Faculty Bibliography

BACKGROUND:The early detection of oral cavity squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMD), followed by appropriate treatment, may improve survival and reduce the risk for malignant transformation respectively. This is an update of a Cochrane Review first published in 2013. OBJECTIVES:To estimate the diagnostic test accuracy of conventional oral examination, vital rinsing, light-based detection, mouth self-examination, remote screening, and biomarkers, used singly or in combination, for the early detection of OPMD or OSCC in apparently healthy adults. SEARCH METHODS:Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 20 October 2020), MEDLINE Ovid (1946 to 20 October 2020), and Embase Ovid (1980 to 20 October 2020). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. We conducted citation searches, and screened reference lists of included studies for additional references. SELECTION CRITERIA:We selected studies that reported the test accuracy of any of the aforementioned tests in detecting OPMD or OSCC during a screening procedure. Diagnosis of OPMD or OSCC was provided by specialist clinicians or pathologists, or alternatively through follow-up. DATA COLLECTION AND ANALYSIS:Two review authors independently screened titles and abstracts for relevance. Eligibility, data extraction, and quality assessment were carried out by at least two authors independently and in duplicate. Studies were assessed for methodological quality using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). We reported the sensitivity and specificity of the included studies. We provided judgement of the certainty of the evidence using a GRADE assessment. MAIN RESULTS:We included 18 studies, recruiting 72,202 participants, published between 1986 and 2019. These studies evaluated the diagnostic test accuracy of conventional oral examination (10 studies, none new to this update), mouth self-examination (four studies, two new to this update), and remote screening (three studies, all new to this update). One randomised controlled trial of test accuracy directly evaluated conventional oral examination plus vital rinsing versus conventional oral examination alone. There were no eligible studies evaluating light-based detection or blood or salivary sample analysis (which tests for the presence of biomarkers for OPMD and OSCC). Only one study of conventional oral examination was judged as at overall low risk of bias and overall low concern regarding applicability. Given the clinical heterogeneity of the included studies in terms of the participants recruited, setting, prevalence of the target condition, the application of the index test and reference standard, and the flow and timing of the process, the data could not be pooled within the broader categories of index test. For conventional oral examination (10 studies, 25,568 participants), prevalence in the test accuracy sample ranged from 1% to 51%. For the seven studies with prevalence of 10% or lower, a prevalence more comparable to the general population, the sensitivity estimates were variable, and ranged from 0.50 (95% confidence interval (CI) 0.07 to 0.93) to 0.99 (95% CI 0.97 to 1.00); the specificity estimates were more consistent and ranged from 0.94 (95% CI 0.88 to 0.97) to 0.99 (95% CI 0.98 to 1.00). We judged the overall certainty of the evidence to be low, and downgraded for inconsistency and indirectness. Evidence for mouth self-examination and remote screening was more limited. We judged the overall certainty of the evidence for these index tests to be very low, and downgraded for imprecision, inconsistency, and indirectness. We judged the evidence for vital rinsing (toluidine blue) as an adjunct to conventional oral examination compared to conventional oral examination to be moderate, and downgraded for indirectness as the trial was undertaken in a high-risk population. AUTHORS' CONCLUSIONS:There is a lack of high-certainty evidence to support the use of screening programmes for oral cavity cancer and OPMD in the general population. Frontline screeners such as general dentists, dental hygienists, other allied professionals, and community healthcare workers should remain vigilant for signs of OPMD and OSCC.

Patients with oral potentially malignant disorders (OPMDs), including oral leukoplakia and erythroplakia, proliferative verrucous leukoplakia, oral submucous fibrosis, and oral lichen planus/lichenoid lesions can be challenging to manage. A small proportion will undergo cancer development and determining a patient's cancer risk is key to making management decisions. Yet, our understanding of the natural history of OPMDs has not been fully elucidated, and a precision approach based on the integration of numerous predictive markers has not been validated by prospective studies. Evidence-based health promotion by clinicians and healthcare systems is not embraced universally. Medical and surgical interventions evaluated by rigorous research measuring important endpoints, such as cancer development, mortality, or survival are difficult and expensive to run. Most of these studies employ non-ideal surrogate endpoints and have deep methodologic flaws. Diagnostic criteria for enrolling research subjects are not uniform, and patients with the highest risk for cancer development comprise small proportions of those enrolled. Few studies explore quality of life and patient preferences. It is time to rethink how we approach the management of these patients, across each OPMD, and considering the healthcare infrastructure and cost effectiveness. Global networks with well-characterized patient populations with OPMDs and well-designed interventional trials using validated outcome measures are needed.

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.

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.

OBJECTIVES/OBJECTIVE:Oral potentially malignant disorders (OPMDs) encompass histologically benign, dysplastic, and cancerous lesions that are often indistinguishable by appearance and inconsistently managed. We assessed the potential impact of test-and-treat pathways enabled by a point-of-care test for OPMD characterization. MATERIALS AND METHODS/METHODS:We constructed a decision-analytic model to compare life expectancy of test-treat strategies for 60-year-old patients with OPMDs in the primary dental setting, based on a trial for a point-of-care cytopathology tool (POCOCT). Eight strategies of OPMD detection and evaluation were compared, involving deferred evaluation (no further characterization), prompt OPMD characterization using POCOCT measurements, or the commonly recommended usual care strategy of routine referral for scalpel biopsy. POCOCT pathways differed in threshold for additional intervention, including surgery for any dysplasia or malignancy, or for only moderate or severe dysplasia or cancer. Strategies with initial referral for biopsy also reflected varied treatment thresholds in current practice between surgery and surveillance of mild dysplasia. Sensitivity analysis was performed to assess the impact of variation in parameter values on model results. RESULTS:Requisite referral for scalpel biopsy offered the highest life expectancy of 20.92 life-years compared with deferred evaluation (+0.30 life-years), though this outcome was driven by baseline assumptions of limited patient adherence to surveillance using POCOCT. POCOCT characterization and surveillance offered only 0.02 life-years less than the most biopsy-intensive strategy, while resulting in 27% fewer biopsies. When the probability of adherence to surveillance and confirmatory biopsy was ≥ 0.88, or when metastasis rates were lower than reported, POCOCT characterization extended life-years (+0.04 life-years) than prompt specialist referral. CONCLUSION/CONCLUSIONS:Risk-based OPMD management through point-of-care cytology may offer a reasonable alternative to routine referral for specialist evaluation and scalpel biopsy, with far fewer biopsies. In patients who adhere to surveillance protocols, POCOCT surveillance may extend life expectancy beyond biopsy and follow up visual-tactile inspection.

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.

The Surveillance, Epidemiology, and End Results program from the National Cancer Institute reports that the aggregate number of oral cavity and pharyngeal cancer cases has been increasing over the past decade and, despite an overall decline in oral cavity cancers, this increase is largely related to a dramatic increase in cancers involving oropharyngeal subsites. Early detection of oral cavity cancers is commensurate with improved survival, and opportunistic screening by trained clinicians to detect oral cavity cancer and oral potentially malignant disorders is recommended by the American Dental Association and the American Academy of Oral Medicine.

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.