Oral Cancer Screening: Past, Present, and Future.

Oral cancer is a major public health problem, and there is an increasing trend for oral cancer to affect young men and women. Public awareness is poor, and many patients present with late-stage disease, contributing to high mortality. Oral cancer is often preceded by a clinical premalignant phase accessible to visual inspection, and thus there are opportunities for earlier detection and to reduce morbidity and mortality. Screening asymptomatic individuals by systematic visual oral examinations to detect the disease has been shown to be feasible. A positive screen includes both oral cancer and oral potentially malignant disorders. We review key screening studies undertaken, including 1 randomized clinical trial. Screening of high-risk groups is cost-effective. Strengths and weaknesses of oral cancer screening studies are presented to help guide new research in primary care settings and invigorated by the prospect of using emerging new technologies that may help to improve discriminatory accuracy of case detection. Most national organizations, including the US Preventive Services Task Force, have so far not recommended population-based screening due a lack of sufficient evidence that screening leads to a reduction in oral cancer mortality. Where health care resources are high, opportunistic screening in dental practices is recommended, although the paucity of research in primary care is alarming. The results of surveys suggest that dentists do perform oral cancer screenings, but there is only weak evidence that screening in dental practices leads to downstaging of disease. Where health care resources are low, the feasibility of using primary health care workers for oral cancer screening has been tested, and measures indicate good outcomes. Most studies reported in the literature are based on 1 round of screening, whereas screening should be a continuous process. This review identifies a huge potential for new research directions on screening for oral cancer.

Nuclear F-actin Cytology in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma.

Oral cavity cancer has a low 5-y survival rate, but outcomes improve when the disease is detected early. Cytology is a less invasive method to assess oral potentially malignant disorders relative to the gold-standard scalpel biopsy and histopathology. In this report, we aimed to determine the utility of cytological signatures, including nuclear F-actin cell phenotypes, for classifying the entire spectrum of oral epithelial dysplasia and oral squamous cell carcinoma. We enrolled subjects with oral potentially malignant disorders, subjects with previously diagnosed malignant lesions, and healthy volunteers without lesions and obtained brush cytology specimens and matched scalpel biopsies from 486 subjects. Histopathological assessment of the scalpel biopsy specimens classified lesions into 6 categories. Brush cytology specimens were analyzed by machine learning classifiers trained to identify relevant cytological features. Multimodal diagnostic models were developed using cytology results, lesion characteristics, and risk factors. Squamous cells with nuclear F-actin staining were associated with early disease (i.e., lower proportions in benign lesions than in more severe lesions), whereas small round parabasal-like cells and leukocytes were associated with late disease (i.e., higher proportions in severe dysplasia and carcinoma than in less severe lesions). Lesions with the impression of oral lichen planus were unlikely to be either dysplastic or malignant. Cytological features substantially improved upon lesion appearance and risk factors in predicting squamous cell carcinoma. Diagnostic models accurately discriminated early and late disease with AUCs (95% CI) of 0.82 (0.77 to 0.87) and 0.93 (0.88 to 0.97), respectively. The cytological features identified here have the potential to improve screening and surveillance of the entire spectrum of oral potentially malignant disorders in multiple care settings.

Proliferative leukoplakia: Proposed new clinical diagnostic criteria.

OBJECTIVE: We aimed to characterize proliferative verrucous leukoplakia (PVL) from a clinical and histopathological standpoint and suggest an updated classification. SUBJECTS AND METHODS: Records of patients seen at three oral medicine centers with a clinical diagnosis of PVL were reviewed for clinical and histopathological features and malignant transformation (MT). RESULTS: There were 42 patients (median age: 69 years [range: 36-88]; 35 females). 12.2% were current smokers. Family history of cancer was present in 43.7% of patients. Partial demarcation of lesion margins was present in 31.3% of lesions, followed by verrucous (27.5%), smooth (22.7%) erythematous (22.3%), and fissured (18.3%) appearance. Large and contiguous and multisite and non-contiguous lesions comprised 57.1% (24/42) and 35.7% (15/42) of PVL cases, respectively. 19.1% had prominent erythema (erythroleukoplakia). The most common histopathological diagnosis at first visit was hyperkeratosis without dysplasia (22/42; 56.4%). MT occurred in 71.4% patients after a median of 37 months [range: 1-210] from initial visit; erythroleukoplakia exhibited MT in 100% of cases. CONCLUSION: The generic term "proliferative leukoplakia (PL)" may be more appropriate than PVL because 18.3% were fissured and 22.7% erythematous. We also propose the term proliferative erythroleukoplakia to more accurately describe the subset of PL with prominent erythema, which had the highest MT rate.

Evidence-based clinical practice guideline for the evaluation of potentially malignant disorders in the oral cavity: a report of the American Dental Association

BACKGROUND: An expert panel convened by the American Dental Association (ADA) Council on Scientific Affairs and the Center for Evidence-Based Dentistry conducted a systematic review and formulated clinical recommendations to inform primary care clinicians about the potential use of adjuncts as triage tools for the evaluation of lesions, including potentially malignant disorders (PMDs), in the oral cavity. TYPES OF STUDIES REVIEWED: This is an update of the ADA's 2010 recommendations on the early diagnosis of PMDs and oral squamous cell carcinoma. The authors conducted a systematic search of the literature in MEDLINE and Embase via Ovid and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials and diagnostic test accuracy studies. The authors used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty in the evidence and to move from the evidence to the decisions. RESULTS: The panel formulated 1 good practice statement and 6 clinical recommendations that concluded that no available adjuncts demonstrated sufficient diagnostic test accuracy to support their routine use as triage tools during the evaluation of lesions in the oral cavity. For patients seeking care for suspicious lesions, immediate performance of a biopsy or referral to a specialist remains the single most important recommendation for clinical practice. In exceptional cases, when patients decline a biopsy or live in rural areas with limited access to care, the panel suggested that cytologic testing may be used to initiate the diagnostic process until a biopsy can be performed (conditional recommendation, low-quality evidence). CONCLUSIONS AND PRACTICAL IMPLICATIONS: The authors urge clinicians to remain alert and take diligent action when they identify a PMD. The authors emphasize the need for counseling because patients may delay diagnosis because of anxiety and denial.(AU)

Host-Microbiome Cross-talk in Oral Mucositis.

Oral mucositis (OM) is among the most common, painful, and debilitating toxicities of cancer regimen-related treatment, resulting in the formation of ulcers, which are susceptible to increased colonization of microorganisms. Novel discoveries in OM have focused on understanding the host-microbial interactions, because current pathways have shown that major virulence factors from microorganisms have the potential to contribute to the development of OM and may even prolong the existence of already established ulcerations, affecting tissue healing. Additional comprehensive and disciplined clinical investigation is needed to carefully characterize the relationship between the clinical trajectory of OM, the local levels of inflammatory changes (both clinical and molecular), and the ebb and flow of the oral microbiota. Answering such questions will increase our knowledge of the mechanisms engaged by the oral immune system in response to mucositis, facilitating their translation into novel therapeutic approaches. In doing so, directed clinical strategies can be developed that specifically target those times and tissues that are most susceptible to intervention.

World Workshop on Oral Medicine VI: a systematic review of medication-induced salivary gland dysfunction.

The aim of this paper was to perform a systematic review of the pathogenesis of medication-induced salivary gland dysfunction (MISGD). Review of the identified papers was based on the standards regarding the methodology for systematic reviews set forth by the World Workshop on Oral Medicine IV and the PRISMA statement. Eligible papers were assessed for both the degree and strength of relevance to the pathogenesis of MISGD as well as on the appropriateness of the study design and sample size. A total of 99 papers were retained for the final analysis. MISGD in human studies was generally reported as xerostomia (the sensation of oral dryness) without measurements of salivary secretion rate. Medications may act on the central nervous system (CNS) and/or at the neuroglandular junction on muscarinic, α-and ß-adrenergic receptors and certain peptidergic receptors. The types of medications that were most commonly implicated for inducing salivary gland dysfunction were those acting on the nervous, cardiovascular, genitourinary, musculoskeletal, respiratory, and alimentary systems. Although many medications may affect the salivary flow rate and composition, most of the studies considered only xerostomia. Thus, further human studies are necessary to improve our understanding of the association between MISGD and the underlying pathophysiology.

World Workshop on Oral Medicine VI: a systematic review of the treatment of mucous membrane pemphigoid.

OBJECTIVE: To determine the efficacy and safety of interventions for mucous membrane pemphigoid (MMP). STUDY DESIGN: We conducted a systematic review from 2003 to 2013 according to the Cochrane Collaboration methodology. Randomized controlled trials (RCTs) or controlled clinical trials and observational studies were included, with diagnosis confirmed by clinical, histopathologic, and immunofluorescence criteria. The primary outcome was lesion remission or healing; several relevant secondary outcomes were also included. RESULTS: In the final analysis, 1 RCT and 32 observational studies were included. The one included RCT with a high risk of bias in multiple domains found limited evidence that pentoxifylline, combined with corticosteroid and cyclophosphamide, was more effective than standard therapy (corticosteroid + cyclophosphamide alone) for ocular MMP. We summarize here the outcomes from 32 observational studies examining 242 patients across 19 unique treatments. Interventions that show promise include rituximab and intravenous immunoglobulin. CONCLUSIONS: This systematic review is the most recent since 2003-2009. There is still lack of high-quality research providing evidence-based MMP treatments.

World Workshop on Oral Medicine VI: a systematic review of the treatment of mucocutaneous pemphigus vulgaris.

OBJECTIVE: To determine the efficacy and safety of interventions for pemphigus vulgaris (PV). STUDY DESIGN: We conducted a systematic review from 2003 to 2013 according to the Cochrane Collaboration methodology. Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) and observational studies were conducted along with diagnosis confirmed by clinical, histopathologic, and immunofluorescence criteria. Primary outcomes were disease remission and mortality; several relevant secondary outcomes were also included. RESULTS: Fourteen RCTs or CCTs and 110 observational studies were included in the final analyses. RCTs or CCTs demonstrated considerable heterogeneity in outcome measures, and all had a high risk of bias for at least 1 of 8 domains. Of the studies, 96.8% (120) described the use of oral corticosteroids. Azathioprine and mycophenolate-mofetil were the most commonly cited treatments. An increasing number of studies described biologic therapies (rituximab, intravenous immunoglobulin [IVIg]). Evidence supporting recent comprehensive treatment guidelines was reviewed. CONCLUSIONS: We found persisting wide variations in treatment practice and inadequate quality of research supporting optimal PV treatment.

The functions of human saliva: A review sponsored by the World Workshop on Oral Medicine VI.

This narrative review of the functions of saliva was conducted in the PubMed, Embase and Web of Science databases. Additional references relevant to the topic were used, as our key words did not generate references which covered all known functions of saliva. These functions include maintaining a moist oral mucosa which is less susceptible to abrasion, and removal of micro-organisms, desquamated epithelial cells, leucocytes and food debris by swallowing. The mucins form a slimy coating on all surfaces in the mouth and act as a lubricant during such processes as mastication, formation of a food bolus, swallowing and speaking. Saliva provides the fluid in which solid tastants may dissolve and distributes tastants around the mouth to the locations of the taste buds. The hypotonic unstimulated saliva facilitates taste recognition. Salivary amylase is involved in digestion of starches. Saliva acts as a buffer to protect oral, pharyngeal and oesophageal mucosae from orally ingested acid or acid regurgitated from the stomach. Saliva protects the teeth against acid by contributing to the acquired enamel pellicle, which forms a renewable lubricant between opposing tooth surfaces, by being supersaturated with respect to tooth mineral, by containing bicarbonate as a buffer and urea and by facilitating clearance of acidic materials from the mouth. Saliva contains many antibacterial, antiviral and antifungal agents which modulate the oral microbial flora in different ways. Saliva also facilitates the healing of oral wounds. Clearly, saliva has many functions which are needed for proper protection and functioning of the human body.

Comparison of two mouthrinses in relation to salivary flow and perceived dryness.

OBJECTIVE: To compare measures of dry mouth following extended use of an alcohol-based mouthrinse (LISTERINE Antiseptic [LA]) and a non-alcohol-based mouthrinse (Crest Pro-Health Rinse [CPH]) on healthy adults with "normal" salivary flow. METHODS: This single-site, randomized, observer-blinded, parallel study compared unstimulated whole salivary flow and perceived dryness following daily use at weeks 4 and 12 versus baseline. Noninferiority, between-treatment flow comparisons (0.15 mL/min margin), and between-treatment comparisons of the mean Bluestone Mouthfeel Questionnaire (BMQ) visual analog scale scores were made using analysis of covariance. RESULTS: Measures of dry mouth were comparable between mouthrinses, as demonstrated by both noninferiority of LA versus CPH flow (P < .001) and no significant differences between groups in the BMQ measures at 4 or 12 weeks. CONCLUSIONS: Extended use of an alcohol-based mouthrinse is no more likely to cause reduction in salivary flow or perceived dryness in individuals with normal salivary flow compared with a non-alcohol-based mouthrinse (CPH).

Report on World Workshops on Oral Medicine (WWOM) IV and V: research themes and citation impact: WWOM VI steering committee.

The first World Workshop on Oral Medicine (WWOM) was held in 1988. The portfolio has continued to expand in scope and impact over the past 26 years. Five World Workshops were conducted between 1988 and 2010, focusing on creation of systematic reviews in biomedicine and health care of importance to the international oral medicine community. WWOM VI was conducted in April 2014 and further extended this modeling. This most recent Workshop also fostered creation of the inaugural joint meeting between the American Academy of Oral Medicine and the European Association of Oral Medicine, together with The British Society for Oral Medicine and the Oral Medicine Academy of Australasia. The goal of the WWOM portfolio is to strategically enhance international oral medicine research, education, and clinical practice. To this end, this report summarizes subject areas for WWOM IV (2004) and research recommendations for WWOM V (2010), as well as citation metrics relative to publications from these two conferences. The information is designed to provide research and clinical context for key issues in oral medicine as delineated by the WWOM portfolio over the past 10 years, as well as for projected outcomes of WWOM VI over the next 12 months.

A systematic review of medical interventions for oral submucous fibrosis and future research opportunities.

Oral Diseases (2011) 17 (Suppl. 1), 42-57 Oral submucous fibrosis (OSF) is a chronic, insidious disease caused by areca nut use, and is associated with both significant morbidity (including pain and reduced oral opening) and an increased risk for malignancy. This systematic review explored and updated the current medical (i.e., non-surgical) interventions available for the management of OSF. Of the 27 published medical interventions, there were four randomized controlled trials. The overall quality of these randomized controlled studies was assessed using the GRADE approach and significant limitations that challenged the conclusions were found. However, this review was valuable in terms of identifying opportunities to provide recommendations for future research, in terms of the populations to research, the types of interventions needed, the types of outcomes to be measured, the study designs needed, and the infrastructure required to conduct studies. The next step is to initiate a pathway for a low-cost research plan leading to the development of a brief protocol for future clinical trials in this field, with an emphasis on conducting studies in regions of the world where OSF is prevalent.

Local drug delivery for oral mucosal diseases: challenges and opportunities.

There are few topical formulations used for oral medicine applications most of which have been developed for the management of dermatological conditions. As such, numerous obstacles are faced when utilizing these preparations in the oral cavity, namely enzymatic degradation, taste, limited surface area, poor tissue penetration and accidental swallowing. In this review, we discuss common mucosal diseases such as oral cancer, mucositis, vesiculo-erosive conditions, infections, neuropathic pain and salivary dysfunction, which could benefit from topical delivery systems designed specifically for the oral mucosa, which are capable of sustained release. Each condition requires distinct penetration and drug retention profiles in order to optimize treatment and minimize side effects. Local drug delivery may provide a more targeted and efficient drug-delivery option than systemic delivery for diseases of the oral mucosa. We identify those mucosal diseases currently being treated, the challenges that must be overcome and the potential of novel therapies. Novel biological therapies such as macromolecular biological drugs, peptides and gene therapy may be of value in the treatment of many chronic oral conditions and thus in oral medicine if their delivery can be optimized.

An international survey in postgraduate training in Oral Medicine.

OBJECTIVES: The aim of this preliminary study was to investigate postgraduate Oral Medicine training worldwide and to begin to identify minimum requirements and/or core content for an International Oral Medicine curriculum. MATERIALS AND METHODS: Countries where there was believed to be postgraduate training in Oral Medicine were identified by the working group. Standardized emails were sent inviting participants to complete an online survey regarding the scope of postgraduate training in Oral Medicine in their respective countries. RESULTS: We received 69 total responses from 37 countries. Of these, 22 countries self-identified as having postgraduate Oral Medicine as a distinct field of study, and they served as the study group. While there is currently considerable variation among Oral Medicine postgraduate training parameters, there is considerable congruency in clinical content of the Oral Medicine syllabi. For example, all of the training programs responded that they did evaluate competence in diagnosis and management of oral mucosal disease. CONCLUSIONS: This preliminary study provides the first evidence regarding international Oral Medicine postgraduate training, from which recommendations for an international core curriculum could be initiated. It is through such an initiative that a universal clinical core syllabus in postgraduate Oral Medicine training may be more feasible.

Long-standing oral ulcers: proposal for a new 'S-C-D classification system'.

Persistent oral ulcers and erosions can be the final common manifestation, sometimes clinically indistinguishable, of a diverse spectrum of conditions ranging from traumatic lesions, infectious diseases, systemic and local immune-mediated lesions up to neoplasms. The process of making correct diagnosis for persistent oral ulcers still represents a challenge to clinicians. Major diagnostic criteria should include the clinical appearance of both ulcer and surrounding non-ulcerated mucosa, together with the evaluation of associated signs and symptoms, such as: number (single or multiple), shape, severity of the ulcer(s), conditions of remaining mucosa (white, red or with vesiculo-bullous lesions) and systemic involvement (e.g. fever, lymphadenopathy or evaluation of haematological changes). The aim of this paper was to review the literature relating to persistent oral ulcers and provide a helpful, clinical-based diagnostic tool for recognising long-standing ulcers in clinical dental practice. The authors, therefore, suggest distinguishing simple, complex and destroying (S-C-D system) ulcerations, as each requires different diagnostic evaluations and management. This classification has arisen from studying the current English literature relating to this topic, performed using MEDLINE / PubMed / Ovid databases.

Safety and effectiveness of topical dry mouth products containing olive oil, betaine, and xylitol in reducing xerostomia for polypharmacy-induced dry mouth.

Polypharmacy is a common cause of salivary hypofunction, producing symptoms of dry mouth or xerostomia, especially among older populations. As the number of older people continues to increase, polypharmacy-induced salivary hypofunction is becoming an increasing problem. Many over-the-counter products are available for relieving symptoms of dry mouth, but few have been tested in controlled clinical investigations. The purpose of this investigation was to evaluate the safety and efficacy of a group of topical dry mouth products (toothpaste, mouth rinse, mouth spray and gel) containing olive oil, betaine and xylitol. Forty adults were entered into this single-blinded, open-label, cross-over clinical study and 39 completed all the visits. Subjects were randomly assigned at baseline to using the novel topical dry mouth products daily for 1 week, or to maintain their normal dry mouth routine care. After 1 week, they were crossed over to the other dry mouth regimen. The results demonstrated that the use of the novel topical dry mouth products increased significantly unstimulated whole salivary flow rates, reduced complaints of xerostomia and improved xerostomia-associated quality of life. No clinically significant adverse events were observed. These data suggest that the daily use of topical dry mouth products containing olive oil, betaine and xylitol is safe and effective in relieving symptoms of dry mouth in a population with polypharmacy-induced xerostomia.

Eating disorders: a threat for women's health. Oral manifestations in a comprehensive overview.

The incidence of eating disorders has progressively increased over the last several years, mainly affecting both the health and quality of life of young women. Such disorders are primarily an outlet for manifest psychic suffering and secondarily, they jeopardize the integrity and function of multiple organ systems resulting in significant morbidity and sometimes, life-threatening outcomes. The complex emerging interplay of etiopathogenetic factors poses many challenges in their prevention and management, which is further complicated by a reluctance by patients with eating disorders to seek medical evaluation and treatment. Recognition of the oral manifestations is important because these signs and symptoms can provide insights about disease progression and parallel general health and psychic status. Oral health care providers may be one of the few providers contacted by this patient population seeking recall prophylaxis or urgent dental care. Thus, improving understanding and knowledge of both general medical aspects of eating disorders and their oral manifestations could be of great impact in elevating the attention of health providers towards this group of very debilitating disorders and, consequently, improving their overall prognosis. In this paper we will review and discuss all these aspects.

Clinical evaluation of chemiluminescent lighting: an adjunct for oral mucosal examinations.

OBJECTIVE: The purpose of this study was to describe the utility of oral chemiluminescent lighting (FDA-cleared ViziLite) as an adjunct to standard visual examination (SVE) to enhance visualization of mucosal lesions, particularly those "clinically suspicious" for oral pre-cancer or cancer. Subjects were considered at risk for oral cancer or pre-cancer if they have no a priori knowledge of the presence or absence of an oral lesion at the time of examination. METHODOLOGY: Five-hundred and one consecutive consenting subjects, over 40 years of age and with a positive tobacco history, received a standard visual examination with conventional incandescent lighting, followed by chemiluminescent lighting. All lesions were recorded, and for lesions detected by both screening modalities, comparisons were made of the subjective parameters of lesion brightness, sharpness, surface texture, and relative size. RESULTS: A total of 410 epithelial lesions were detected in 270 subjects by standard visual examination, of which 127 were clinically "suspicious" for oral cancer and pre-cancer. Ninety-eight lesions were also visualized by chemiluminescent lighting as "aceto-white" (CL+), in addition to six lesions not previously seen by standard visual examination. Seventy-seven of the CL+ lesions (78.5%) were clinically suspicious; all "suspicious" lesions with an ulcerative component and ulcerated lesions consistent with trauma were CL+. Leukoplakias were significantly more likely to be CL+ than erythroplakias (p < 0.01). Overall, those lesions illuminated by chemiluminescent lighting appeared brighter, sharper, and smaller compared to incandescent illumination. CONCLUSION: The results of this study suggest that oral chemiluminescent lighting, when used as a screening adjunct following the standard visual oral examination, provides additional visual information. Leukoplakias may be more readily visualized by chemiluminescence. Studies are underway to explore the clinical significance and predictive value of oral chemiluminescent lighting.