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.

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.

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.

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.

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.

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

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 8.3%, 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.

Salivary inflammatory proteins in patients with oral potentially malignant disorders.

Cytokines are a group of small proteins involved in the regulation of infection, immune responses and inflammation. Since altered cytokine responsiveness has been linked to Oral Squamous Cell Carcinoma (OSCC), research to date indicates the possibility of using salivary pro- and anti-inflammatory proteins for screening of oral disorders. OSCC is a multistep neoplasia in which many genetic and epigenetic changes have been correlated to cancerous transformation of oral potentially malignant disorders (OPMD) such as oral leukoplakia, erythroplakia and lichen planus. The goal of the innovative salivary diagnostics is the identification of a single or multiple biomarkers that will serve as a clinical test facilitating the diagnosis of patients predisposed to develop OSCC. Based on scientific literature review, this article summarizes the results from nine articles, all of them being case-control studies where TNF-α, IL-1ß, IL-6 and IL-8 were considered possible indicators of malignant transformation. Key words:Interleukins, saliva, oral premalignant lesions.

Concept, diagnosis and classification of bisphosphonate-associated osteonecrosis of the jaws. A review of the literature

BACKGROUND: Bisphosphonates (BPs) and other antiresorptive agents such as denosumab are widely prescribed for the treatment of osteoporosis and are also used in patients with multiple myeloma and metastatic breast or prostate cancer for avoiding bone reabsorption and fractures that result in increased morbidity-mortality among such individuals. MATERIAL AND METHODS: We made a bibliographic search to analyze the concept, diagnosis and the different classifications for bisphosphonate-associated osteonecrosis of the jaws. RESULTS: Osteonecrosis of the jaws (ONJ) is an important complication of exposure to BPs or other antiresorptive agents, and although its prevalence is low, it can pose management problems. The definition, diagnosis and classification of osteonecrosis have evolved since Marx reported the first cases in 2003. CONCLUSIONS: The present study offers a literature review and update on the existing diagnostic methods and classification of the disorder, with a view to facilitating earlier and more effective treatment

Effect of nonsurgical periodontal treatment in patients with periodontitis and rheumatoid arthritis: A systematic review

BACKGROUND: Periodontitis has been regarded as a potential risk factor for rheumatoid arthritis (RA). A systematic review is made to determine whether nonsurgical periodontal treatment in patients with RA offers benefits in terms of the clinical activity and inflammatory markers of the disease. MATERIAL AND METHODS: A search was made of the Medline-PubMed, Cochrane, Embase and Scopus databases to identify studies on the relationship between the two disease processes, and especially on the effects of nonsurgical treatment in patients of this kind. The search was based on the following keywords: rheumatoid arthritis AND periodontitis (MeSH), rheumatoid arthritis AND periodontal treatment. RESULTS: Eight articles on the nonsurgical treatment of patients with periodontitis and RA were finally included in the study. All of them evaluated clinical (DAS28) and laboratory test activity (ESR, CRP, IL-6, TNFá) before and after treatment. A clear decrease in DAS28 score and ESR was recorded, while other parameters such as CRP, IL-6 and TNFá showed a nonsignificant tendency to decrease as a result of treatment. CONCLUSIONS: Nonsurgical treatment improved the periodontal condition of patients with periodontitis and RA, with beneficial effects upon the clinical and laboratory test parameters (DAS28 and ESR), while other inflammatory markers showed a marked tendency to decrease. However, all the studies included in the review involved small samples sizes and follow-up periods of no more than 6 months. Larger and particularly longitudinal studies are therefore needed to more firmly establish possible significant relations between the two disease processes

Prevalence of salivary epstein-barr virus in potentially malignant oral disorders and oral squamous cell carcinoma

BACKGROUND: To analyze the presence of salivary Epstein-Barr virus (EBV) DNA in oral squamous cell carcinoma and potentially malignant oral disorders. MATERIAL AND METHODS: Three groups were studied: Group 1 (12 oral squamous cell carcinomas (OSCC)), Group 2 (12 potentially malignant oral disorders (PMD)) and Group 3 (47 healthy controls). EBV DNA salivary analysis was performed by PCR. RESULTS: The highest percentage of positive salivary EBV DNA corresponded to the OSCC group (58.3%), followed by the PMD group (41.7%) and the controls (40.4%). The differences between groups were not statistically significant, however (p > 0.05). CONCLUSIONS: Salivary EBV DNA was more prevalent in OSCC than in PMD or the controls

Prevalence of salivary Epstein-Barr virus in potentially malignant oral disorders and oral squamous cell carcinoma.

BACKGROUND: To analyze the presence of salivary Epstein-Barr virus (EBV) DNA in oral squamous cell carcinoma and potentially malignant oral disorders. MATERIAL AND METHODS: Three groups were studied: Group 1 (12 oral squamous cell carcinomas (OSCC)), Group 2 (12 potentially malignant oral disorders (PMD)) and Group 3 (47 healthy controls). EBV DNA salivary analysis was performed by PCR. RESULTS: The highest percentage of positive salivary EBV DNA corresponded to the OSCC group (58.3%), followed by the PMD group (41.7%) and the controls (40.4%). The differences between groups were not statistically significant, however (p>0.05). CONCLUSIONS: Salivary EBV DNA was more prevalent in OSCC than in PMD or the controls.

Salivary and serum interleukin-6 levels in proliferative verrucous leukoplakia.

BACKGROUND: Cytokines and chemokines have been analysed in patients with oral squamous cell carcinoma and potentially malignant disorders. We selected interleukin-6 (IL-6) because it is a multifunctional interleukin reported to be altered in potentially malignant oral disorders and in malignant lesions. To date, this has not been evaluated or tested in proliferative verrucous leukoplakia (PVL), however. OBJECTIVES: This study aimed to analyse the differences in serum and saliva IL-6 levels among patients with PVL, oral squamous cell carcinoma (OSCC) and healthy controls and to examine the relationship between salivary IL-6 levels and the extent of the verrucous area. METHODS: Using an enzyme-linked immunosorbent assay, we determined the serum and saliva IL-6 levels in three groups: 20 patients with PVL, 20 with OSCC and 20 healthy controls. RESULTS: There were significant (p < 0.01) differences in the serum and saliva IL-6 levels among the three groups and among the three grades of extent of the verrucous areas (p = 0.01). In the OSCC group, there was a significant difference in the saliva IL-6 levels between patients with and without lymph node metastasis at diagnosis (p = 0.02). CONCLUSIONS: We found that patients with OSCC had the highest salivary and serum IL-6 levels, while PVL had lower values than OSCC, but higher than the controls, and these altered levels were associated with the extent of the verrucous areas. CLINICAL RELEVANCE: Salivary and plasma IL-6 are altered in patients with PVL, with more extensive verrucous areas being associated to the highest IL-6 levels. This could be a significant tool for monitoring patients with PVL, their progression to more advances stages and their recurrences.

Apixaban and oral implications.

BACKGROUND: Thrombotic disorders remain a leading cause of death in the Western world, and in this regard a number of anticoagulation treatment have been used, including heparins, fondaparinux, vitamin K antagonists (warfarin, acenocoumarol), and new oral anticoagulants such as apixaban. For years there has been great controversy regarding the use of anticoagulants in planning dental treatments that imply bleeding. The main concerns about using new oral anticoagulants in invasive dental procedures are bleeding due to the lack of an antidote, and the thrombotic risk of the disease for which anticoagulation was indicated in the first place. MATERIAL AND METHODS: A literature search was conducted through May 2014 using the keyword "apixaban" for publications in the ISI Web of Knowledge. The search was extended to other databases (PubMed, Scopus and the Cochrane Library). RESULTS: Based on the results of the different studies, apixaban seems to be a good alternative to conventional anticoagulation and a reasonable treatment option, though its main and most common adverse effect is bleeding. Dose adjustment is needed in some patients, though regular laboratory monitoring is not required. The use of the drug in different patient populations will define its final indications and doses. CONCLUSIONS: Regarding the use of apixaban in the dental setting, there is a compelling need for further clinical studies in order to establish more evidence-based guidelines for patients requiring antithrombotic treatment. KEY WORDS: Apixaban, dental treatment, dental implications.

Utility of imaging techniques in the diagnosis of oral cancer.

PURPOSE: Imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) are often used to complement the clinical exploration and staging of oral squamous cell carcinoma (OSCC). Which of these techniques is best in establishing correct staging and treatment planning is not clear, however. This study aims to determine which technique is most appropriate for diagnosing the primary tumor and for detecting bone invasion and neck metastases. MATERIAL AND METHODS: A Medline literature search was made over the last 10 years. In each selected study, we recorded the sample size and sensitivity, specificity and precision. Strengths and limitations of each study were assessed also. RESULTS: Eight articles relating to detection of the primary tumor, 19 to bone invasion, and 28 to neck metastases were selected and compared. CONCLUSION: Despite the high precision of positron emission tomography (PET) or hybrid techniques in detecting the primary tumor, they have not replaced magnetic resonance imaging (MRI) or computed tomography (CT), particularly in the case of small lesions. MRI and CT are adequate techniques in the assessment of bone invasion.Recent studies have shown good results with PET-CT and cone-beam CT, but future studies are needed to demonstrate their benefits. Despite the high precision of PET and PET-CT, their use in assessing neck metastases remains subject to controversy, and their use in all patients with OSCC is not justified. CT and MRI are useful in determining the N category.

Oral mucosal precancer and cancer: A helpful discriminating clinical tool

The authors have collaborated with many colleagues in several countries in formulating a useful and practical clinical tool for evaluating oral mucosal findings on routine examination. Consideration of several factors including history, evolution of positive findings and clinical information allows placement of examination results into one of three categories which are graded by a color scheme along a spectrum of concerns (green to red, or no concern to serious concern). Afforded to the clinician is a straightforward grading system as a starting point for office end clinic use for all patients

Oral mucosal precancer and cancer: A helpful discriminating clinical tool.

The authors have collaborated with many colleagues in several countries in formulating a useful and practical clinical tool for evaluating oral mucosal findings on routine examination. Consideration of several factors including history, evolution of positive findings and clinical information allows placement of examination results into one of three categories which are graded by a color scheme along a spectrum of concerns (green to red, or no concern to serious concern). Afforded to the clinician is a straightforward grading system as a starting point for office end clinic use for all patients.

Graft-versus-host disease affecting oral cavity. A review.

Graft versus host disease (GVHD) is one of the most frequent and serious complications of hematopoietic stem cell transplantation, and is regarded as the leading cause of late mortality unrelated to the underlying malignant disease. GVHD is an autoimmune and alloimmune disorder that usually affects multiple organs and tissues, and exhibits a variable clinical course. It can manifest in either acute or chronic form. The acute presentation of GVHD is potentially fatal and typically affects the skin, gastrointestinal tract and liver. The chronic form is characterized by the involvement of a number of organs, including the oral cavity. Indeed, the oral cavity may be the only affected location in chronic GVHD. The clinical manifestations of chronic oral GVHD comprise lichenoid lesions, hyperkeratotic plaques and limited oral aperture secondary to sclerosis. The oral condition is usually mild, though moderate to severe erosive and ulcerated lesions may also be seen. The diagnosis is established from the clinical characteristics, though confirmation through biopsy study is sometimes needed. Local corticosteroids are the treatment of choice, offering overall response rates of close to 50%. Extracorporeal photopheresis and systemic corticosteroids in turn constitute second line treatment. Oral chronic GVHD is not considered a determinant factor for patient survival, which is close to 52% five years after diagnosis of the condition. Key words:Chronic graft-versus-host disease, oral chronic graft-versus-host disease, pathogenics, management, survival.