A brief review of cytology in dentistry.

Oral cytology is a non-invasive adjunctive diagnostic tool with a number of potential applications in the practice of dentistry. This brief review begins with a history of cytology in medicine and how cytology was initially applied in oral medicine. A description of the different technical aspects of oral cytology is provided, including the collection and processing of oral cytological samples, and the microscopic interpretation and reporting, along with their advantages and limitations. Applications for oral cytology are listed with a focus on the triage of patients presenting with oral potentially malignant disorders and oral mucosal infections. Furthermore, the utility of oral cytology roles across both expert (for example, secondary oral medicine or tertiary head and neck oncology services) and non-expert (for example, primary care general dental practice) clinical settings is explored. A detailed section covers the evidence-base for oral cytology as a diagnostic adjunctive technique in both the early detection and monitoring of patients with oral cancer and oral epithelial dysplasia. The review concludes with an exploration of future directions, including the integration of artificial intelligence for automated analysis and point of care 'smart diagnostics', thereby offering some insight into future opportunities for a wider application of oral cytology in dentistry.

Standard examination and adjunctive techniques for detection of oral premalignant and malignant lesions.

This article outlines how to perform a standard comprehensive extraoral and intraoral examination and the existing commercially available adjunctive techniques for the early detection of oral cancer and premalignant lesions. Visualization-based techniques (e.g., autofluorescence and chemiluminescence), toluidine blue vital staining, cytopathologic tests and high-risk human papillomavirus testing are discussed in detail, including the indications and protocols for use, their advantages and disadvantages and clinical cases.

Severe and rapid erosion of dental enamel from swimming: a clinical report.

The diagnosis and treatment of a patient with excessive and rapid erosion of enamel is presented. Although the Center for Disease Control and the dental literature have reported on dental enamel erosion resulting from swimming pool chlorination, the awareness of such etiology among dental professionals may be limited. Common findings in these reports include cold sensitivity, a distinctive appearance resembling laminate veneer preparations of the facial surfaces of anterior teeth, occurrence of diastemas, and at times, a rough or gritty texture of the remaining tooth structure. Clinical presentations of erosive lesions can be diagnosed and the best course of treatment determined.

Oral and pharyngeal cancer control and early detection.

Sixty-four standardized continuing education courses were given for dentists throughout the ten public health districts of the USA to determine if certain behaviors regarding oral and pharyngeal cancer (OPC) control could be modified. Questionnaires were obtained at baseline and at 6 months along with matched control groups. One thousand eight hundred two general dentists participated at baseline and 988 at a 6-month questionnaire follow-up. Analysis of the data indicated that continuing education courses had a positive influence on participants' oral cancer attitudes, knowledge, and behavior that potentially could make a difference on prevention, early detection, and ultimately OPC control.

Oncogenes overexpressed in metastatic oral cancers from patients with pain: potential pain mediators released in exosomes.

Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n = 5) compared to N0 cancers (n = 10) and normal tissue (n = 5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.

Point-of-care oral cytology tool for the screening and assessment of potentially malignant oral lesions.

BACKGROUND: The effective detection and monitoring of potentially malignant oral lesions (PMOL) are critical to identifying early-stage cancer and improving outcomes. In the current study, the authors described cytopathology tools, including machine learning algorithms, clinical algorithms, and test reports developed to assist pathologists and clinicians with PMOL evaluation. METHODS: Data were acquired from a multisite clinical validation study of 999 subjects with PMOLs and oral squamous cell carcinoma (OSCC) using a cytology-on-a-chip approach. A machine learning model was trained to recognize and quantify the distributions of 4 cell phenotypes. A least absolute shrinkage and selection operator (lasso) logistic regression model was trained to distinguish PMOLs and cancer across a spectrum of histopathologic diagnoses ranging from benign, to increasing grades of oral epithelial dysplasia (OED), to OSCC using demographics, lesion characteristics, and cell phenotypes. Cytopathology software was developed to assist pathologists in reviewing brush cytology test results, including high-content cell analyses, data visualization tools, and results reporting. RESULTS: Cell phenotypes were determined accurately through an automated cytological assay and machine learning approach (99.3% accuracy). Significant differences in cell phenotype distributions across diagnostic categories were found in 3 phenotypes (type 1 ["mature squamous"], type 2 ["small round"], and type 3 ["leukocytes"]). The clinical algorithms resulted in acceptable performance characteristics (area under the curve of 0.81 for benign vs mild dysplasia and 0.95 for benign vs malignancy). CONCLUSIONS: These new cytopathology tools represent a practical solution for rapid PMOL assessment, with the potential to facilitate screening and longitudinal monitoring in primary, secondary, and tertiary clinical care settings.

Development of a cytology-based multivariate analytical risk index for oral cancer.

OBJECTIVES: The diagnosis and management of oral cavity cancers are often complicated by the uncertainty of which patients will undergo malignant transformation, obligating close surveillance over time. However, serial biopsies are undesirable, highly invasive, and subject to inherent issues with poor inter-pathologist agreement and unpredictability as a surrogate for malignant transformation and clinical outcomes. The goal of this study was to develop and evaluate a Multivariate Analytical Risk Index for Oral Cancer (MARIO) with potential to provide non-invasive, sensitive, and quantitative risk assessments for monitoring lesion progression. MATERIALS AND METHODS: A series of predictive models were developed and validated using previously recorded single-cell data from oral cytology samples resulting in a "continuous risk score". Model development consisted of: (1) training base classification models for each diagnostic class pair, (2) pairwise coupling to obtain diagnostic class probabilities, and (3) a weighted aggregation resulting in a continuous MARIO. RESULTS AND CONCLUSIONS: Diagnostic accuracy based on optimized cut-points for the test dataset ranged from 76.0% for Benign, to 82.4% for Dysplastic, 89.6% for Malignant, and 97.6% for Normal controls for an overall MARIO accuracy of 72.8%. Furthermore, a strong positive relationship with diagnostic severity was demonstrated (Pearson's coefficient = 0.805 for test dataset) as well as the ability of the MARIO to respond to subtle changes in cell composition. The development of a continuous MARIO for PMOL is presented, resulting in a sensitive, accurate, and non-invasive method with potential for enabling monitoring disease progression, recurrence, and the need for therapeutic intervention of these lesions.

Adjunctive techniques for oral cancer examination and lesion diagnosis: a systematic review of the literature.

BACKGROUND: Adjunctive techniques that may facilitate the early detection of oral premalignant and malignant lesions (OPML) have emerged in the past decades. METHODS: The authors undertook a systematic review of the English-language literature to evaluate the effectiveness of toluidine blue (TB), ViziLite Plus with TBlue (Zila Pharmaceuticals, Phoenix), ViziLite (Zila Pharmaceuticals), Microlux DL (AdDent, Danbury, Conn.), Orascoptic DK (Orascoptic, a Kerr Company, Middleton, Wis.), VELscope (LED Dental, White Rock, British Columbia, Canada) and OralCDx (Oral CDx Laboratories, Suffern, N.Y.) brush biopsy. They abstracted data relating to study design, sampling and characteristics of the study group, interventions, reported outcomes and diagnostic accuracy of adjunctive aids from 23 articles meeting inclusion and exclusion criteria, including availability of histologic outcomes. RESULTS: The largest evidence base was for TB. A limited number of studies was available for ViziLite, ViziLite Plus with TBlue and OralCDx. Studies of VELscope have been conducted primarily to assess the margins of lesions in known OPML. The authors identified no studies of Microlux DL or Orascoptic DK. Study designs had various limitations in applicability to the general practice setting, including use of higher-risk populations and expert examiners. CONCLUSIONS: There is evidence that TB is effective as a diagnostic adjunct for use in high-risk populations and suspicious mucosal lesions. OralCDx is useful in assessment of dysplastic changes in clinically suspicious lesions; however, there are insufficient data meeting the inclusion criteria to assess usefulness in innocuous mucosal lesions. Overall, there is insufficient evidence to support or refute the use of visually based examination adjuncts. Practical Implications. Given the lack of data on the effectiveness of adjunctive cancer detection techniques in general dental practice settings, clinicians must rely on a thorough oral mucosal examination supported by specialty referral and/or tissue biopsy for OPML diagnosis.

Improving oral health in women: nurses' call to action.

The purpose of this article is to discuss the most significant oral health and related problems experienced by women, and to provide a Nurse's Plan of Action to respond to these largely preventable diseases. Oral health is integral to women's overall health and well-being, with poor oral health being associated with cancer, heart disease, diabetes, depression, and the birth of preterm, low-birthweight babies. Poor nutrition and lifestyle, principally tobacco and heavy alcohol use, can further increase the risk for oral diseases. Disparities are evident in women's reported poor access of regular dental care related to lack of dental insurance and low income. These facts are disturbing because most oral diseases are preventable. The Surgeon General's report on oral health in America (U.S. Department of Health and Human Services, 2000) and, more recently, the "National Call to Action to Promote Oral Health" (U.S. Department of Health and Human Services, 2003) emphasized the need for partnerships of key stakeholders, including nurses, to get involved in oral disease prevention. Nurses are in an ideal position to provide health promotion education and screening across the multitude of settings in which they work regarding oral health and risk factors for oral disease. Nursing interventions aimed at promoting healthy outcomes and preventing disease should include a focus on oral health.

White sponge nevus.

A 33-year-old-man presented with a 13-year history of asymptomatic, white, folded, soft, poorly-demarcated, diffuse plaques bilaterally on his buccal mucosae and lateral surfaces of his tongue. There is no family history of similar lesions. The physical examination and histopathologic findings were consistent with a diagnosis of white sponge nevus. This rare disorder is typically inherited; however, as in this case, there have been a few other cases reported without a familial background.

Disparities in oral and pharyngeal cancer incidence, mortality and survival among black and white Americans.

BACKGROUND: The authors present statistics and long-term trends in oral and pharyngeal cancer (OPC) incidence, mortality and survival among U.S. blacks and whites. METHODS: The authors obtained incidence, mortality and five-year relative survival rates via the Surveillance, Epidemiology and End Results (SEER) Program Web site. Current rates and time trends for 1975 through 2002 are presented. RESULTS: From 1975 through 2002, age-adjusted incidence rates (AAIRs) and mortality rates (AAMRs) were higher among males than among females and highest for black males. By the mid-1980s, incidence and mortality rates were declining for black and white males and females; however, disparities persisted. During the period 1998-2002, AAIRs were more than 20 percent higher for black males compared with white males, while the difference in rates for black and white females was small. AAMRs were 82 percent higher for black males compared with white males, but rates were similar for black and white females. Five-year relative survival rates for patients diagnosed during the period 1995-2001 were higher for whites than for blacks and lowest for black males. CONCLUSIONS: Despite recent declines in OPC incidence and mortality rates, disparities persist. Disparities in survival also exist. Black males bear the brunt of these disparities. PRACTICE IMPLICATIONS: Dentists can aid in reducing OPC incidence and mortality by assisting patients in the prevention and cessation of tobacco use and alcohol abuse. Five-year relative survival may be improved through early detection.

Oral submucous fibrosis: a review of the current management and possible directions for novel therapies.

This literature review addresses the attempted interventions for the management of oral submucous fibrosis. The literature supports the use of several medical interventions, including micronutrients, antioxidants, proteolytic enzymes, immune modulators (mainly steroids), and agents to promote blood flow. However, the numbers of reported randomized controlled trials are limited. Therefore, no recommendation can be made for any specific intervention. Until now, no single molecular pathway has been identified that is either necessary or sufficient for the development of fibrosis. This has been a bar for any molecular-targeted therapies. Because areca nut (an ingredient of betel quid) plays a major etiologic role in oral submucous fibrosis, cessation of areca nut use remains pivotal in the management of this disorder.

Oral medicine (stomatology) across the globe: birth, growth, and future.

Oral medicine (stomatology) is a recognized and increasingly important dental specialty in many parts of the world that recognizes and fosters the interplay between medical health and oral health. Its dental activities rely greatly on the underlying biology of disease and evidence-based outcomes. However, full recognition of the importance of oral medicine to patient care, research, and education is not yet totally universally acknowledged. To address these shortcomings, we outline the birth, growth, and future of oral medicine globally, and record identifiable past contributions to the development of the specialty, providing an accurate, unique, and valuable resource on oral medicine. Although it was challenging to gather the data, we present this information as a review that endeavors to summarize the salient points about oral medicine, based on MEDLINE, other internet searches, communication with oral medicine and stomatological societies across the world, the web page http://en.wikipedia.org/wiki/List_of_dental_organizations, and discussions with a wide range of key senior persons in the specialty.

'Cytology-on-a-chip' based sensors for monitoring of potentially malignant oral lesions.

UNLABELLED: Despite significant advances in surgical procedures and treatment, long-term prognosis for patients with oral cancer remains poor, with survival rates among the lowest of major cancers. Better methods are desperately needed to identify potential malignancies early when treatments are more effective. OBJECTIVE: To develop robust classification models from cytology-on-a-chip measurements that mirror diagnostic performance of gold standard approach involving tissue biopsy. MATERIALS AND METHODS: Measurements were recorded from 714 prospectively recruited patients with suspicious lesions across 6 diagnostic categories (each confirmed by tissue biopsy -histopathology) using a powerful new 'cytology-on-a-chip' approach capable of executing high content analysis at a single cell level. Over 200 cellular features related to biomarker expression, nuclear parameters and cellular morphology were recorded per cell. By cataloging an average of 2000 cells per patient, these efforts resulted in nearly 13 million indexed objects. RESULTS: Binary "low-risk"/"high-risk" models yielded AUC values of 0.88 and 0.84 for training and validation models, respectively, with an accompanying difference in sensitivity+specificity of 6.2%. In terms of accuracy, this model accurately predicted the correct diagnosis approximately 70% of the time, compared to the 69% initial agreement rate of the pool of expert pathologists. Key parameters identified in these models included cell circularity, Ki67 and EGFR expression, nuclear-cytoplasmic ratio, nuclear area, and cell area. CONCLUSIONS: This chip-based approach yields objective data that can be leveraged for diagnosis and management of patients with PMOL as well as uncovering new molecular-level insights behind cytological differences across the OED spectrum.

World Workshop on Oral Medicine VI: an international validation study of clinical competencies for advanced training in oral medicine.

OBJECTIVE: To explore international consensus for the validation of clinical competencies for advanced training in Oral Medicine. STUDY DESIGN: An electronic survey of clinical competencies was designed. The survey was sent to and completed by identified international stakeholders during a 10-week period. To be validated, an individual competency had to achieve 90% or greater consensus to keep it in its current format. RESULTS: Stakeholders from 31 countries responded. High consensus agreement was achieved with 93 of 101 (92%) competencies exceeding the benchmark for agreement. Only 8 warranted further attention and were reviewed by a focus group. No additional competencies were suggested. CONCLUSION: This is the first international validated study of clinical competencies for advanced training in Oral Medicine. These validated clinical competencies could provide a model for countries developing an advanced training curriculum for Oral Medicine and also inform review of existing curricula.

World Workshop on Oral Medicine VI: clinical implications of medication-induced salivary gland dysfunction.

OBJECTIVE: This study aimed to systematically review the available literature on the clinical implications of medication-induced salivary gland dysfunction (MISGD). STUDY DESIGN: The systematic review was performed using PubMed, Embase, and Web of Science (through June 2013). Studies were assessed for degree of relevance and strength of evidence, based on whether clinical implications of MISGD were the primary study outcomes, as well as on the appropriateness of study design and sample size. RESULTS: For most purported xerogenic medications, xerostomia was the most frequent adverse effect. In the majority of the 129 reviewed papers, it was not documented whether xerostomia was accompanied by decreased salivary flow. Incidence and prevalence of medication-induced xerostomia varied widely and was often associated with number and dose of medications. Xerostomia was most frequently reported to be mild-to-moderate in severity. Its onset occurred usually in the first weeks of treatment. There was selected evidence that medication-induced xerostomia occurs more frequently in women and older adults and that MISGD may be associated with other clinical implications, such as caries or oral mucosal alterations. CONCLUSIONS: The systematic review showed that MISGD constitutes a significant burden in many patients and may be associated with important negative implications for oral health.

Interobserver agreement in dysplasia grading: toward an enhanced gold standard for clinical pathology trials.

OBJECTIVE: Interobserver agreement in the context of oral epithelial dysplasia (OED) grading has been notoriously unreliable and can impose barriers for developing new molecular markers and diagnostic technologies. This paper aimed to report the details of a 3-stage histopathology review and adjudication process with the goal of achieving a consensus histopathologic diagnosis of each biopsy. STUDY DESIGN: Two adjacent serial histologic sections of oral lesions from 846 patients were independently scored by 2 different pathologists from a pool of 4. In instances where the original 2 pathologists disagreed, a third, independent adjudicating pathologist conducted a review of both sections. If a majority agreement was not achieved, the third stage involved a face-to-face consensus review. RESULTS: Individual pathologist pair κ values ranged from 0.251 to 0.706 (fair-good) before the 3-stage review process. During the initial review phase, the 2 pathologists agreed on a diagnosis for 69.9% of the cases. After the adjudication review by a third pathologist, an additional 22.8% of cases were given a consensus diagnosis (agreement of 2 out of 3 pathologists). After the face-to-face review, the remaining 7.3% of cases had a consensus diagnosis. CONCLUSIONS: The use of the defined protocol resulted in a substantial increase (30%) in diagnostic agreement and has the potential to improve the level of agreement for establishing gold standards for studies based on histopathologic diagnosis.

Management strategies for HIV-associated aphthous stomatitis.

Recurrent aphthous stomatitis (RAS) is the most common oral mucosal disorder found in men and women of all ages, races, and geographic regions. There are three forms of the lesions (minor, major, and herpetiform), with major aphthous ulcers causing significant pain and potential for scarring. In HIV-infected individuals, these ulcers occur more frequently, last longer, and produce more painful symptoms than in immunocompetent persons. In addition, they may be associated with similar ulcerations involving the esophagus, rectum, anus, and genitals. The diagnosis of HIV-induced RAS requires a careful history of the condition, and a thorough extra- and intra-oral examination. Oral mucosal biopsies are required for non-healing ulcers in order to exclude the possibility of deep fungal infections, viral infections, and neoplasms. The cause of the ulcers in HIV-positive persons has not been elucidated--local diseases, genetic, immunologic, and infectious factors all probably play a role. The goals of current treatments are to promote ulcer healing, to reduce ulcer duration and pain while maintaining nutritional intake, and to prevent or diminish the frequency of recurrence. Initial therapy for infrequent RAS recurrences includes over-the-counter topical protective and analgesic products. Initial therapy for frequent RAS outbreaks requires topical anesthetics, binding agents, and corticosteroids. Major RAS and non-healing minor or herpetiform RAS may require intralesional corticosteroids and systemic prednisone. Second-line immunomodulators for frequent and non-healing ulcers includes thalidomide and other immunomodulators.

The efficacy and safety of 50 mg penicillin G potassium troches for recurrent aphthous ulcers.

PURPOSE: To determine both the efficacy and safety of the topical application of 50 mg penicillin G potassium troches (Cankercillin) in the treatment of minor recurrent aphthous stomatitis (RAS). STUDY DESIGN: The investigation used a phase 2 double-blind, randomized placebo-controlled trial with a no-treatment arm. Subjects with minor aphthous ulcers of duration <48 hours were followed for 1 week. The primary endpoint for efficacy was time (days) to complete ulcer resolution, and the secondary endpoint was time (days) to complete pain relief. RESULTS: Thirty-one, 33, and 36 subjects were randomized to the active treatment, placebo, and no-treatment arms, respectively. Baseline findings were heterogeneous across arms. Subjects who received penicillin G treatment had complete ulcer healing and pain relief significantly earlier than those in the placebo and no-treatment arms. No allergic reactions were observed. CONCLUSIONS: Topical penicillin G, by mechanisms which remain unclear, reduces the time of healing and pain relief of minor aphthous ulcers with minimal safety concerns. Larger phase 3 studies are necessary to confirm these findings.