Oral Potentially Malignant Disorders: A Consensus Report

1862 wileyonlinelibrarycomjournalodi Oral Diseases 20212718621880 2020 Wiley Periodicals LLC Received 20 September 2020 Revised 21 October 2020 Accepted 25 October 2020 DOI 101111odi13704 R E V I E W A R T I C L E Oral potentially malignant disorders A consensus report from an international seminar on nomenclature and classification convened by the WHO Collaborating Centre for Oral Cancer Saman Warnakulasuriya1 Omar Kujan2 José M AguirreUrizar3 José V Bagan45 Miguel Ángel GonzálezMoles67 Alexander R Kerr8 Giovanni Lodi9 Fernanda Weber Mello10 Luis Monteiro11 Graham R Ogden12 Philip Sloan13 Newell W Johnson1415 1The WHO Collaborating Centre for Oral Cancer and Faculty of Dentistry Oral and Craniofacial Sciences Kings College London London UK 2UWA Dental School The University of Western Australia Perth WA Australia 3Oral and Maxillofacial Medicine Pathology Unit Department of Stomatology II Faculty of Medicine and Nursery University of the Basque CountryEHU Bilbao Spain 4Oral Medicine Valencia University Valencia Spain 5Department of Oral and Maxillofacial Surgery University General Hospital Valencia Spain 6School of Dentistry University of Granada Granada Spain 7Biohealth Research Institute IBS Granada Spain 8Department of Oral and Maxillofacial Pathology Radiology and Medicine New York University College of Dentistry New York NY USA 9Dipartimento di Scienze Biomediche Chirurgiche e Odontoiatriche Università degli Studi di Milano Milano Italy 10Federal University of Santa Catarina Florianópolis Brazil 11CESPU Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde IINFACTS IUCS Instituto Universitário de Ciências da Saúde Gandra Portugal 12Department of Oral Surgery Dundee Dental School Dundee Scotland UK 13School of Dental Sciences Faculty of Abstract 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 leukopla kia erythroplakia proliferative verrucous leukoplakia oral lichen planus oral submu cous 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 diag nosed with oral lichenoid lesions and among those diagnosed with oral manifesta tions of chronic graftversushost 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 evi dence 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 multicenter longitudinal studies with uniform diag nostic criteria to improve the identification and cancer risk stratification of patients with OPMDs link them to evidencebased interventions with a goal to facilitate the prevention and management of lip and oral cavity cancer 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1863 WARNAKULASURIYA et AL 1 INTRODUCTION In March 2020 the WHO Collaborating Centre for Oral Cancer in the UK convened a workshop attended by invited experts to dis cuss the advances in knowledge and recent changes in the under standing of oral potentially malignant disorders OPMDs OPMDs are a significant group of mucosal disorders that may precede the diagnosis of oral squamous cell carcinoma OSCC Warnakulasuriya et al 2007 Since the introduction of this terminology potentially malignant disorders of the oral mucosa PMD later OPMD health care providers and researchers over the globe have enthusiastically adopted this term and the classification of entities therein and this has resulted in better reporting of this important group of disorders A recent review identified over 750 publications on the topic of OPMDs published since 2007 Liu et al 2020 However discrep ancies in describing these disorders are still found in the published literature leading to inconsistency and a degree of confusion The terminology for disorders that precede development of cancers has evolved over the years to align with greater scientific evidence and to reflect temporal advances in understanding of the natural history of these disorders OPMDs refer to a group of lesions and condi tions characterized by a variably increased risk of developing can cers of the lip C00 and the oral cavity C02C06 Warnakulasuriya et al 2007 The terminology has been endorsed by the latest WHO classification on Head and Neck Tumours Reibel et al 2017 The concept of precancer was introduced in 1805 when a European panel of physicians suggested that there are benign dis eases that may develop into invasive malignancy if followed for a long time Baillie Simms 1806 The thinking behind the concept of OPMDs as reported by the 2005 workshop and reaffirmed by the Working Group 2020 is that OPMDs represent tissue fields with more or less distinctive clinical appearances at initial assess ment and where a proportion within each clinical category have been documented to have subsequently developed a cancer during followup Viz tissues within these categories have enhanced ma lignant potential Some of these clinical alterations red and white patches in particular are seen to coexist at the margins of overt OSCCs they possess similar morphological and cytological changes observed in superficially invasive carcinomas and some of the chro mosomal genomic and molecular alterations detected in early in vasive OSCCs are also found in OPMDs presented in later chapters in this supplement It is also important to recognize that OSCC can present without the patient or a clinician having been aware of a pre ceding clinically altered mucosa at the site The expert opinion at the 2005 workshop published in 2007 proposed a shift from previously used terms precancer epithelial precursor lesions premalignant precancerous and intraepithelial lesion to OPMD Lesions and conditions were combined into one category of disorders in recog nition of the fact that field change usually exists due to exposure to environmental carcinogens across much of the upper aerodigestive tract and that the whole person may have changes which influence the risk of cancer development Johnson 2017 2020 Potentially malignant implies that not all patients diagnosed with any of these mucosal abnormalities will develop an oral malignancy Nor does it imply that a carcinoma will arise exactly at the site where an OPMD was previously diagnosed The observed clinical and biological course of these disorders has been discussed recently by Speight et al 2018 The concept that the mere presence of OPMDs is but one of several factors increasing the risk for cancer development is important Patients diagnosed with OPMDs may have an increased suscep tibility to develop cancer anywhere in their mouth during their life time The majority of these OPMDs may not progress to carcinoma but rather they provide a field of abnormality in which cancer devel opment is more likely than in their clinically normal mucosa and more likely than in patients without such disorders Clinically normal mu cosa can by molecularly abnormal As alluded to earlier the cancer does not necessarily occur in the site of the visibly altered mucosa An important challenge faced by clinicians managing patients with OPMDs is to be able to identify the small proportion of patients most likely to develop a future malignancy Updating the classification of OPMDs is not just an academic endeavor but necessity for clinicians as they make evidencebased management decisions for patients diagnosed with these disorders Such decisions have the potential for serious consequences and can impact the patients quality of life and need to be carefully consid ered to minimize the risks for both under or overmanagement In Medical Sciences Newcastle University Newcastle upon Tyne UK 14Menzies Health Institute Queensland and School of Dentistry and Oral Health Griffith University Gold Coast Qld Australia 15Faculty of Dentistry Oral and Craniofacial Sciences Kings College London London UK Correspondence Saman Warnakulasuriya Kings College London London UK Email swarnekclacuk K E Y W O R D S erythroplakia leukoplakia lichen planus oral potentially malignant disorders proliferative verrucous leukoplakia submucous fibrosis 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1864 WARNAKULASURIYA et AL the ICD11 classification of diseases the World Health Organization has proposed revisions for the following purposes a increasing us ability b updating scientific content c integrating with eHealth and d accommodating the needs for multiusers in recording re porting and analysis World Health Organisation 2019 The 2020 workshop on OPMDs adheres to this rationale The collective ex pert opinion favors perpetuation of the existing OPMD nomencla ture to describe oral mucosal disorders that indicate an increased risk for cancer development and consideration of new evidence from both basic science and clinical studies With these objectives in mind inclusion of some additional disorders has been proposed Warnakulasuriya 2018 2020 oral lichenoid lesions and reactions oral chronic graftversushost disease chronic hyperplastic candido sis and oral exophytic verrucous hyperplasia We discuss the avail able evidence on these disorders in section 4 of this report This paper lays out the updated classification provides or en dorses definitions of each disorder and highlights areas of uncer tainty that warrant further investigation The objective is to present a consensus on a revised classification of OPMDs recommended nomenclature and definitions for each disorder Such classification is predominantly albeit not exclusively based on clinical features 2 DEFINITION AND GENERAL FEATURES The working group has defined OPMD as any oral mucosal abnormal ity that is associated with a statistically increased risk of developing oral cancer The presence of an OPMD does indicate an increased risk for cancer of the lip or the oral cavity during the lifetime of the patient but only a minority progress to cancer On the other hand in some patients with an OPMD microinvasive carcinoma may be discovered on biopsy at the initial assessment Patients presenting with overt clinical signs and symptoms suggestive of the presence of a frank carcinoma ie deeply ulcerated exophytic or indurated would not be designated as having an OPMD Table 1 provides definitions for the disorders listed as OPMDs OPMDs have a wide range of clinical features including color variations white red and mixed white and red topographic changes plaqueplateau smooth corrugated verrucous granular atrophic and may be of variable size Speight et al 2018 Williams et al 2008 Some OPMDs particularly oral leukoplakia may super ficially ulcerate due to abrasion of the surface by trauma from teeth or appliances OPMDs can involve any anatomical site in the oral cavity and may be uni or multifocal Farah et al 2014 Extraoral sites eg pharynx larynx esophageal and genital may demon strate analogous PMDs OPMDs have an unpredictable clinical courseremaining static or may demonstrate progression or regres sion Farah et al 2019 Gupta et al 1980 Holmstrup et al 2006 Speight et al 2018 The majority of patients with OPMDs are diagnosed in mid dleaged or elderly patients predominantly males Napier Speight 2008 Speight et al 2018 In Western populations elderly females with longstanding leukoplakia and without obvious risk factors have paradoxically a significant risk of progression to can cer These individuals could carry an endogenous risk factor rather than being exposed to an environmental factor Ethnicity and asso ciated dominance of particular cultural risk factors have influenced the type and pattern of OPMDs reported in specific populations For example betel quidareca nut chewing habits are widely preva lent in South Asian populations resulting in a greater prevalence of OPMDs Lee Ko et al 2012 Lee MinShan Ko et al 2012 Mello et al 2018 Reverse smoking habit is also known to induce spe cific mucosal changes on the palate in some geographic regions see Section 37 3 DETAILED DESCRIPTIONS OF THE ORAL POTENTIALLY MALIGNANT DISORDERS 31 Leukoplakia Leukoplakia is among the most common and most studied OPMD encountered in clinical practice and in population surveys A bib liometric study of the mostcited articles on oral leukoplakia that provide a historical perspective on scientific evolution of our un derstanding of this disorder was published recently Liu et al 2019 Historically several definitions have been proposed for leukoplakia Table S1 The most recent definition by the WHO Collaborating Centre published in 2007 was A predominantly white plaque of ques tionable risk having excluded other known diseases or disorders that carry no increased risk for cancer Warnakulasuriya et al 2007 The present Working Group found no reason to change this definition which is now being reported widely in the global literature The following criteria should be considered when making a clini cal diagnosis of oral leukoplakia A predominantly white patchplaque that cannot be rubbed off Most homogeneous Leukoplakia affect a circumscribed area and have welldemarcated borders A smaller subset can present with diffuse borders Nonhomogeneous Leukoplakia typically present with more dif fuse borders and may have red or nodular components No evidence of chronic traumatic irritation to the area eg a sharp tooth rubbing on the tongue a white patch on the alveolar ridge or retromolar pad from masticatory friction a white patch on gingiva from overzealous toothbrushing Is not reversible on elimination of apparent traumatic causes that is demonstrates a persistence feature Does not disappear or fade away on stretching retracting the tissue By exclusion of other white or whitered lesions outlined in Table 2 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1865 WARNAKULASURIYA et AL It is emphasized that the term leukoplakia is used as a clinical di agnosis having excluded other clinically recognizable white or white red lesions Warnakulasuriya 2019 Table 2 The term persistent has been used under inclusion criteria but it must be noted that a his tory of persistence cannot always be ascertained at baseline When the clinical features are clear it is not always important to defini tively establish persistence During clinical examination of a white patch it is important to first look for a local traumatic cause If this is evident the white patch should not be considered a leukoplakia but rather be designated as a frictional keratosis Frictional kerato ses are typically diffuse and upon removal of the putative frictional source they should resolve It is important they are not regarded as an OPMD and must be distinguished from leukoplakia because the latter indicates a future cancer risk Leukoplakia can be subclassified clinically into homogenous and nonhomogenous types using distinct features based on color and surface texture Table 3 Homogenous Leukoplakia are typically asymptomatic and present as a uniformly thin white plaquepatch TA B LE 1 Recommended definitions for OPMDs Disorder Definition Source Leukoplakia A predominantly white plaque of questionable risk having excluded other known diseases or disorders that carry no increased risk for cancer Warnakulasuriya et al 2007 Proliferative Verrucous Leukoplakia PVL Progressive persistent and irreversible disorder characterized by the presence of multiple Leukoplakia that frequently become warty WHO Collaborating Centre 2020 Erythroplakia A predominantly fiery red patch that cannot be characterized clinically or pathologically as any other definable disease WHO Collaborating Centre 2007 Oral Submucous Fibrosis OSF A chronic insidious disease that affects the oral mucosa initially resulting in loss of fibroelasticity of the lamina propria and as the disease advances results in fibrosis of the lamina propria and the submucosa of the oral cavity along with epithelial atrophy Modified from World Workshop on Oral Medicine V Kerr et al 2011 Oral Lichen Planus OLP A chronic inflammatory disorder of unknown etiology with characteristic relapses and remissions displaying white reticular lesions accompanied or not by atrophic erosive and ulcerative andor plaque type areas Lesions are frequently bilaterally symmetrical Desquamative gingivitis may be a feature WHO Collaborating Centre 2020 Actinic Keratosis Actinic Cheilitis AKAC A disorder that results from sun damage and affects exposed areas of the lips most commonly the vermilion border of the lower lip with a variable presentation of atrophic and erosive areas and white plaques WHO Collaborating Centre 2020 Palatal Lesions in Reverse Smokers White andor red patches affecting the hard palate in reverse smokers frequently stained with nicotine WHO Collaborating Centre 2020 Oral Lupus Erythematosus OLE An autoimmune connective tissue disease which may affect the lip and oral cavity where it presents as an erythematous area surrounded by whitish striae frequently with a target configuration WHO Collaborating Centre 2020 Dyskeratosis Congenita DC A rare cancerprone inherited bone marrow failure syndrome caused by aberrant telomere biology It is characterized clinically by the presence of the diagnostic triad of dysplastic nails lacy reticular skin pigmentation and oral leukoplakia Ballew and Savage 2013 Newly included in 2020 classification Oral Lichenoid Lesion OLL Oral lesions with lichenoid features but lacking the typical clinical or histopathological appearances of OLP that is may show asymmetry or are reactions to dental restorations or are druginduced WHO Collaborating Centre 2020 Oral Graft versus Host Disease OGVHD Clinical and histopathological presentations similar to oral lichen planus in a patient developing an autoimmune multiorgan complication after allogeneic hematopoietic cell transplantation WHO Collaborating Centre 2020 Removed from the 2020 classification due to limited evidence Oral Epidermolysis Bullosa OEB A severe epidermal fragility disorder associated with trauma induced blistering progressive soft tissue scarring and increased risk of epidermal cancer Fritsch et al 2008 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1866 WARNAKULASURIYA et AL They have a smooth surface with a consistent surface topography throughout are usually sharply demarcated and often exhibit shal low surface cracksfissures On the other hand nonhomogenous Leukoplakia may pres ent with diverse clinical presentations including speckled also re ferred to as erythroleukoplakia ie mixed white and red nodular small polypoid projections rounded red or white excrescences and verrucous wrinkled or corrugated surface Leukoplakia predominantly nonhomogeneous Leukoplakia may show focal superficial ulceration Nonhomogenous Leukoplakia carry a higher risk of transformation than homogeneous Leukoplakia Diz et al 2011 Speight et al 2018 and it is not uncommon for nonhomogeneous leukoplakia to exhibit severe dysplasia or even superficially invasive SCC following biopsy at baseline detection Lee et al 2006 Pentenero et al 2003 Lee et al 2006 re ported carcinomas in 12 of incisional biopsies taken from oral leukoplakia samples in Taiwan The variable and often severe his topathology within the field of nonhomogeneous Leukoplakia raises the importance of selecting the correct biopsy site or sites to avoid underdiagnosis Indeed multiple mapping biopsies may be indicated It is important to document whether the patient with a leukopla kia is a never smoker because these patients may experience a more aggressive natural history In the 2007 classification mixed white and red lesions were con sidered as a separate entity under the term erythroleukoplakia The consensus of the current Working Group was to classify erythroleu koplakia under nonhomogeneous leukoplakia Table 3 TA B LE 2 Other white lesions and disorders to be excluded based on clinical features alone before considering a clinical diagnosis of oral leukoplakia Normal and pathological entities Diagnostic features White sponge nevus Noted in early life family history lesions are throughout the mouth Genital mucosa may be affected Frictional keratosis History of friction or other mechanical trauma mostly along the occlusal plane an etiological cause apparent mostly reversible upon removal of the cause Biting of lip commissures or cheeks morsicatio buccorum Habit of lip andor cheek biting known irregular whitish flakes with jagged outline Chemical injury Known history of exposure to a chemical eg an aspirin tablet or a caustic agent eg sodium hypochlorite The site of lesion corresponds to chemical injury painful resolves rapidly Oral lichen planus White papules joined up with lines to form a reticular appearance on the surface of variably inflamed mucosa It can also present as desquamative gingivitis Plaque type may be difficult to distinguish from oral leukoplakia Acute pseudomembranous Candidiasis Generally widespread The white membrane can be scraped off sometimes revealing an erythematousraw footprint Associated with local or systemic eg immunodeficiency underlying causes Chronic hyperplastic candidosis An adherent white or white and red patch caused by a chronic fungal infection usually Candida albicans Leukoedema Bilateral on buccal mucosae and disappears upon stretching retracting Predilection among some racial groups Fordyces spots condition 1 mm diameter elevated circular buffcolored spots papules distinctly demarcated from the normal surrounding lining mucosa Skin graft Known history of a skin graft Oral hairy leukoplakia Bilateral keratosis with vertical streaking most common on the lateral borders of the tongue but can focally affect other mucosal sites especially in nonkeratinized areas Positive history of immunosuppression from HIV disease or drugsthe latter often following organ transplantation or the use of high potency steroid inhalers Nicotinic stomatitis leukokeratosis nicotina palati or smokers palate Greyish white palate with red spots inflamed minor mucous glands Smoking history Uremic stomatitis White sharply demarcated adherent plaques made of fibrinous exudate with some desquamated epithelial cells History of renal disease Several terms are used for white patches induced by trauma Frictional keratosis typically appears as a patch with diffuse borders when found on alveolar ridges these are referred to as alveolar ridge keratosis ARK a white line along the occlusal plane is referred to as linea alba buccalis Morsicatio buccarum is a condition characterized by chronic irritation or injury to the commissures andor to the buccal mucosa caused by repetitive chewing biting or nibbling None of these should be characterized as oral leukoplakia Acute pseudomembranous candidiasis is usually a widespread and distinctive infection of oral and sometimes oropharyngeal mucosa and should be easily differentiated from oral leukoplakia 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1867 WARNAKULASURIYA et AL TA B LE 3 Clinical presentations and differential diagnosis of some common OPMDs and newly added disorders Disorder Symptoms Clinical presentation Clinical conditions to exclude in the diagnosis Oral Leukoplakia OL Generally asymptomatic Some discomfort Homogeneous leukoplakia Uniformly white flat and thin with a smooth surface which may exhibit shallow cracks Cannot be rubbed off Nonhomogeneous Leukoplakia subtypes Nodular leukoplakia Small polypoid or rounded outgrowths red or white excrescences Verrucous leukoplakia The surface is raised exophytic wrinkled or corrugated Erythroleukoplakia Mixed white and red speckled but retaining predominantly white character Margins may be irregular White Sponge Nevus Frictional keratoses including Alveolar Ridge Keratosis Chemical injury Chronic candidal infection Leukoedema Fordyces spotscondition Skin graft Oral Hairy Leukoplakia OHL Leukokeratosis Nicotina Palati Smokers palate HPV Lesions for example CondylomataWarts Geographic tongueErythema Migrans Lichen Planus or Lichenoid Lesions Oral Erythroplakia Discomfort tingling and sensitivity to touch hot beverages or spicy foods A localized red patch with welldefined margins and a matt surface Erythematous candidiasis Dentureassociated stomatitis Erythema migrans Erosive and inflammatoryinfective disorders Desquamative gingivitis Discoid lupus erythematosus Erosive lichen planus Pemphigoid Pemphigus vulgaris Vascular hamartomas Vascular neoplasms Proliferative verrucous leukoplakia PVL Some discomfort Multiple thick white patches in more than two different oral sites frequently found on the gingiva alveolar processes and palate Majority present with a verrucous pattern Lesions spread and coalesce during development Recurrence in a previously treated area Lichen planus particularly in early stages Oral Lichen Planus OLP Asymptomatic Erosiveulcerative variety is sore Mostly white lines or as a white plaque Reticular lacelike white lines Linear annular various presentations as lines or rings Papular white dots Plaque type white patch Atrophic erosive and ulcerative red and ulcerated Bullous vesicular Oral lichenoid contact hypersensitivity reactions Oral lichenoid drug reactions Oral lichenoid lesions see below Lichenoid lesions in a betel quid user Mucous Membrane Pemphigoid Lichen planus pemphigoides Chronic ulcerative stomatitis Chronic graftversushost disease Lichen sclerosus Oral lupus erythematosus Proliferative verrucous leukoplakia Oral Submucous Fibrosis OSF Burning sensation to spicy food Later restricted mouth opening Blanching of oral mucosa Marked loss of tongue papillae Leathery mucosa Fibrous bands Limited mobility of tongue rigidity Shrunken or deformed uvula Limitation of mouth opening Sunken cheeks Scleroderma New in 2020 Classification Oral Lichenoid Lesion OLL Asymptomatic Red and atrophic areas could be sore White lines reticular lacelike linear or annular papular sometimes plaque type Red and erosive with white striae Asymmetrical Oral lichen planus Continues 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1868 WARNAKULASURIYA et AL The current expert group emphasizes that at the time of baseline detection oral leukoplakia is a provisional clinical diagnosis made by exclusion of other white disorders A diagnostic biopsy is indicated to confirm this clinical diagnosis or modify it ie oral lichen planus or hyperplastic candidosis One or more underlying histopatho logical diagnoses ranging from simple epithelial hyperplasia with hyperparakeratosis or hyperorthokeratosis varying severity of ep ithelial dysplasia are consistent with oral leukoplakia Ranganathan Loganathan 2019 Reibel et al 2017 It is customary that the pathologist mentions whether the histology is compatible with the clinical diagnosis of leukoplakia or not indicates the presence or ab sence of dysplasia and if present and provides the grades of dyspla sia To achieve uniformity in reporting we recommend a pathology report to state keratosis with nomildmoderatesevere dysplasia consistent with oral leukoplakia A biopsy may on occasion demon strate superficially invasive carcinoma and then the diagnosis of leukoplakia is revised to carcinoma These pathological aspects of leukoplakia are presented in detail by Kujan et al in this issue Any field surveys that have not included a protocol for biopsy should clarify that the diagnosis was based on clinical features with out histopathological confirmation Misdiagnosis and misclassification of Leukoplakia have led to confusion and inaccurate reporting of prevalence Auluck Pai 2005 also thereby underreporting malignant transformation in cases of oral leukoplakia One source of confusion is conflating the many different situations in which frictional keratosis is misclassi fied under the umbrella of leukoplakia Keratosis is unfortunately misused by some clinicians to clinically describe a white lesion We discourage keratosis as a clinical term unless it is part of a specific name such as frictional keratosis The published literature refers to other disorders which include keratosis in their name and that need to be better defined Tobacco pouch keratosisthis is a white patch found on the lower buccal grooves among smokeless tobacco users who retain their tobacco quid at the site Müller 2019 Most of them will resolve following discontinuation of the habit but those that per sist should be included within the group leukoplakia A biopsy is indicated at baseline and further study is needed to assess their natural history Sublingual keratosisA white patch when found of the floor of the mouth or inferior surface of the tongue was termed sublin gual keratosis by Kramers group Kramer et al 1978 The authors attributed high significance to these having noted that a large proportion of their patients with such white patches developed squamous cell carcinomas in that area Subsequent studies have not confirmed the extremely high risk of transformation noted in early studies but the floor of mouth remains a highrisk site and Leukoplakia at this site merit careful followup The Working Group recommends that any white patch on floor of mouthhav ing excluded other known conditionsshould be clinically consid ered a leukoplakia Sanguinariaassociated keratosisDamm et al 1999 Eversole et al 2000 and Mascarenhas et al 2002 described a unique form of a white patch that could be attributed to the use of a den tifrice andor mouth rinse containing the herbal additive sangui naria Sanguinarine is the principal alkaloid in an extract from the Indian bloodroot plant Sanguinuriu canadensis L Sanguinaria associated keratosis is rarely reported these days since the product was banned This condition should not be considered a leukoplakia as it has an established cause and would generally resolve on removal of the cause Palatal keratosis in reverse smokersThis has a very specific ap pearance and is classified as a separate entity in the OPMD lit erature and is not considered as a leukoplakia Reverse smokers keratosis is considered a disorder with a comparatively high risk of malignant transformation Gupta et al 1980 see Section 37 Keratosis of unknown significance KUSThis term was intro duced by Woo et al 2014 and refers to the histologic entity of hyperkeratosis with minimal to no epithelial dysplasia or cellular atypia Villa et al 2019 Woo et al 2014 There is no rationale to apply this term in the clinical context In fact over 50 of Leukoplakia will be in this histologic category The Working Group does not recommend use of the term keratosis of unknown significance 32 Proliferative verrucous leukoplakia This condition is defined as a distinct form of multifocal oral leuko plakia characterized by having a progressive clinical course chang ing clinical and histopathological features and is associated with the highest proportion of oral cavity cancer development com pared with other OPMDs Cabay et al 2007 Iocca et al 2020 Other terms proposed in the literature are Proliferative Multifocal Leukoplakia AguirreUrizar 2011 and Proliferative Leukoplakia Villa et al 2018 From a clinical perspective the evolution of this type of OPMD often begins as one or more Leukoplakia later pre senting in multiple locations due to gradual spread of an individual focus or resulting from fusion over time of several adjacent foci Villa Disorder Symptoms Clinical presentation Clinical conditions to exclude in the diagnosis Oral Graft versus host disease OGVHD Red and atrophic areas could be sore As above A history of allogeneic haematopoietic cell transplantation Oral lichen planus Oral lichenoid contact reaction Oral lichenoid drug reaction TA B LE 3 Continued 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1869 WARNAKULASURIYA et AL et al 2018 The original report by Hansen et al 1985 coining the term Proliferative Verrucous Leukoplakia proposed that the diag nosis be made by a combination of clinical and histological features Hansen et al 1985 Specific clinical diagnostic criteria were later proposed by CereroLapiedra et al 2010 and Carrard et al 2013 Their criteria included the disorder affecting more than two differ ent oral sites and the existence of a verrucous area Initial clinical presentation could be flat white lesions without any verrucous component Batsakis et al 1999 Villa et al 2018 and initially may also sometimes have a lichenoid clinical appearance GarciaPola et al 2016 McParland Warnakulasuriya 2020 and be signed out as being lichenoid by the pathologist In the latter situation it is possible that a case could be erroneously treated as OLP for many years with the risk of missing or of accelerating subsequent malig nancy Despite the imperfection of the term PVL to capture an ex panded group of patients with multifocal disease the term is widely reported and the Working Group recommended retaining this term A high proportion of patients diagnosed with PVL eventually de velops oral cancer A recent systematic review estimated the pro portion to be 495 CI 267724 Iocca et al 2020 Patients with a diagnosis of PVL may subsequently develop either conven tional squamous cell carcinomas or verrucous carcinomas Multiple primary carcinomas were documented in a case series mostly affect ing gingival sites Bagan et al 2019 33 Erythroplakia Erythroplakia is a solitary lesion defined Table 1 as a predomi nantly fiery red patch that cannot be characterised clinically or path ologically as any other definable disease Erythroplakia exhibits a clinical appearance of a sharply de marcated flat or depressed erythematous area of mucosa with a matt appearance Inflammatory conditions that may result in a red clinical appearance are excluded prior to arriving at this diagno sis see Table 3 Kramer et al 1978 van der Waal Scully 2011 Warnakulasuriya 2019 The solitary presentation of erythropla kia helps to distinguish it from other more widespread conditions such as erosive lichen planus lupus erythematosus and erythema tous candidiasis which present more often in multiple sites van der Waal 2010 Other conditions include autoimmune disorders infec tions and vascular hamartomasvascular neoplasms that may exhibit similar clinical features and should be considered in the differential diagnosis Reichart Phillipsen 2005 Most oral erythroplakias at the time of diagnosis are either histopathologically a squamous cell carcinoma or show highgrade epithelial dysplasia 34 Oral submucous fibrosis OSF Oral submucous fibrosis is a wellrecognized OPMD characterized by fibrosis of the oral mucosa inc submucosa and there is a higher risk for oral cancer development in patients with OSF In moderate to advanced cases fibrosis may also involve the oropharynx and the upper third of the oesophagus Maher et al 1991 Misra et al 1998 Tilakaratne et al 2016 The definition proposed by Kerr et al 2011 following the World Workshop of Oral Medicine V that has gained acceptance was slightly modified by the Working Group A chronic insidious disease that affects the oral mucosa ini tially resulting in loss of fibroelasticity of the lamina propria and as the disease advances results in fibrosis of the lamina propria and the submucosa of the oral cavity along with epithelial atrophy The clini cal diagnostic features are listed in Table 3 The clinical features at the time of presentation of oral submucous fibrosis depend on the stage of the disease It is generally characterized by patients reporting a burning sensation of the oral mucosa and intolerance to spicy foods Initial signs include a leathery mucosa pallor loss of tongue papillae petechiae and occasionally vesicles As the disease progresses fibrous bands develop in lips cheek mucosa and soft palate and this hallmark feature leads to a limited mouth opening Kerr et al 2011 There is growing evidence to support the role of genetic susceptibility and family history in the patho genesis and clinical presentation of OSF Ray et al 2019 Several grading systems have been proposed Based on objective criteria a 5grade system was proposed by Kerr et al 2011 The working group endorses this for clinical use 35 Oral lichen planus Carrozzo et al 2019 characterized oral lichen planus OLP as a disease with bilateral white reticular patches affecting buccal mu cosae tongue and gingivae More severe presentations include erosionsareas of atrophy and ulceration Despite being a common noninfectious disorder in the oral cavity Roopashree et al 2010 oral lichen planus OLP continues to be a disorder without clear causative factors Aghbari et al 2017 Cheng et al 2016 Krutchkoff et al 1978 van der Meij et al 1999 Cancer develop ment in patients with a diagnosis of OLP was recently reviewed by GonzalezMoles et al 2019 OLP should be diagnosed using both clinical and histopathological characteristics Table 4 Al Hashimi et al 2007 Cheng et al 2016 van der Meij van der Waal 2003 and should be clearly distinguished from disorders with similar clinical appearances but due to other causes including oral lichenoid lesions van der Meij van der Waal 2003 oral lichenoid drug reactions Scully Bagan 2004 oral lichenoid contact hypersensitivity reactions AlHashimi et al 2007 lichen planus pemphigoides chronic ulcerative stomatitis acute and chronic graftversushost disease lichen sclerosus lupus erythe matosus and the early stages of PVL Carrozzo et al 2019 Cheng et al 2016 When defining cancer development in patients with OLP authors should follow strict criteria in diagnosing OLP that incorporate clinical histopathological and patient characteristics Idrees et al 2020 Diagnostic criteria of oral lichen planus en dorsed by the Working Group based on previous proposals are listed in Table 4 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1870 WARNAKULASURIYA et AL 36 Actinic KeratosisActinic Cheilitis Actinic Keratosis AK is produced by the effect of actinic solar predominantly ultraviolet radiation to exposed areas of the face and therefore predominantly the skin and vermilion of the lower lip The precise areas affected are important in clinical assessment Savage et al 2010 AK occurs predominantly in middleaged and lightskinned men with outdoor occupations Dancyger et al 2018 There may be localized or diffuse lesions of white flaking plaques or scaly lesions with interspersed red areas Markopoulos et al 2004 In very mild cases patients may present simply with dryness of lips Savage et al 2010The white surface is due to hyperkeratosis while the red color results from epithelial atrophy or even erosion allowing the vasculature to shine through It is not possible to predict which AKs will progress regardless of the histological grade AK IAK III Fernandez Figueras 2017 Histologically the epithelium may show hyperplasia or atrophy disordered maturation varying degrees of keratinization or parake ratinization cytological atypia and increased mitotic activity The lamina propria often shows basophilic degeneration of collagen elas tosis and vasodilatation Cavalcante et al 2008 Mello et al 2019 de Santana Sarmento et al 2014 Lichenoid inflammation is often present and a histopathological diagnosis of lichenoid actinic ker atosis should then be rendered Benign lichenoid keratosis lichen planuslike keratosis is an important differential diagnosis in facial skin including vermillion border In a case series n 124 reported from Brazil 25 displayed early SCC in the biopsy specimens Mello et al 2019 A systematic review on AK found no reliable estimates concerning the frequency of AK developing into invasive carcinoma Werner et al 2013 37 Palatal lesions in reverse smokers In reverse smoking the burning end of a cigarette or cigar is held in side the mouth Where this is practiced as many as 50 of all oral ma lignancies are found on the hard palate a site usually spared by other OPMDs except among pipe smokers Reverse smoking is an endemic tobacco habit practiced in the coastal rural Andhra Pradesh India The habit is also prevalent among the people of the Caribbean Islands in Latin America Colombia Panama Venezuela Sardinia and among some Pacific Islanders for example the Philippines but there are no followup studies published outside India Field research undertaken by the Tata Institute of Fundamental Research TIFR India Gupta et al 1980 first described palatal changes in reverse smokers in sev eral Indian cohorts as thickened white plaques of palate mucosal nodularity excrescences around orifices of palatal minor mucosal glands yellowish brown staining erythema and ulceration Lesions can present as red white or mixed red and white in a background of tobacco staining In a later Indian study of reverse smokers 32 were found white and red patches on their palates Bharath et al 2015 38 Oral lupus erythematosus Lupus erythematosus is a chronic autoimmune disease which can be principally subdivided into three forms a systemic b drug induced and c discoid Oral lesions may manifest in approximately 20 patients with systemic lupus Oral lesions of lupus erythe matosus OLE exhibit similar clinical presentations as found in OLP Typically OLE presents as a central circular zone of atrophic mucosa with superficial ulceration surrounded by whitish striae Odell 2017 Buccal mucosae palate and lips are most commonly affected Histopathological criteria for the diagnosis of discoid lupus erythematosus are described by Schiødt 1984 Carcinomas developing within lesions OLE are rare intraorally and most arise on the lips Arvanitidou et al 2018 It is not always possible to con fidently distinguish OLP from OLE intraorally so that in the absence of systemic features it is quite possible that malignancy arising in LE would be misclassified as a malignancy arising in OLP 39 Dyskeratosis congenita Dyskeratosis Congenita DKC also called ZinsserColeEngman syndrome is a rare hereditary condition of dysfunctional telomere maintenance that is regarded as a potentially malignant disorder A higher frequency of oral cancers is noted among patients affected by this condition Bongiorno et al 2017 The pathogenesis is at tributed to mutations of several genes that help maintain telomere TA B LE 4 Diagnostic criteria of oral lichen planus based on previous proposals AguirreUrizar et al 2020 AlHashimi et al 2007 Cheng et al 2016 van der Meij van der Waal 2003 Clinical criteria Presence of bilateral more or less symmetrical white lesions affecting buccal mucosa andor tongue andor lip andor gingiva Presence of a white papular lesions and lacelike network of slightly raised white lines reticular annular or linear pattern with or without erosions and ulcerations Sometimes presents as desquamative gingivitis Histopathological criteria Presence of a welldefined bandlike predominantly lymphocytic infiltrate that is confined to the superficial part of the connective tissue Signs of vacuolar degeneration of the basal andor supra basal cell layers with keratinocyte apoptosis In the atrophic type there is epithelial thinning and sometimes ulceration caused by failure of epithelial regeneration as a result of basal cell destruction A mixed inflammatory infiltrate may be found 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1871 WARNAKULASURIYA et AL structure and function such as the DKC1 gene DKC1 gene encodes for the ribonucleoprotein dyskerin AbdelKarim et al 2009 Ballew Savage 2013 Most cases are inherited and may be Xlinked au tosomal dominant or autosomal recessive with variable penetrance Handley Ogden 2006 The condition often arises early and should always be considered and excluded in a child presenting with oral leu koplakia It consists of the triad of oral Leukoplakia usually on the dor sal tongue but can arise in any mucous membranes within the body hyperpigmentation of the skin usually with a reticular pattern on the neck and nail dystrophy Ogden et al 1988 Lichenoidlike lesions have also been reported Handley Ogden 2006 The prognosis is often poor due to either malignant change within the oral lesions or bone marrow failure resulting in overwhelming infection and death Attempts have been made to identify potential markers for future cancerous change within these oral lesions Evidence for disturbed cytokeratin abnormal p53 expression and changes at an ultrastruc tural level fetalneonatal features have been reported some 10 years before malignant change McKay et al 1991 Ogden et al 1993 4 CONDITIONS NEWLY ADDED IN 2020 CLASSIFICATION 41 Oral lichenoid lesions OLL Oral lichenoid lesions OLL lack the typical clinical or histological ap pearance of OLP that is they may not be symmetrical and could be unilateral According to van der Meij and van der Waal 2003 OLL would be those disorders that do not present the clinical and or histo pathological characteristics considered typical but compatible with OLP Oral lichenoid lesions include a atypical OLP and unilateral li chenoid lesions as characterized by van der Meij et al 1999 2007 van der Meij van der Waal 2003 b those in close contact rela tionship to a dental restoration often amalgam referred to as oral li chenoid contact reactions OLCR AlHashimi et al 2007 McParland Warnakulasuriya 2012 c lichenoid drug reactions LDR Al Hashimi et al 2007 e oral lesions following intake of food or some substances such as cinnamon and f oral lesions of graftversushost disease Furthermore lichenoid contact reactions to betel quid BQ are reported among BQ users Reichart Warnakulasuriya 2012 It is a diagnostic challenge to clinically distinguish OLL from OLP Recently AguirreUrizar et al 2020 proposed grouping OLP and OLLs under the term oral lichenoid disease which they define as a potentially malignant disorder of the oral mucosa that cannot be clinically or histopathologically diagnosed as any other specific oral disease Oral lichenoid diseases encompass both OLP and OLL and characteristically show white papules and reticular formation and are sometimes accompanied by other types erosiveulcerative atro phic plaque and bullous GonzalezMoles et al 2019 also argues for abandoning the term OLL as defined by van der Meij and van der Waal 2003 The evidence from their systematic review suggests that patients with OLL have more or less similar malignant potential to OLP GonzalezMoles et al 2019 Importantly the current Working Group recommends health professionals refrain from using the term oral lichenoid dysplasia to describe an entity among OLP or lichenoid disorders which show dysplastic changes If dysplasia is present the diagnosis should be oral epithelial dysplasia with lichenoid features ie if the latter fea tures are indeed evident or OLP with dysplasia Additional details regarding this topic are reported by Kujan et al 2021 in this volume 42 Oral graftversushost disease OGVHD OGVHD is reported in patients with hematologic malignancies receiv ing allogeneic stem cell transplants Elad et al 2019 They present in acute and chronic forms that usually involve several organs Flowers et al 1999 Oral lesions with a lichenoid appearance erythema at rophy and ulceration were reported in more than 90 of patients who suffered from GVHD Fricain et al 2005 Schubert et al 1984 Since our previous Workshop Report on OPMDs Warnakulasuriya et al 2007 progression to cancer in OGVHDrelated oral lichenoid lesions has subsequently been reported in several case studies Demarosi et al 2005 Frydrych et al 2019 Hashimoto et al 2019 Mawardi et al 2011 Atsuta et al 2014 analyzed a database of 17545 adult recipients of an allogeneic stem cell transplantation be tween 1990 and 2007 in Japan Multisystem chronic graftversus host disease GVHD was a significant risk factor for the development of all solid tumors RR 18 p 001 significantly higher for oral cancer RR 29 p 001 among patients after 1year posttrans plant The possible role of immunosuppressant therapy for chronic graftversushost disease on the development of oral squamous cell carcinoma needs consideration de Araújo et al 2014 5 DISORDERS WITH LIMITED OR INSUFFICIENT EPIDEMIOLOGICAL EVIDENCE FOR MALIGNANT POTENTIAL The current literature refers to three other disorders that are prob ably associated with an increased frequency of oral cancers epi dermolysis bullosa chronic hyperplastic candidosis and exophytic verrucous hyperplasia We describe here the available evidence and highlight the con troversies surrounding these disorders Disorders with limited epidemiological evidence of malignant potential 51 Oral epidermolysis bullosa Epidermolysis bullosa was included as a potentially malignant dis order in our 2007 classification of OPMDs A specific potentially 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1872 WARNAKULASURIYA et AL malignant oral lesion associated with epidermolysis bullosa is not well characterized in the literature Squamous cell carcinomas are common in sun exposed areas among patients with recessive dys trophic type of epidermolysis bullosa RDEB A review by Wright 2010 includes case reports of oral SCCs particularly among indi viduals with severe generalized RDEB Disorders with insufficient epidemiological evidence The Working Group reviewed the available evidence on the following disorders and found insufficient evidence for their malignant poten tial At present these are not recommended for inclusion within the OPMD group of disorders 52 Chronic hyperplastic candidosis CHC CHC presents as an adherent white patch caused by a chronic fun gal infection usually Candida albicans Farah et al 2019 The clinical presentation is thick white plaques or mixed red and nodular nonho mogenous white patches most commonly involving the anterior buc cal mucosae and commissures or on the dorsum of the tongue Dilhari et al 2016 There is some experimental evidence that Candida causes epithelial hyperproliferation Rast et al 2016 Sitheeque Samaranayake 2003 It is known that C albicans dramatically modifies the clinical and histological aspects of oral white plaques commonly referred to as candida leukoplakia Candida is frequently present in the biopsies of moderate and severe dysplasia and significant dysplastic changes are noted in the epithelium of candida Leukoplakia harbor ing Candida species McCullough et al 2002 Shukla et al 2019 It is postulated that Candidarelated oral carcinogenesis could arise from acetaldehyde production from alcoholic beverages by specific Candida isoforms Alnuaimi et al 2016 Candidalysina cytolytic peptide toxin secreted by C albicansby interacting with epithelial growth factor receptors EGFR could activate human EGF pathways to produce increased cell proliferation Ho et al 2019 The distinction between candida leukoplakia and chronic hy perplastic candidosis is not clear and most authors consider these two terms synonymous The first description of candidal leuko plakia was published by Cawson and Lehner 1968 and reviewed by Sitheeque and Samaranayake 2003 Both sets of authors emphasize that the lesions responded readily to antifungal treat ment which supports a causal relationship Nevertheless it must be noted that while many cases improve with antifungal treatment they do not disappear completely The current Working Group noted that it is important to have consistency in the way we use these two terms and that antifungal treatment should be part of the diagnostic process A recent systematic review on candida leukoplakia Shukla et al 2019 identified 3 studies quoting malignant transformation ratios of 25 65 and 287 such a wide range implies incon sistent diagnostic criteria The definition of leukoplakia excludes specific causes and the Working Group noted that candidal leuko plakia was now a deprecated term 53 Exophytic verrucous hyperplasiaOral verrucous hyperplasia Verrucous hyperplasia of the oral mucosaa relatively unrec ognized entity that may resemble verrucous carcinoma both clinically and histologically was first described by Shear and Pindborg 1980 VH was considered a precursor of verrucous carcinoma Batsakis et al 1999 A new entity was proposed by a group of South Asian pathologists to describe a mass type lesion with an exophytic and verrucous appearance specifically recog nized among areca nut and betel quid users Patil et al 2016 Zain et al 2016 This disorder was first noted in Taiwanese patients di agnosed with OPMDs Wang et al 2009 and the name proposed by these authors was oral verrucous hyperplasia A second cohort was described later by the same group among which 6 10 devel oped an oral cancer Wu et al 2018 This disorder can present in two forms a as an exophytic fleshy verrucopapillary outgrowth with a white andor pink surface color or b as a white plaque like exophytic verrucous lesion It typically manifests as a discrete or solitary lesion and may coexist in patient presenting with oral submucous fibrosis The clinical presentation could masquerade as a squamous cell carcinoma or verrucous carcinoma Absence of deep induration is a cardinal feature Hsue et al 2007 reported on a group of 1458 Taiwanese patients with OPMDs and based on clinical and histopathologi cal criteria 324 22 were classified as oral verrucous hyperpla sia 10 patients developed malignancies during a mean followup time of 43 months Wang et al 2014 reporting on 5071 south ern Taiwanese patients from Kaohsiung city diagnosed with OPMDs described the clinical presentation of 869 OVH patients 59 of whom 679 developed cancer in a followup period of 335 months Cancers were found mostly on the buccal mucosa but the lower lip dorsolateral surfaces of the tongue soft palate and gingiva were also affected The clinical and histological diag nostic criteria for oral verrucous hyperplasia aka oral exophytic verrucous hyperplasia OEVH are outlined by Zain et al 2016 A high proportion of these disorders in Taiwanese subjects demon strated OED at the initial histopathological investigation and a pro portion developed oral cancer at the sites of the presenting lesion Recent reports on exophyticoral verrucous hyperplasia proposed that this disorder be regarded as an OPMD Hsue et al 2007 Patil et al 2016 Wang et al 2009 2014 Wu et al 2018 Zain et al 2016 Several cases presented at a workshop held in Kuala Lumpur Zain et al 2016 have provided new evidence that these may arise as a secondary lesion in patients with oral submucous fibrosis Shah et al 2019 Having considered the recent publica tions describing these disorders the Working Group was of the opinion that it would be desirable to obtain more followup data from several countries in regions where betel quid chewing is 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1873 WARNAKULASURIYA et AL common The Working Group recommends the term OEVH rather than OVH for this apparent entity 6 CARCINOMAS ARISING IN PATIENTS WITH OPMDs The most common histopathological diagnosis reported for a cancer arising in a patient with an OPMD is a conventional squamous cell carcinoma OPMDs are a heterogeneous group and have variability in their ratios of progression to cancer 14495 over a follow up period ranging from 12 months to 20 years Iocca et al 2020 Predicting the risk of transformation remains a significant challenge even in specialist practice At one end of the spectrum patients di agnosed with PVL and erythroplakia show high frequencies of can cer development close to 3050 and on the other hand oral lichen planus OLP show lower frequencies of cancer development 12 Oral leukoplakia has a variable risk with nonhomogene ous forms showing higher risk compared with homogeneous leuko plakia The presence and grade of epithelial dysplasia have shown prognostic utility in stratifying the risk of cancer development In a metaanalysis Mehanna et al 2009 have shown that higher grades of dysplasia have significantly higher frequencies of cancer devel opment Techniques such as ploidy assessment when combined with dysplasia grading may refine the prediction of risk Alaizari et al 2018 Accompanying publications in this volume discuss in greater detail cancer development in patients with OPMDs pathol ogy tools biomarkers and how ploidy analysis may assist in stratify ing risk The biomarkers currently investigated for predicting the risk are not in routine clinical use anywhere in the world 7 CARCINOMA ARISING FROM CLINICALLY NORMAL MUCOSA Malignancy can arise from an area of normallooking mucosa without the patient or a clinician being aware of an OPMD being present earlier at the site This is consistent with the concept of a field change that apparently normal mucosa may contain significant molecular aberrations that increase the likelihood of cancer Farah et al 2018 Farah Shearston et al 2019 Nikitakis et al 2018 Thomson et al 2017 There is a need to further investigate the basic biology associ ated with the concept of field cancerization as proposed by Slaughter et al 1953not least in ensuring common terminology Ogden Hall 1997 Field cancerization is characterized by phenotypic and genetic changes in the neighboring areas of frank carcinomas while the term field change should be reserved for alterations in tissues that show no evidence of disease clinically or histologically Ogden et al 1990 A proliferating field that gradually displaces the nor mal mucosa have been detected on the basis of mutations in TP53 whereas they are usually not detected by routine diagnostic tech niques Braakhuis et al 2003 2005 Thus the identification of a marker usually associated with malignant disease would signify a field change effect in the absence of histomorphological evidence of dysplasia Such patients may not have yet developed nor indeed may never develop a tumor Currently available adjunctive tools Kerr 2020 Rashid Warnakulasuriya 2015 have not been adequately researched to test whether the new optical devices are able to identify these oc cult lesions within field changes However evidence for field change based on a variety of markers eg cytokeratins p53 and markers of angiogenesis has been identified within biopsies of clinically nor mal mucosa from oral cancer patients ElGazzar et al 2005 Ogden et al 1993 1997 and by Ogden 1997 using exfoliative cytology eg cytomorphology cytokeratins However a reliable marker that can predict future malignant change in every case has yet to be found Future molecular techniques might make these invisible changes detectable but further research is needed 8 SYNDROMES THAT MAY POTENTIATE CANCER DEVELOPMENT IN THE ORAL CAVITY Close to 20 familial cancer syndromes are described and people born with inherited genetic predispositions develop hematological malignancies and solid cancers at a younger age and with a relatively high frequency Important examples are Fanconi anemia xeroderma pigmentosum Li Fraumeni syndrome Bloomss syndrome ataxia telangiectasia and Cowden syndrome Many of these syndromes are caused by alterations in tumor suppressor genes or DNA repair genes that can be broadly divided into two groups called gatekeepers and caretakers respectively Prime et al 2001 examined whether there is an increase in the incidence of oral cancer in inherited cancer syndromes and whether the genes that are known to be relevant to the pathogenesis of these cancer syndromes also play a role in the development and behavior of oral cancer These authors provide a comprehensive list of gate keeper genes associated with several hereditary cancer syndromes Prime et al 2001 Of the many familial cancer syndromes described Fanconi ane mia has the strongest evidence for a predisposition for oral cancer and a short description appears below 81 Fanconi anemia FA An increased susceptibility of Fanconi anemia FA patients to earlyonset OSCCslargely in the absence of known lifestyle risk factorshas been observed for decades Fanconi anemia FA is a rare autosomal recessive disorder of DNA repair genes in which the defects lie in the repair of DNA crosslinks It is characterized by physical congenital anomalies skeletal malformations aplastic ane mia and then progressive pancytopenia FA may lead to bone mar row failure leukemia andor solid tumors including head and neck 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1874 WARNAKULASURIYA et AL cancers with oral squamous cell carcinoma being the most common type Recently there has been renewed interest among researchers on development of OSCCs in FA Masserot et al 2008 described head and neck squamous cell carcinoma in 13 patients 8 in oral cav ity with Fanconi anemia after hematopoietic stem cell transplanta tion In a systematic review Furquim et al 2018 identified a total of 121 individuals affected by FA and OSCC among 47 published from 1970 to 2016 The tongue was the most affected site The overall risk was estimated to increase 500 to 700fold for head and neck cancer in FA patients compared to the general population Kutler et al 2003 and the majority developed carcinomas at an early age Therefore young people who develop HNSCC must receive FA diag nostic tests Patients with FA can present with potentially malignant disorders especially oral leukoplakia Amenábar et al 2019 Among 138 Brazilian patients with FA who had not undergone hematopoi etic stem cell transplantation HSCT 16 cases 12 were diagnosed with oral leukoplakia with a median age of 165 years Cavalcanti et al 2015 82 PlummerVinson syndrome PlummerVinson PatersonKelly syndrome PVSa constellation of symptoms relating to postcricoid esophageal webs atrophic glos sitis koilonychia and dysphagia considered to be caused by micro cytic hypochromic anemiawas linked to predisposition to upper digestive tract cancer Baron 1991 claimed in an analysis of a Welsh cohort that this syndrome no longer existed Anemia causes atrophy of the oral epithelium Ranasinghe et al 1987 Rennie et al 1984 and could be a cofactor among people with OPMDs and deserves attention in future research 9 OTHER TERMINOLOGIES It has recently been suggested to replace the term OPMD with po tentially premalignant oral epithelial lesion PPOEL Nikitakis 2018 van der Waal 2018 The terminology oral potentially malignant dis orders is now well established in the literature with over 750 publi cations and the Working Group could not see any reason for change Both in the 2007 paper and here we argue distinction between the terms potentially malignant and premalignant the former indi cates an unknown potential for the later development of a malignant tumor the latter an inevitability given sufficient time Potentially premalignant may indicate lack of premalignancy Moreover changes observed in histology are not limited to epithelium and therefore epithelial lesion is inappropriate Epithelialconnective tissue interactions are fundamental to homeostasis and disease and connective tissue changes are a striking component of many disorders Johnson 2020 Vucicevic Boras et al 2018 including in oral lichen planus and oral submucous fibrosis OSMF Arakeri et al 2018 Lodi et al 2005 10 IMPLICATIONS FOR RESEARCH The complete natural history of the individual OPMDs is yet to be confirmed There is a need for further research to identify the potential risk of cancer in patients with different OPMDs based on strict clini copathological diagnostic criteria There is a need to better understand the number of oral cancer cases developing from apparently normal oral mucosa There is a need to elucidate the role if any of Candida infection in dysplastic tissues The role of immunosuppression in GVHD toward the develop ment of oral cancer needs study There is a need to identify molecular differences between ho mogenous and nonhomogenous Leukoplakia and dysplastic and nondysplastic Leukoplakia There is a need to identify reliable molecular predictive and prog nostic biomarkers to guide personalized management of OPMDs as the current model to estimate the risk of malignant transforma tion is based only on clinical and histopathological features of the observed mucosal changes The Working Group reiterates the need for good quality longitu dinal studies assembling cases by the precise clinicopathological criteria defined here gathering extensive metadata on demogra phy and risk factors and analyzing followup data appropriately Studies with inconsistent designs should not be pooled 11 CONCLUSIONS This paper provides an update on the 2007 WHO Collaborating Centres classification of oral potentially malignant disorders The Working Group identified sufficient evidence on oral lichenoid le sions and oral graftversushost disease that merit their addition to the classification proposed in 2007 The natural history and the bio logical behavior of many OPMDs remain unknown and there was consensus that further research on these disorders is warranted A global research consortium to study OPMDs is needed to establish multisite longitudinal studies with welldefined clinicopathological diagnostic criteria to address questions and characterize their natu ral history and possibly to prevent development of oral cancer in patients diagnosed with these disorders ACKNOWLEDGEMENTS We thank the Royal College of Physicians and Surgeons RCPSG for providing logistic support for holding this expert symposium and Henry Schein Cares for an educational grant for travel expenses of some invited experts who attended the workshop CONFLICT OF INTEREST The authors filed detailed disclosure of potential conflicts relevant to the workshop topics and none were declared 16010825 2021 8 Downloaded from httpsonlinelibrarywileycomdoi101111odi13704 by UNIVERSIDADE ESTADUAL PAULISTA Wiley Online Library on 14122022 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1875 WARNAKULASURIYA et AL AUTHOR CONTRIBUTIONS Saman Warnakulasuriya Conceptualization Methodology Project administration Writingoriginal draft Writingreview editing Omar Kujan Conceptualization Writingoriginal draft Writing review editing José Manuel AguirreUrizar Writingreview editing Jose Bagan Writingreview editing Miguel Angel Gonzalez Moles Writingreview editing Alexander Ross Kerr Conceptualization Writingreview editing Fernanda Weber Mello Writingreview editing Luis Monteiro Writingreview editing Graham Ogden Writingreview editing Philip Sloan Writingreview editing Newell Walte Johnson Conceptualization Writingoriginal draft Writingreview editing PEER REVIEW The peer review history for this article is available at httpspublo nscompublo n101111odi13704 ORCID Saman Warnakulasuriya httpsorcid org0000000321030746 Omar Kujan httpsorcidorg0000000259518280 José M AguirreUrizar httpsorcidorg0000000226520755 José V Bagan httpsorcidorg0000000202952916 Miguel Ángel GonzálezMoles httpsorcid org0000000307916639 Alexander R Kerr httpsorcidorg0000000221628572 Giovanni Lodi httpsorcidorg0000000202188292 Fernanda Weber Mello httpsorcidorg000000022566268X Luis Monteiro httpsorcidorg0000000289381297 Graham R Ogden httpsorcidorg0000000333944537 Philip Sloan httpsorcidorg0000000201420213 Newell W Johnson httpsorcidorg000000015866262X REFERENCES AbdelKarim A Frezzini C Viggor S Davidson L E Thornhill M H Yeoman C M 2009 Dyskeratosis congenita A case report Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics 108 e20e24 httpsdoiorg101016jtripl eo200903042 Aghbari S M H Abushouk A I Attia A Elmaraezy A Menshawy A Ahmed M S Elsaadany B A Ahmed E M 2017 Malignant transformation of oral lichen planus and oral 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