVL. Several OTUs were found to be more abundant in either group. Among those that were significantly enriched in PVL patients, potential protumorigenic pathogens like Oribacterium sp. oral taxon 108, Campylobacter jejuni, uncultured Eubacterium sp., Tannerella, and Porphyromonas were identified. CONCLUSION: Oral microbiome dysbiosis was found in patients suffering from PVL. To the best of our knowledge, this is the first study investigating the oral microbiome alterations in PVL and, due to the limited number of participants, additional studies are needed. Oral microbiota-based biomarkers may be helpful in predicting the risks for the development of PVL.

Assembling a consensus on actinic cheilitis: A Delphi study.

AIMS: To discuss the terminology to define and classify actinic cheilitis (AC) and to build a consensus on the diagnostic and therapeutic approaches to AC. METHODS: Two-round Delphi study using a questionnaire including 34 closed sentences (9 on terminology and taxonomy, 5 on potential for malignant transformation, 12 on diagnostic aspects, 8 on treatment) and 8 open questions. Experts' agreement was rated using a Likert scale (1-7). RESULTS: A consensus was reached on 24 out 34 statements (73.5%) and on 5 out of 8 (62.5%) close-ended questions. The response rate was identical in both rounds (attrition of 0%). AC is the term with the highest agreement (median of 7 (strongly agree; IQR: 6-7)) and the lowest dispersion (VC = 21.33). 'Potentially malignant disorder' was the preferred classification group for AC (median of 7) and 85.6% of participants showing some level of agreement (CV < 50). Experts (66.75%) consider AC a clinical term (median: 7; IQR: 4-7) and believe definitive diagnosis can be made clinically (median: 6; IQR: 5-7), particularly by inspection and palpation (median: 5; IQR: 4-6). Histopathological confirmation is mandatory for the management of AC (median: 5; IQR: 2.5-7), even for homogeneous lesions (median: 5; IQR: 3.5-6). Consensus was reached on all treatment statements (VC < 50). CONCLUSIONS: AC is a potentially malignant disorder with a significant lack of agreement on diagnostic criteria, procedures, biopsy indications and the importance of techniques to assist in biopsy. A consensus was reached on nomenclature and management of this disorder.

Retraction: Oral leukoplakia, a clinical-histopathological study in 412 patients.

The authors detected some minor errors in the published manuscript (Rubert A, Bagán L, Bagán JV. Oral leukoplakia, a clinical-histopathological study in 412 patients. J Clin Exp Dent. 2020 Jun 1;12(6):e540-e546. doi: 10.4317/jced.57091. PMID: 32665812; PMCID: PMC7335600.) and have requested that the entire article be republished with these errors already rectified. BACKGROUND: A retrospective clinical-histopathological study was made of the evolution of oral leukoplakia over time, staging the disease according to the classification of van der Waal. MATERIAL AND METHODS: A study was made of 412 patients with oral leukoplakia, analyzing the corresponding clinical factors and histopathological findings; assessing associations between the different clinical presentations and epithelial dysplasia; and evaluating the factors influencing malignant transformation of the lesions. RESULTS: Clinically, homogeneous presentations were seen to predominate (n = 336, 81.6%), while histologically most of the lesions exhibited no dysplastic changes (n = 271; 65.7%). Stage 1 of the van der Waal classification was the most common presentation (n = 214; 51.9%). The lesion malignization rate was 8.5%, and the factors associated to a significantly increased malignization risk were non-homogeneous OL lesions (p=0.00), lesion location in the tongue (p=0.00), and the presence of epithelial dysplasia (p=0.00). CONCLUSIONS: In our series of patients with oral leukoplakia, malignization was associated to the less common clinical presentations of the disease, i.e., non-homogeneous lesions, and the latter tended to exhibit high grade epithelial dysplasia. Key words:Oral leukoplakia, potentially malignant disorders, malignant transformation.

Malignant transformation of oral proliferative verrucous leukoplakia: A systematic review and meta-analysis.

OBJECTIVES: To investigate the available evidence on the malignant transformation (MT) of oral proliferative verrucous leukoplakia (PVL). MATERIAL AND METHODS: We searched six main electronic and three grey literature databases in a two-phase process. Cohort studies investigating MT of PVL were eligible for inclusion. The risk of bias (RoB) was assessed using a specific tool developed by the Joanna Briggs Institute. Proportion meta-analyses were performed using a random-effects model. RESULTS: Study selection resulted in the inclusion of 17 studies. The pooled proportion of MT was 43.87% (95% CI = 31.93-56.13). Females (64.02%, 95% CI = 54.87-72.75) were more affected by PVL than males (35.98%, 95% CI = 27.25-45.13). Gingiva (39.6%) and buccal mucosa (21.6%) were the most frequent PVL sites. No conclusive results were found between MT and sex or age distribution, tobacco, or alcohol consumption. Gingiva was the most common site for MT (39.9%), and the most frequent histopathological subtype was conventional squamous cell carcinoma (62.1%). Four studies were classified as low, nine as moderate, and four as high RoB. CONCLUSION: The MT pooled proportion was 43.87%. Among OPMDs, PVL has the highest risk to transform to malignancy. Development and agreement on diagnostic criteria for PVL would reduce the heterogeneity among future studies.

Stimulated whole salivary flow rate: The most appropriate technique for assessing salivary flow in Sjögren syndrome / Caudal salival total estimulado: la técnica más adecuada para evaluar el flujo salival en el síndrome de Sjögren

Background: We sought to determine the most appropriate method for measuring salivary flow to aid the diag-nosis of Sjögren's syndrome (SS). Specifically, we compared the unstimulated whole salivary flow rate (UWSFR)with the stimulated whole salivary flow rate (SWSFR).Material and Methods: This case-control study comprised one group of 103 patients with SS and a control group of50 healthy people. We measured the UWSFR and SWSFR in both groups according to the guidelines establishedby Navacet (1993).Results: The UWSFR and SWSFR were significantly lower in the patient group compared with the controls ( p <0.01). Among the participants in the patient group, we found a decreased UWSFR in 84 individuals (81.5%) and adecreased SWSFR in 90 individuals (87.4%). We encountered difficulties obtaining saliva in 37 (35.9%) patientsduring the UWSFR test, and in 12 (11.7%) patients during the SWSFR test. There was no significant statisticaldifference in the UWSFR or SWSFR between patients with primary and secondary SS.Conclusions: Compared with the UWSFR, the SWSFR is a more suitable and effective method for measuringsalivary flow in patients with SS, as well as for qualitative analysis of the obtained saliva.(AU)

Potential Non-Invasive Biomarkers for Early Diagnosis of Oral Squamous Cell Carcinoma.

This study aimed to investigate the role of a panel of salivary cytokines as biomarkers for early detection oral squamous cell carcinoma (OSCC), comparing their levels among healthy individuals, patients with oral leukoplakia (OL), and malignant lesions. Cytokine profiling analysis performed in a minimally invasive sample was correlated with clinicopathological variables in our patient cohorts. Unstimulated saliva was obtained from subjects with OSCC at early (n = 33) and advanced (n = 33) disease, OL with homogeneous (n = 33) and proliferative verrucous (n = 33) clinical presentations, and healthy controls (n = 25). Salivary IL-1α, IL-6, IL-8, IP-10, MCP-1, TNF-α, HCC-1, and PF-4 levels were analyzed by a sensitive bead-based multiplex immunoassay. Mean levels of IL-6, IL-8, TNF-α, HCC-1, MCP-1, and PF-4 differed significantly between OSCC, OL, and control saliva (p < 0.05). We found notably higher IL-6 and TNF-α in advanced compared to early OSCC stages. The area under the curve (AUC) for OSCC vs. control was greater than 0.8 for IL-6, IL-8, TNF-α, and HCC-1, and greater than 0.7 for PF-4. The presence of neck metastases (NM) was associated with increased IL-6 and TNF-α levels. Our findings suggest that salivary IL-6, IL-8, TNF-α, HCC-1, and PF-4 may discriminate between OSCC, OL, and healthy controls. IL-6 and TNF-α may indicate OSCC progression, being distinctive in the presence of NM.

Recurrences following treatment of proliferative verrucous leukoplakia: A systematic review and meta-analysis.

BACKGROUND: A systematic review and meta-analysis were made of the incidence of recurrences in patients with proliferative verrucous leukoplakia (PVL) subjected to different types of treatment. METHODS: The study was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. A literature search was made in the Medline (PubMed), EMBASE, and Web of Science databases, together with a manual search, covering the period from 1985 to January 2020, with no language restrictions. Studies were included if they described treatments applied to at least 10 patients with the corresponding outcomes. Methodological quality was evaluated using Jadad scale and Newcastle-Ottawa tool. Global incidence was calculated by random effects meta-analysis using the Comprehensive Meta-analysis version 3.0 software. Publication bias was assessed using funnel plots and the Duval and Tweedie trim and fill method. RESULTS: Of the 922 identified articles, 12 were found to meet the inclusion criteria. Most of them presented moderate or low risk of bias. A total of 397 patients were analyzed. The mean age was 62.34 years and 248 were women (62.5%). The mean follow-up was 79.3 months. The most frequent treatment was surgical removal with a cold scalpel or laser (339 patients). A total of 232 subjects presented lesion recurrence. The combination of proportions global effect meta-analysis yielded a recurrence rate of 67.2% (95% CI: 48.3-81.8), with the absence of publication bias. CONCLUSIONS: There is not enough scientific evidence to conclude that any treatment strategy is able to reduce the recurrence in PVL.

Differentially methylated genes in proliferative verrucous leukoplakia reveal potential malignant biomarkers for oral squamous cell carcinoma.

OBJECTIVES: To explore the pathophysiology of proliferative verrucous leucoplakia (PVL) through a methylated DNA immunoprecipitation and high-throughput sequencing (MeDIP-seq) case-control study. MATERIALS AND METHODS: Oral biopsies from ten PVL patients and five healthy individuals were obtained and used to compare their epigenetic patterns. Network biology methods and integrative analyses of MeDIP-seq and RNAseq data were applied to investigate functional relations among differentially methylated genes (DMGs). The value of selected genes as malignant biomarkers was evaluated in a large cohort of oral squamous cell carcinoma (OSCC) patients from TCGA. RESULTS: A total of 4647 differentially methylated regions were found, with a prominent state of hypermethylation in PVL patients. At the gene level, differentially methylated regions (DMRs) covered 826 genes with distinct roles, including transcription factors and binding proteins with functions in cell adhesion, migration, proliferation, regulation of transcription, bone morphogenesis, and cell signalling. Network analysis revealed three major hubs, two of them collecting proteins related to the response of the patients to PVL and treatment and one hub collecting proteins related to PVL and cancer. The integrative analysis revealed 8 genes (ARTN, CD8A, GATA3, HOXD10, MYO7A, OSR2, PLCB1, and SPOCK2) significantly upregulated in PVL compared to control and 5 genes (ANKRD6, DLG2, GPX3, PITX2, and ZNF736) significantly downregulated. The status of de-regulation found for PVL patients was concordant with what was found for OSCC samples compared to normal adjacent tissue. CONCLUSION: Our findings show the potential of methylation markers in PVL and suggest novel OSCC diagnostic biomarkers which may boost the development of novel epigenetic-based therapies.

Oral potentially malignant disorders: A consensus report from an international seminar on nomenclature and classification, convened by the WHO Collaborating Centre for Oral Cancer.

Oral potentially malignant disorders (OPMDs) are associated with an increased risk of occurrence of cancers of the lip or oral cavity. This paper presents an updated report on the nomenclature and the classification of OPMDs, based predominantly on their clinical features, following discussions by an expert group at a workshop held by the World Health Organization (WHO) Collaborating Centre for Oral Cancer in the UK. The first workshop held in London in 2005 considered a wide spectrum of disorders under the term "potentially malignant disorders of the oral mucosa" (PMD) (now referred to as oral potentially malignant disorders: OPMD) including leukoplakia, erythroplakia, proliferative verrucous leukoplakia, oral lichen planus, oral submucous fibrosis, palatal lesions in reverse smokers, lupus erythematosus, epidermolysis bullosa, and dyskeratosis congenita. Any new evidence published in the intervening period was considered to make essential changes to the 2007 classification. In the current update, most entities were retained with minor changes to their definition. There is sufficient evidence for an increased risk of oral cancer among patients diagnosed with "oral lichenoid lesions" and among those diagnosed with oral manifestations of 'chronic graft-versus-host disease'. These have now been added to the list of OPMDs. There is, to date, insufficient evidence concerning the malignant potential of chronic hyperplastic candidosis and of oral exophytic verrucous hyperplasia to consider these conditions as OPMDs. Furthermore, due to lack of clear evidence of an OPMD in epidermolysis bullosa this was moved to the category with limited evidence. We recommend the establishment of a global research consortium to further study the natural history of OPMDs based on the classification and nomenclature proposed here. This will require multi-center longitudinal studies with uniform diagnostic criteria to improve the identification and cancer risk stratification of patients with OPMDs, link them to evidence-based interventions, with a goal to facilitate the prevention and management of lip and oral cavity cancer.

Immune expression profile identification in a group of proliferative verrucous leukoplakia patients: a pre-cancer niche for oral squamous cell carcinoma development.

OBJECTIVES: To explore the pathophysiology of proliferative verrucous leukoplakia, a rare oral disorder that exhibits high rates of recurrence and malignant transformation, through a RNAseq case-control study. MATERIAL AND METHODS: We obtained oral biopsies from 10 patients with verrucous leukoplakia lesions and from the mucosa of 5 healthy individuals for sequencing using RNAseq technology. Using bioinformatic methods, we investigated gene expression and enrichment differences between patients both with and without the disorder. We applied network biology methods to investigate functional relations among those genes that were differentially deregulated. RESULTS: We detected 140 differentially expressed genes with distinct roles in immune surveillance, tissue and organ morphogenesis, development, and organization. Of these 140 genes, 111 have been previously described as cancer expression biomarkers, being oral squamous cell carcinoma the most represented type of cancer among them. Of these 140 genes, 26 were prioritized for further investigation as biomarkers using larger sample sizes. CONCLUSIONS: The gene expression patterns of healthy and unhealthy patients differed in 140 genes whose deregulation has a functional impact on normal functioning of the immune system. This immune expression profile provides a plausible hypothesis to explain the transformation to oral squamous cell carcinoma observed in 6 of the 10 assayed cases. CLINICAL RELEVANCE: By determining the molecular bases of the proliferative verrucous leukoplakia disorder and identifying early biomarkers of malignancy, this can allow us to develop new treatment strategies.

Osteonecrosis of the jaws associated with denosumab: Study of clinical and radiographic characteristics in a series of clinical cases.

BACKGROUND: The objective of this study was to describe the clinical and radiographic characteristics of our series of medication-related osteonecrosis of the jaws (ONJ) associated with denosumab. MATERIAL AND METHODS: We presented 15 cases of ONJ associated with denosumab; 11 received treatment for their osteoporosis and four for cancer treatments. We recorded the most frequent clinical findings, symptoms and radiographic characteristics in our patient group, as well as local and systemic contributing factors. RESULTS: The mean time of treatment with denosumab was 23.83 ± 12.84 months. 40% of the patients had a previous history of treatment with bisphosphonates. The most common local factor was tooth extraction (11 cases; 73.3%), and in most cases there was necrotic bone exposure (13/15, 86.67%). Osteolysis, bone sclerosis and cortical erosion were the most common radiographic findings. Stage 1 was the most frequent, present in 60% of the cases. CONCLUSIONS: In our patient group, most were in the early stages of ONJ. Key words:Denosumab, osteonecrosis, jaws, radiology.