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Management of Oral Potentially Malignant Disorders

Kerr, A Ross; Lodi, Giovanni
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.
PMID: 34324758
ISSN: 1601-0825
CID: 4951262

Oral Cancer Screening: Past, Present, and Future

Warnakulasuriya, S; Kerr, A R
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.
PMID: 34036828
ISSN: 1544-0591
CID: 4908462

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

McRae, M P; Kerr, A R; Janal, M N; Thornhill, M H; Redding, S W; Vigneswaran, N; Kang, S K; Niederman, R; Christodoulides, N J; Trochesset, D A; Murdoch, C; Dapkins, I; Bouquot, J; Modak, S S; Simmons, G W; McDevitt, J T
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.
PMID: 33179547
ISSN: 1544-0591
CID: 4675972

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

Warnakulasuriya, Saman; Kujan, Omar; Aguirre-Urizar, José M; Bagan, José V; González-Moles, Miguel Ángel; Kerr, Alexander R; Lodi, Giovanni; Mello, Fernanda Weber; Monteiro, Luis; Ogden, Graham R; Sloan, Philip; Johnson, Newell W
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.
PMID: 33128420
ISSN: 1601-0825
CID: 4950132

Oral Potentially Malignant Disorders and Oral Cavity Cancer

Ojeda, David; Huber, Michaell A; Kerr, Alexander R
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.
PMID: 32892859
ISSN: 1558-0520
CID: 4601512

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

Bhattacharya, Aditi; Janal, Malvin N; Veeramachaneni, Ratna; Dolgalev, Igor; Dubeykovskaya, Zinaida; Tu, Nguyen Huu; Kim, Hyesung; Zhang, Susanna; Wu, Angie K; Hagiwara, Mari; Kerr, A Ross; DeLacure, Mark D; Schmidt, Brian L; Albertson, Donna G
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.
PMID: 32895418
ISSN: 2045-2322
CID: 4588822

Cues used by dentists in the early detection of oral cancer and oral potentially malignant lesions: findings from the National Dental Practice-Based Research Network

Kerr, Alexander Ross; Robinson, Michael E; Meyerowitz, Cyril; Morse, Douglas E; Aguilar, Maria L; Tomar, Scott L; Guerrero, Lisa; Caprio, Dianne; Kaste, Linda M; Makhija, Sonia K; Mungia, Rahma; Rasubala, Linda; Psoter, Walter J
OBJECTIVE:The aim of this study was to assess the influence of clinical cues on risk assessment of cancer-associated mucosal abnormalities. STUDY DESIGN/METHODS:We differentiated lesions with a low risk from those with a high risk for premalignancy or malignancy by using 4 cues: (1) color, (2) location, (3) induration, and (4) pain on exploration. Combinations of color and location were presented through 8 photographs, with induration and pain status variably presented in the standardized history and physical findings. This created 16 clinical scenarios (vignettes) that were permutations of the 4 cues. Three questions assessed the extent to which each cue was used in obtaining a clinical impression as to whether a lesion was benign, premalignant, or malignant. RESULTS:Completed vignette questionnaires were obtained from 130 of 228 invited dentists, (two-thirds males; 79% white; mean age 52 years; average weekly hours of practice 33 hours). Only 40% of the responding dentists had statistically significant decision policies to assign a clinical diagnosis of a lesion as benign, premalignant, or malignant. Lesion location and color were the 2 dominant cues. As a cue, induration was used as a cue by more of the respondents in determining a clinical diagnosis of malignancy, and pain was infrequently used as a cue. CONCLUSIONS:Many dentists do not to have a decision strategy for the clinical diagnosis and risk stratification of oral potentially malignant lesions.
PMID: 32561250
ISSN: 2212-4411
CID: 4492512

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

McRae, Michael P; Modak, Sayli S; Simmons, Glennon W; Trochesset, Denise A; Kerr, A Ross; Thornhill, Martin H; Redding, Spencer W; Vigneswaran, Nadarajah; Kang, Stella K; Christodoulides, Nicolaos J; Murdoch, Craig; Dietl, Steven J; Markham, Roger; McDevitt, John T
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.
PMID: 32032477
ISSN: 1934-6638
CID: 4300912

How Can Dental Practitioners Join the Fight Against HPV-Associated Oropharyngeal Cancer?

Dillenberg, Jack; Kerr, A Ross; Koskan, Alexis; Patel, Seena; Duong, Mai-Ly
PMID: 32017590
ISSN: 2158-1797
CID: 4301062

Oral submucous fibrosis: a contemporary narrative review with a proposed inter-professional approach for an early diagnosis and clinical management

Rao, Naman R; Villa, Alessandro; More, Chandramani B; Jayasinghe, Ruwan D; Kerr, Alexander Ross; Johnson, Newell W
Oral Submucous fibrosis (OSMF) has traditionally been described as "a chronic, insidious, scarring disease of the oral cavity, often with involvement of the pharynx and the upper esophagus". Millions of individuals are affected, especially in South and South East Asian countries. The main risk factor is areca nut chewing. Due to its high morbidity and high malignant transformation rate, constant efforts have been made to develop effective management. Despite this, there have been no significant improvements in prognosis for decades. This expert opinion paper updates the literature and provides a critique of diagnostic and therapeutic pitfalls common in developing countries and of deficiencies in management. An inter-professional model is proposed to avoid these pitfalls and to reduce these deficiencies.
PMID: 31915073
ISSN: 1916-0216
CID: 4256992