Oral Diseases - 2020 - Warnakulasuriya - Oral Potentially Malignant Disorders A Consensus Report From An International

Received: 20 September 2020 | Revised: 21 October 2020 | Accepted: 25 October 2020
DOI: 10.1111/odi.13704
REVIEW ARTICLE
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. Aguirre-Urizar3 |

4,5 6,7 8
José V. Bagan | Miguel Ángel González-Moles | Alexander R. Kerr |
9 10
Giovanni Lodi | Fernanda Weber Mello | Luis Monteiro11 |
12 13 14,15
Graham R. Ogden | Philip Sloan | Newell W. Johnson
1
The WHO Collaborating Centre for Oral
Cancer and Faculty of Dentistry, Oral Abstract
and Craniofacial Sciences, King’s College Oral potentially malignant disorders (OPMDs) are associated with an increased risk
London, London, UK
2 of occurrence of cancers of the lip or oral cavity. This paper presents an updated
UWA Dental School, The University of
Western Australia, Perth, WA, Australia report on the nomenclature and the classification of OPMDs, based predominantly
3
Oral and Maxillofacial Medicine & on their clinical features, following discussions by an expert group at a workshop held
Pathology Unit, Department of Stomatology
II, Faculty of Medicine and Nursery,
by the World Health Organization (WHO) Collaborating Centre for Oral Cancer in
University of the Basque Country/EHU, the UK. The first workshop held in London in 2005 considered a wide spectrum of
Bilbao, Spain
4
disorders under the term “potentially malignant disorders of the oral mucosa” (PMD)
Oral Medicine, Valencia University,
Valencia, Spain (now referred to as oral potentially malignant disorders: OPMD) including leukopla-
5
Department of Oral and Maxillofacial kia, erythroplakia, proliferative verrucous leukoplakia, oral lichen planus, oral submu-
Surgery, University General Hospital,
cous fibrosis, palatal lesions in reverse smokers, lupus erythematosus, epidermolysis
Valencia, Spain
6
School of Dentistry, University of Granada, bullosa, and dyskeratosis congenita. Any new evidence published in the intervening
Granada, Spain period was considered to make essential changes to the 2007 classification. In the
7
Biohealth Research Institute (IBS), Granada,
current update, most entities were retained with minor changes to their definition.
Spain
8
Department of Oral and Maxillofacial
There is sufficient evidence for an increased risk of oral cancer among patients diag-
Pathology, Radiology, and Medicine, New nosed with “oral lichenoid lesions” and among those diagnosed with oral manifesta-
York University College of Dentistry, New
York, NY, USA
tions of ‘chronic graft-versus-host disease’. These have now been added to the list of
9
Dipartimento di Scienze Biomediche, OPMDs. There is, to date, insufficient evidence concerning the malignant potential
Chirurgiche e Odontoiatriche, Università of chronic hyperplastic candidosis and of oral exophytic verrucous hyperplasia to
degli Studi di Milano, Milano, Italy
10 consider these conditions as OPMDs. Furthermore, due to lack of clear evidence of
Federal University of Santa Catarina,
Florianópolis, Brazil an OPMD in epidermolysis bullosa this was moved to the category with limited evi-
11
CESPU, Instituto de Investigação dence. We recommend the establishment of a global research consortium to further
e Formação Avançada em Ciências e
Tecnologias da Saúde (IINFACTS), IUCS - study the natural history of OPMDs based on the classification and nomenclature
Instituto Universitário de Ciências da Saúde, proposed here. This will require multi-center longitudinal studies with uniform diag-
Gandra, Portugal
12 nostic criteria to improve the identification and cancer risk stratification of patients
Department of Oral Surgery, Dundee
Dental School, Dundee, Scotland, UK with OPMDs, link them to evidence-based interventions, with a goal to facilitate the
13
School of Dental Sciences, Faculty of prevention and management of lip and oral cavity cancer.
1862 | © 2020 Wiley Periodicals LLC wileyonlinelibrary.com/journal/odi Oral Diseases. 2021;27:1862–1880.

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WARNAKULASURIYA et al. | 1863
Medical Sciences, Newcastle University,

KEYWORDS
Newcastle upon Tyne, UK
14 erythroplakia, leukoplakia, lichen planus, oral potentially malignant disorders, proliferative
Menzies Health Institute Queensland
and School of Dentistry and Oral Health, verrucous leukoplakia, submucous fibrosis
Griffith University, Gold Coast, Qld,
Australia
15
Faculty of Dentistry, Oral and Craniofacial
Sciences, King’s College London, London,
UK
Correspondence
Saman Warnakulasuriya, King’s College
London, London, UK.
Email: [email protected]
observed in superficially invasive carcinomas; and some of the chro-

1 | I NTRO D U C TI O N mosomal, genomic, and molecular alterations detected in early in-
vasive OSCCs are also found in OPMDs (presented in later chapters
In March 2020, the WHO Collaborating Centre for Oral Cancer in in this supplement). It is also important to recognize that OSCC can
the UK convened a workshop attended by invited experts to dis- present without the patient or a clinician having been aware of a pre-
cuss the advances in knowledge and recent changes in the under- ceding clinically altered mucosa at the site. The expert opinion at the
standing of oral potentially malignant disorders (OPMDs). OPMDs 2005 workshop (published in 2007) proposed a shift from previously
are a significant group of mucosal disorders that may precede the used terms “precancer”, “epithelial precursor lesions”, “premalignant”,
diagnosis of oral squamous cell carcinoma (OSCC) (Warnakulasuriya “precancerous”, and “intra-epithelial lesion” to OPMD. Lesions and
et al., 2007). Since the introduction of this terminology, “potentially conditions were combined into one category of “disorders”, in recog-
malignant disorders of the oral mucosa” (PMD) (later OPMD), health- nition of the fact that field change usually exists due to exposure to
care providers and researchers over the globe have enthusiastically environmental carcinogens across much of the upper aero-digestive
adopted this term and the classification of entities therein, and this tract and that the whole person may have changes which influence
has resulted in better reporting of this important group of disorders. the risk of cancer development (Johnson, 2017, 2020). “Potentially
A recent review identified over 750 publications on the topic of malignant” implies that not all patients diagnosed with any of these
OPMDs published since 2007 (Liu et al., 2020). However, discrep- mucosal abnormalities will develop an oral malignancy. Nor does it
ancies in describing these disorders are still found in the published imply that a carcinoma will arise exactly at the site where an OPMD
literature leading to inconsistency and a degree of confusion. The was previously diagnosed. The observed clinical and biological
terminology for disorders that precede development of cancers has course of these disorders has been discussed recently by Speight
evolved over the years to align with greater scientific evidence and et al. (2018). The concept that the mere presence of OPMDs is but
to reflect temporal advances in understanding of the natural history one of several factors increasing the risk for cancer development is
of these disorders. OPMDs refer to a group of lesions and condi- important.
tions characterized by a variably increased risk of developing can- Patients diagnosed with OPMDs may have an increased suscep-
cers of the lip (C00) and the oral cavity (C02-C06) (Warnakulasuriya tibility to develop cancer anywhere in their mouth during their life-
et al., 2007). The terminology has been endorsed by the latest WHO time. The majority of these OPMDs may not progress to carcinoma,
classification on Head and Neck Tumours (Reibel et al., 2017). but rather they provide a field of abnormality in which cancer devel-
The concept of “precancer” was introduced in 1805 when a opment is more likely than in their clinically normal mucosa and more
European panel of physicians suggested that there are benign dis- likely than in patients without such disorders. “Clinically normal mu-
eases that may develop into invasive malignancy if followed for a cosa” can by molecularly abnormal. As alluded to earlier, the cancer
long time (Baillie & Simms, 1806). The thinking behind the concept does not necessarily occur in the site of the visibly altered mucosa.
of OPMDs as reported by the 2005 workshop and re-affirmed by An important challenge faced by clinicians managing patients with
the Working Group (2020) is that OPMDs represent tissue “fields” OPMDs is to be able to identify the small proportion of patients
with more or less distinctive clinical appearances at initial assess- most likely to develop a future malignancy.
ment, and where a proportion within each clinical category have Updating the classification of OPMDs is not just an academic
been documented to have subsequently developed a cancer during endeavor, but necessity for clinicians as they make evidence-based
follow-up; Viz: tissues within these categories have enhanced ma- management decisions for patients diagnosed with these disorders.
lignant potential. Some of these clinical alterations, red and white Such decisions have the potential for serious consequences and can
patches in particular, are seen to co-exist at the margins of overt impact the patient's quality of life and need to be carefully consid-
OSCCs; they possess similar morphological and cytological changes ered to minimize the risks for both under- or over-management. In
1864 | WARNAKULASURIYA et al.
the ICD-11 classification of diseases, the World Health Organization Speight, 2008; Speight et al., 2018). In Western populations, elderly
has proposed revisions for the following purposes: (a) increasing us- females with long-standing leukoplakia and without obvious risk
ability, (b) updating scientific content, (c) integrating with eHealth, factors have, paradoxically, a significant risk of progression to can-
and (d) accommodating the needs for multi-users in recording, re- cer. These individuals could carry an endogenous risk factor, rather
porting, and analysis (World Health Organisation, 2019). The 2020 than being exposed to an environmental factor. Ethnicity and asso-
workshop on OPMDs adheres to this rationale. The collective ex- ciated dominance of particular cultural risk factors have influenced
pert opinion favors perpetuation of the existing OPMD nomencla- the type and pattern of OPMDs reported in specific populations.
ture to describe oral mucosal disorders that indicate an increased For example, betel quid/areca nut chewing habits are widely preva-
risk for cancer development and consideration of new evidence lent in South Asian populations resulting in a greater prevalence of
from both basic science and clinical studies. With these objectives OPMDs (Lee, Ko, et al., 2012; Lee, Min-Shan Ko, et al., 2012; Mello
in mind, inclusion of some additional disorders has been proposed et al., 2018). Reverse smoking habit is also known to induce spe-
(Warnakulasuriya, 2018, 2020): oral lichenoid lesions and reactions, cific mucosal changes on the palate in some geographic regions (see
oral chronic graft-versus-host disease, chronic hyperplastic candido- Section 3.7).
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- 3 | D E TA I LE D D E S C R I P TI O N S O F
dorses definitions of each disorder and highlights areas of uncer- TH E O R A L P OTE NTI A LLY M A LI G N A NT
tainty that warrant further investigation. The objective is to present DISORDERS
a consensus on a revised classification of OPMDs, recommended
nomenclature and definitions for each disorder. Such classification 3.1 | Leukoplakia
is predominantly, albeit not exclusively, based on clinical features.
Leukoplakia is among the most common and most studied OPMD
encountered in clinical practice and in population surveys. A bib-
2 | D E FI N ITI O N A N D G E N E R A L FE AT U R E S liometric study of the most-cited articles on oral leukoplakia that
provide a historical perspective on scientific evolution of our un-
The working group has defined OPMD as “any oral mucosal abnormal- derstanding of this disorder was published recently (Liu et al., 2019).
ity that is associated with a statistically increased risk of developing oral Historically, several definitions have been proposed for leukoplakia
cancer.” (Table S1). The most recent definition by the WHO Collaborating
The presence of an OPMD does indicate an increased risk for Centre, published in 2007, was “A predominantly white plaque of ques-
cancer of the lip or the oral cavity during the lifetime of the patient, tionable risk having excluded (other) known diseases or disorders that
but only a minority progress to cancer. On the other hand, in some carry no increased risk for cancer” (Warnakulasuriya et al., 2007). The
patients with an OPMD, microinvasive carcinoma may be discovered present Working Group found no reason to change this definition
on biopsy at the initial assessment. Patients presenting with overt which is now being reported widely in the global literature.
clinical signs and symptoms suggestive of the presence of a “frank The following criteria should be considered when making a clini-
carcinoma,” (i.e., deeply ulcerated, exophytic, or indurated) would cal diagnosis of oral leukoplakia:
not be designated as having an OPMD. Table 1 provides definitions
for the disorders listed as OPMDs. • A predominantly white patch/plaque that cannot be rubbed off.
OPMDs have a wide range of clinical features including color • Most homogeneous Leukoplakia affect a circumscribed area and
variations (white, red, and mixed white and red), topographic have well-demarcated borders. A smaller subset can present with
changes (plaque/plateau, smooth, corrugated, verrucous, granular, diffuse borders.
atrophic) and may be of variable size (Speight et al., 2018; Williams • Non-homogeneous Leukoplakia typically present with more dif-
et al., 2008). Some OPMDs, particularly oral leukoplakia may super- fuse borders and may have red or nodular components.
ficially ulcerate due to abrasion of the surface by trauma from teeth • No evidence of chronic traumatic irritation to the area (e.g., a
or appliances. OPMDs can involve any anatomical site in the oral sharp tooth rubbing on the tongue, a white patch on the alveolar
cavity and may be uni- or multifocal (Farah et al., 2014). Extraoral ridge or retromolar pad from masticatory friction, a white patch
sites (e.g., pharynx, larynx, esophageal, and genital) may demon- on gingiva from overzealous toothbrushing).
strate analogous PMDs. OPMDs have an unpredictable clinical • Is not reversible on elimination of apparent traumatic causes, that
course-remaining static or may demonstrate progression or regres- is demonstrates a persistence feature.
sion (Farah et al., 2019; Gupta et al., 1980; Holmstrup et al., 2006; • Does not disappear or fade away on stretching (retracting) the
Speight et al., 2018). tissue.
The majority of patients with OPMDs are diagnosed in mid- • By exclusion of other white or white/red lesions outlined in
dle-aged or elderly patients, predominantly males (Napier & Table 2.
TA B L E 1 Recommended definitions for OPMDs
Disorder Definition Source
Leukoplakia A predominantly white plaque of questionable risk having Warnakulasuriya et al, 2007
excluded (other) known diseases or disorders that carry no
increased risk for cancer
Proliferative Verrucous Leukoplakia Progressive, persistent, and irreversible disorder characterized WHO Collaborating Centre 2020
(PVL) by the presence of multiple Leukoplakia that frequently become
warty
Erythroplakia A predominantly fiery red patch that cannot be characterized WHO Collaborating Centre, 2007
clinically or pathologically as any other definable disease
Oral Submucous Fibrosis (OSF) A chronic, insidious disease that affects the oral mucosa, initially Modified from: World Workshop on
resulting in loss of fibroelasticity of the lamina propria and as Oral Medicine V, Kerr et al. (2011)
the disease advances, results in fibrosis of the lamina propria
and the submucosa of the oral cavity along with epithelial
atrophy
Oral Lichen Planus (OLP) A chronic inflammatory disorder of unknown etiology with WHO Collaborating Centre 2020
characteristic relapses and remissions, displaying white reticular
lesions, accompanied or not by atrophic, erosive and ulcerative
and/or plaque type areas. Lesions are frequently bilaterally
symmetrical. Desquamative gingivitis may be a feature
Actinic Keratosis (Actinic Cheilitis) A disorder that results from sun damage and affects exposed WHO Collaborating Centre 2020
(AK/AC) 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
Palatal Lesions in Reverse Smokers White and/or red patches affecting the hard palate in reverse WHO Collaborating Centre 2020
smokers, frequently stained with nicotine
Oral Lupus Erythematosus (OLE) An autoimmune connective tissue disease which may affect WHO Collaborating Centre 2020
the lip and oral cavity, where it presents as an erythematous
area surrounded by whitish striae, frequently with a target
configuration
Dyskeratosis Congenita (DC) A rare cancer-prone inherited bone marrow failure syndrome Ballew and Savage (2013)
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
Newly included in 2020 classification
Oral Lichenoid Lesion (OLL) Oral lesions with lichenoid features but lacking the typical WHO Collaborating Centre 2020
clinical or histopathological appearances of OLP, that is, may
show asymmetry or are reactions to dental restorations or are
drug-induced
Oral Graft versus Host Disease Clinical and histopathological presentations similar to oral lichen WHO Collaborating Centre 2020
(OGVHD) planus in a patient developing an autoimmune, multi-organ
complication after allogeneic hematopoietic cell transplantation
Removed from the 2020 classification due to limited evidence
Oral Epidermolysis Bullosa (OEB) A severe epidermal fragility disorder associated with trauma- Fritsch et al. (2008)
induced blistering, progressive soft tissue scarring, and
increased risk of epidermal cancer
It is emphasized that the term leukoplakia is used as a clinical di- but rather be designated as a frictional keratosis. Frictional kerato-
agnosis having excluded other clinically recognizable white or white/ ses are typically diffuse, and upon removal of the putative frictional
red lesions (Warnakulasuriya, 2019) (Table 2). The term “persistent” source, they should resolve. It is important they are not regarded as
has been used under inclusion criteria but it must be noted that a his- an OPMD and must be distinguished from leukoplakia because the
tory of persistence cannot always be ascertained at baseline. When latter indicates a future cancer risk.
the clinical features are clear, it is not always important to defini- Leukoplakia can be sub-classified clinically into homogenous and
tively establish persistence. During clinical examination of a white non-homogenous types using distinct features based on color and
patch, it is important to first look for a local traumatic cause. If this surface texture (Table 3). Homogenous Leukoplakia are typically
is evident, the white patch should not be considered a leukoplakia, asymptomatic and present as a uniformly thin white plaque/patch.
TA B L E 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, Habit of lip and/or cheek biting known; irregular whitish flakes with jagged outline
commissures or
cheeks (morsicatio
buccorum)
Chemical injury Known history of exposure to a chemical (e.g., an aspirin tablet or a caustic agent, e.g., 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 Generally widespread. The white membrane can be scraped off sometimes revealing an erythematous/raw footprint
pseudomembranous Associated with local or systemic (e.g., immunodeficiency) underlying causes
Candidiasis**
Chronic hyperplastic An adherent white or white and red patch caused by a chronic fungal infection, usually Candida albicans
candidosis
Leukoedema Bilateral on buccal mucosae and disappears upon stretching (retracting). Predilection among some racial groups.
Fordyce's spots/ <1 mm diameter, elevated, circular buff-colored spots/ papules distinctly demarcated from the normal surrounding
condition 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 non-keratinized areas
Positive history of immunosuppression from HIV disease or drugs—the latter often following organ transplantation or
the use of high potency steroid inhalers
Nicotinic stomatitis Greyish white palate with red spots (inflamed minor mucous glands). Smoking history
(leukokeratosis
nicotina palati or
smokers’ palate)
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 and/or 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.
They have a smooth surface with a consistent surface topography (Lee et al., 2006; Pentenero et al., 2003). Lee et al., (2006) re-
throughout, are usually sharply demarcated, and often exhibit shal- ported carcinomas in 12% of incisional biopsies taken from oral
low surface cracks/fissures. leukoplakia samples in Taiwan. The variable and often severe his-
On the other hand, non-homogenous Leukoplakia may pres- topathology within the field of non-homogeneous Leukoplakia
ent with diverse clinical presentations including speckled (also re- raises the importance of selecting the correct biopsy site (or sites)
ferred to as erythroleukoplakia; i.e., mixed white and red), nodular to avoid underdiagnosis: Indeed, multiple mapping biopsies may
(small polypoid projections, rounded red, or white excrescences), be indicated.
and verrucous (wrinkled or corrugated surface). Leukoplakia, It is important to document whether the patient with a leukopla-
predominantly non-homogeneous Leukoplakia, may show focal kia is a never smoker because these patients may experience a more
superficial ulceration. Non-homogenous Leukoplakia carry a aggressive natural history.
higher risk of transformation than homogeneous Leukoplakia In the 2007 classification, mixed white and red lesions were con-
(Diz et al., 2011; Speight et al., 2018), and it is not uncommon for sidered as a separate entity under the term erythroleukoplakia. The
non-homogeneous leukoplakia to exhibit severe dysplasia or even consensus of the current Working Group was to classify erythroleu-
superficially invasive SCC following biopsy at baseline detection koplakia under non-homogeneous leukoplakia (Table 3).
TA B L E 3 Clinical presentations and differential diagnosis of some common OPMDs and newly added disorders
Clinical conditions to exclude in the

Disorder Symptoms Clinical presentation diagnosis
Oral Leukoplakia Generally asymptomatic Homogeneous leukoplakia: Uniformly white, White Sponge Nevus
(OL) Some discomfort flat and thin, with a smooth surface which may Frictional keratoses, including
exhibit shallow cracks. Cannot be rubbed off Alveolar Ridge Keratosis
Non-homogeneous Leukoplakia: Chemical injury
(sub-types) Chronic candidal infection
Nodular leukoplakia: Small polypoid or rounded Leukoedema
outgrowths, red or white excrescences. Fordyce's spots/condition
Verrucous leukoplakia: The surface is raised, Skin graft
exophytic, wrinkled, or corrugated Oral Hairy Leukoplakia (OHL)
Erythroleukoplakia: Leukokeratosis Nicotina Palati
Mixed, white and red (speckled) but retaining (Smoker's palate)
predominantly white character. Margins may be HPV Lesions, for example,
irregular Condylomata/Warts
Geographic tongue/Erythema
Migrans
Lichen Planus or Lichenoid Lesions
Oral Discomfort, tingling and A localized red patch with well-defined margins Erythematous candidiasis
Erythroplakia sensitivity to touch, hot and a matt surface Denture-associated stomatitis
beverages or spicy foods Erythema migrans
Erosive and inflammatory/infective
disorders
Desquamative gingivitis
Discoid lupus erythematosus
Erosive lichen planus
Pemphigoid
Pemphigus vulgaris
Vascular hamartomas
Vascular neoplasms
Proliferative Some discomfort Multiple, thick, white patches in more than two Lichen planus (particularly in early
verrucous different oral sites, frequently found on the stages)
leukoplakia gingiva, alveolar processes, and palate. Majority
(PVL) present with a verrucous pattern. Lesions spread
and coalesce during development. Recurrence in
a previously treated area
Oral Lichen Asymptomatic Mostly white lines or as a white plaque Oral lichenoid contact
Planus (OLP) Erosive/ulcerative variety is Reticular: lace-like white lines hypersensitivity reactions
sore Linear, annular: various presentations as lines or, rings Oral lichenoid drug reactions
Papular: white dots Oral lichenoid lesions (see below)
Plaque type: white patch Lichenoid lesions in a betel quid user
Atrophic, erosive and ulcerative: red and ulcerated Mucous Membrane Pemphigoid
Bullous: vesicular Lichen planus pemphigoides
Chronic ulcerative stomatitis
Chronic graft-versus-host disease
Lichen sclerosus
Oral lupus erythematosus
Proliferative verrucous leukoplakia
Oral Submucous Burning sensation to spicy Blanching of oral mucosa Scleroderma
Fibrosis (OSF) food Marked loss of tongue papillae
Later, restricted mouth Leathery mucosa
opening Fibrous bands
Limited mobility of tongue (rigidity)
Shrunken or deformed uvula
Limitation of mouth opening
Sunken cheeks
New in 2020 Classification
Oral Lichenoid Asymptomatic White lines (reticular: lace-like, linear or annular), Oral lichen planus
Lesion (OLL) Red and atrophic areas could papular, sometimes plaque type. Red and erosive
be sore with white striae. Asymmetrical
(Continues)
TA B L E 3 (Continued)
Clinical conditions to exclude in the

Disorder Symptoms Clinical presentation diagnosis
Oral Graft versus Red and atrophic areas could As above Oral lichen planus
host disease be sore A history of allogeneic haematopoietic cell Oral lichenoid contact reaction
(OGVHD) transplantation. Oral lichenoid drug reaction
The current expert group emphasizes that at the time of baseline squamous cell carcinomas in that area. Subsequent studies have
detection, oral leukoplakia is a provisional clinical diagnosis made by not confirmed the extremely high risk of transformation noted
exclusion of other white disorders. A diagnostic biopsy is indicated in early studies, but the floor of mouth remains a high-risk site
to confirm this clinical diagnosis or modify it (i.e., oral lichen planus, and Leukoplakia at this site merit careful follow-up. The Working
or hyperplastic candidosis). One or more underlying histopatho- Group recommends that any white patch on floor of mouth—hav-
logical diagnoses ranging from simple epithelial hyperplasia with ing excluded other known conditions—should be clinically consid-
hyperparakeratosis or hyper(ortho)keratosis, varying severity of ep- ered a leukoplakia.
ithelial dysplasia are consistent with oral leukoplakia (Ranganathan • Sanguinaria-associated keratosis—Damm et al., (1999), Eversole
& Loganathan, 2019; Reibel et al., 2017). It is customary that the et al., (2000), and Mascarenhas et al. (2002) described a unique
pathologist mentions whether the histology is compatible with the form of a white patch that could be attributed to the use of a den-
clinical diagnosis of leukoplakia or not, indicates the presence or ab- tifrice and/or mouth rinse containing the herbal additive sangui-
sence of dysplasia and if present, and provides the grade(s) of dyspla- naria. Sanguinarine is the principal alkaloid in an extract from the
sia. To achieve uniformity in reporting, we recommend a pathology Indian bloodroot plant (Sanguinuriu canadensis L.). Sanguinaria-
report to state “keratosis with no/mild/moderate/severe dysplasia, associated keratosis is rarely reported these days since the
consistent with oral leukoplakia.” A biopsy may on occasion demon- product was banned. This condition should not be considered a
strate superficially invasive carcinoma, and then, the diagnosis of leukoplakia, as it has an established cause, and would generally
leukoplakia is revised to carcinoma. These pathological aspects of resolve on removal of the cause.
leukoplakia are presented in detail by Kujan et al. in this issue. • Palatal keratosis in reverse smokers—This has a very specific ap-
Any field surveys that have not included a protocol for biopsy pearance and is classified as a separate entity in the OPMD lit-
should clarify that the diagnosis was based on clinical features with- erature and is not considered as a leukoplakia. Reverse smokers’
out histopathological confirmation. keratosis is considered a disorder with a comparatively high risk of
Misdiagnosis and misclassification of Leukoplakia have led malignant transformation (Gupta et al., 1980) (see Section 3.7)
to confusion and inaccurate reporting of prevalence (Auluck & • Keratosis of unknown significance (KUS)—This term was intro-
Pai, 2005), also thereby under-reporting malignant transformation in duced by Woo et al. (2014) and refers to the histologic entity of
cases of oral leukoplakia. One source of confusion is conflating the hyperkeratosis with minimal to no epithelial dysplasia or cellular
many different situations in which “frictional keratosis” is misclassi- atypia (Villa et al., 2019; Woo et al., 2014). There is no rationale
fied under the umbrella of “leukoplakia”. Keratosis is unfortunately to apply this term in the clinical context. In fact, over 50% of
misused by some clinicians to clinically describe a white lesion. We Leukoplakia will be in this histologic category. The Working Group
discourage keratosis as a clinical term unless it is part of a specific does not recommend use of the term “keratosis of unknown
name such as frictional keratosis. The published literature refers to significance”.
other disorders which include keratosis in their name and that need
to be better defined:
3.2 | Proliferative verrucous leukoplakia
• Tobacco pouch keratosis—this is a white patch found on the
lower buccal grooves among smokeless tobacco users who retain This condition is defined as a distinct form of multifocal oral leuko-
their tobacco quid at the site (Müller, 2019). Most of them will plakia characterized by having a progressive clinical course, chang-
resolve following discontinuation of the habit but those that per- ing clinical, and histopathological features and is associated with
sist should be included within the group leukoplakia. A biopsy is the highest proportion of oral cavity cancer development com-
indicated at baseline and further study is needed to assess their pared with other OPMDs (Cabay et al., 2007; Iocca et al., 2020).
natural history. Other terms proposed in the literature are Proliferative Multifocal
• Sublingual keratosis—A white patch when found of the floor of Leukoplakia (Aguirre-Urizar, 2011) and Proliferative Leukoplakia
the mouth or inferior surface of the tongue was termed sublin- (Villa et al., 2018). From a clinical perspective, the evolution of this
gual keratosis by Kramer's group (Kramer et al., 1978). The authors type of OPMD often begins as one or more Leukoplakia, later pre-
attributed high significance to these, having noted that a large senting in multiple locations due to gradual spread of an individual
proportion of their patients with such white patches developed focus or resulting from fusion over time of several adjacent foci (Villa
et al., 2018). The original report by Hansen et al., (1985) coining the to advanced cases, fibrosis may also involve the oropharynx and
term Proliferative Verrucous Leukoplakia proposed that the diag- the upper third of the oesophagus (Maher et al., 1991; Misra
nosis be made by a combination of clinical and histological features et al., 1998; Tilakaratne et al., 2016). The definition proposed by
(Hansen et al., 1985). Specific clinical diagnostic criteria were later Kerr et al., (2011) following the World Workshop of Oral Medicine
proposed by Cerero-Lapiedra et al., (2010) and Carrard et al., (2013). V that has gained acceptance was slightly modified by the Working
Their criteria included the disorder affecting more than two differ- Group; “A chronic, insidious disease that affects the oral mucosa, ini-
ent oral sites and the existence of a verrucous area. Initial clinical tially resulting in loss of fibroelasticity of the lamina propria and as
presentation could be flat white lesions (without any verrucous the disease advances, results in fibrosis of the lamina propria and the
component) (Batsakis et al., 1999; Villa et al., 2018) and initially may submucosa of the oral cavity along with epithelial atrophy.” The clini-
also sometimes have a lichenoid clinical appearance (Garcia-Pola cal diagnostic features are listed in Table 3. The clinical features
et al., 2016; McParland & Warnakulasuriya, 2020) and be signed at the time of presentation of oral submucous fibrosis depend on
out as being lichenoid by the pathologist. In the latter situation, it is the stage of the disease. It is generally characterized by patients
possible that a case could be erroneously treated as OLP for many reporting a burning sensation of the oral mucosa and intolerance
years, with the risk of missing, or of accelerating, subsequent malig- to spicy foods. Initial signs include a leathery mucosa, pallor, loss
nancy. Despite the imperfection of the term PVL to capture an ex- of tongue papillae, petechiae, and occasionally vesicles. As the
panded group of patients with multifocal disease, the term is widely disease progresses fibrous bands develop in lips, cheek mucosa
reported, and the Working Group recommended retaining this term. and soft palate and this hallmark feature leads to a limited mouth
A high proportion of patients diagnosed with PVL eventually de- opening (Kerr et al., 2011). There is growing evidence to support
velops oral cancer. A recent systematic review estimated the pro- the role of genetic susceptibility and family history in the patho-
portion to be 49.5% (CI 26.7%–72.4%) (Iocca et al., 2020). Patients genesis and clinical presentation of OSF (Ray et al., 2019). Several
with a diagnosis of PVL may subsequently develop either conven- grading systems have been proposed. Based on objective criteria,
tional squamous cell carcinomas or verrucous carcinomas. Multiple a 5-grade system was proposed by Kerr et al., (2011). The working
primary carcinomas were documented in a case series mostly affect- group endorses this for clinical use.
ing gingival sites (Bagan et al., 2019).
3.5 | Oral lichen planus

3.3 | Erythroplakia
Carrozzo et al., (2019) characterized oral lichen planus (OLP) as a
Erythroplakia is a solitary lesion defined (Table 1) as “a predomi- disease with bilateral white reticular patches affecting buccal mu-
nantly fiery red patch that cannot be characterised clinically or path- cosae, tongue, and gingivae. More severe presentations include
ologically as any other definable disease”. erosions/areas of atrophy and ulceration. Despite being a common
Erythroplakia exhibits a clinical appearance of a sharply de- non-infectious disorder in the oral cavity (Roopashree et al., 2010),
marcated, flat, or depressed, erythematous area of mucosa with a oral lichen planus (OLP) continues to be a disorder without
matt appearance. Inflammatory conditions that may result in a red clear causative factors (Aghbari et al., 2017; Cheng et al., 2016;
clinical appearance are excluded prior to arriving at this diagno- Krutchkoff et al., 1978; van der Meij et al., 1999). Cancer develop-
sis (see Table 3) (Kramer et al., 1978; van der Waal & Scully, 2011; ment in patients with a diagnosis of OLP was recently reviewed
Warnakulasuriya, 2019) The solitary presentation of erythropla- by Gonzalez-Moles et al., (2019). OLP should be diagnosed using
kia helps to distinguish it from other more widespread conditions both clinical and histopathological characteristics (Table 4) (Al-
such as erosive lichen planus, lupus erythematosus, and erythema- Hashimi et al., 2007; Cheng et al., 2016; van der Meij & van der
tous candidiasis which present more often in multiple sites (van der Waal, 2003) and should be clearly distinguished from disorders
Waal, 2010). Other conditions include autoimmune disorders, infec- with similar clinical appearances but due to other causes including
tions, and vascular hamartomas/vascular neoplasms that may exhibit oral lichenoid lesions (van der Meij & van der Waal, 2003), oral
similar clinical features and should be considered in the differential lichenoid drug reactions (Scully & Bagan, 2004), oral lichenoid
diagnosis (Reichart & Phillipsen, 2005). Most oral erythroplakias, at contact hypersensitivity reactions (Al-Hashimi et al., 2007), lichen
the time of diagnosis, are either histopathologically a squamous cell planus pemphigoides, chronic ulcerative stomatitis, acute and
carcinoma or show high-grade epithelial dysplasia. chronic graft-versus-host 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
3.4 | Oral submucous fibrosis (OSF) OLP, authors should follow strict criteria in diagnosing OLP that
incorporate clinical, histopathological, and patient characteristics
Oral submucous fibrosis is a well-recognized OPMD characterized (Idrees et al., 2020). Diagnostic criteria of oral lichen planus en-
by fibrosis of the oral mucosa (inc. submucosa), and there is a higher dorsed by the Working Group based on previous proposals are
risk for oral cancer development in patients with OSF. In moderate listed in Table 4.
TA B L E 4 Diagnostic criteria of oral lichen planus based on previous proposals (Aguirre-Urizar et al., 2020; Al-Hashimi 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, and/or tongue, and/or lip,
and/or gingiva
• Presence of a white papular lesions and lace-like 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 well-defined band-like predominantly lymphocytic infiltrate that is confined to the superficial part
of the connective tissue
• Signs of vacuolar degeneration of the basal and/or 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
3.6 | Actinic Keratosis/Actinic Cheilitis Latin America (Colombia, Panama, Venezuela), Sardinia, and among
some Pacific Islanders, for example, the Philippines, but there are no
Actinic Keratosis (AK) is produced by the effect of actinic (solar, follow-up studies published, outside India. Field research undertaken
predominantly ultraviolet) radiation to exposed areas of the face by the Tata Institute of Fundamental Research (TIFR), India, (Gupta
and therefore predominantly the skin and vermilion of the (lower) et al., 1980) first described palatal changes in reverse smokers in sev-
lip. The precise areas affected are important in clinical assessment eral Indian cohorts as “thickened white plaques of palate, mucosal
(Savage et al., 2010). AK occurs predominantly in middle-aged and nodularity, excrescences around orifices of palatal (minor) mucosal
light-skinned men with outdoor occupations (Dancyger et al., 2018). glands, yellowish brown staining, erythema, and ulceration. Lesions
There may be localized or diffuse lesions of white flaking plaques or can present as red, white or mixed red and white, in a background of
scaly lesions with interspersed red areas (Markopoulos et al., 2004). tobacco staining”. In a later Indian study of reverse smokers, 32% were
In very mild cases, patients may present simply with dryness of lips found white and red patches on their palates (Bharath et al., 2015).
(Savage et al., 2010).The 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 3.8 | Oral lupus erythematosus
AKs will progress, regardless of the histological grade (AK I-AK III)
(Fernandez Figueras, 2017). Lupus erythematosus is a chronic autoimmune disease which can
Histologically, the epithelium may show hyperplasia or atrophy, be principally subdivided into three forms: (a) systemic, (b) drug-
disordered maturation, varying degrees of keratinization or parake- induced, and (c) discoid. Oral lesions may manifest in approximately
ratinization, cytological atypia, and increased mitotic activity. The 20% patients with systemic lupus. Oral lesions of lupus erythe-
lamina propria often shows basophilic degeneration of collagen, elas- matosus (OLE) exhibit similar clinical presentations as found in
tosis, and vasodilatation (Cavalcante et al., 2008; Mello et al., 2019; OLP. Typically, OLE presents as a central circular zone of atrophic
de Santana Sarmento et al., 2014). Lichenoid inflammation is often mucosa, with superficial ulceration surrounded by whitish striae
present, and a histopathological diagnosis of lichenoid actinic ker- (Odell, 2017). Buccal mucosae, palate, and lips are most commonly
atosis should then be rendered. Benign lichenoid keratosis (lichen affected. Histopathological criteria for the diagnosis of (discoid)
planus-like keratosis) is an important differential diagnosis in facial lupus erythematosus are described by Schiødt, (1984). Carcinomas
skin, including vermillion border. In a case series (n = 124) reported developing within lesions OLE are rare intra-orally, and most arise
from Brazil, 25% displayed early SCC in the biopsy specimens (Mello on the lips (Arvanitidou et al., 2018). It is not always possible to con-
et al., 2019). A systematic review on AK found no reliable estimates fidently distinguish OLP from OLE intra-orally, so that in the absence
concerning the frequency of AK developing into invasive carcinoma of systemic features it is quite possible that malignancy arising in LE
(Werner et al., 2013). would be misclassified as a malignancy arising in OLP.
3.7 | Palatal lesions in reverse smokers 3.9 | Dyskeratosis congenita
In reverse smoking, the burning end of a cigarette or cigar is held in- Dyskeratosis Congenita (DKC) (also called Zinsser-Cole-Engman
side the mouth. Where this is practiced, as many as 50% of all oral ma- syndrome) is a rare hereditary condition of dysfunctional telomere
lignancies are found on the hard palate, a site usually spared by other maintenance that is regarded as a potentially malignant disorder. A
OPMDs, except among pipe smokers. Reverse smoking is an endemic higher frequency of oral cancers is noted among patients affected
tobacco habit practiced in the coastal rural Andhra Pradesh, India. The by this condition (Bongiorno et al., 2017). The pathogenesis is at-
habit is also prevalent among the people of the Caribbean Islands, in tributed to mutations of several genes that help maintain telomere
structure and function, such as the DKC1 gene. DKC1 gene encodes Importantly, the current Working Group recommends health
for the ribonucleoprotein dyskerin (Abdel-Karim et al., 2009; Ballew professionals refrain from using the term “oral lichenoid dysplasia”
& Savage, 2013). Most cases are inherited and may be X-linked, au- to describe an entity among OLP or lichenoid disorders which show
tosomal dominant, or autosomal recessive, with variable penetrance dysplastic changes. If dysplasia is present, the diagnosis should be
(Handley & Ogden, 2006). The condition often arises early and should oral epithelial dysplasia with lichenoid features (i.e., if the latter fea-
always be considered and excluded in a child presenting with oral leu- tures are indeed evident) or OLP with dysplasia. Additional details
koplakia. It consists of the triad of oral Leukoplakia (usually on the dor- regarding this topic are reported by Kujan et al. (2021) in this volume.
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). Lichenoid-like lesions 4.2 | Oral graft-versus-host disease (OGVHD)
have also been reported (Handley & Ogden, 2006). The prognosis is
often poor, due to either malignant change within the oral lesions or OGVHD is reported in patients with hematologic malignancies receiv-
bone marrow failure resulting in overwhelming infection and death. ing allogeneic stem cell transplants (Elad et al., 2019). They present in
Attempts have been made to identify potential markers for future acute and chronic forms that usually involve several organs (Flowers
cancerous change within these oral lesions. Evidence for disturbed et al., 1999). Oral lesions with a lichenoid appearance, erythema, at-
cytokeratin, abnormal p53 expression and changes at an ultrastruc- rophy, and ulceration were reported in more than 90% of patients
tural level (fetal/neonatal features) have been reported some 10 years who suffered from GVHD (Fricain et al., 2005; Schubert et al., 1984).
before malignant change (McKay et al., 1991; Ogden et al., 1993). Since our previous Workshop Report on OPMDs (Warnakulasuriya
et al., 2007), progression to cancer in OGVHD-related oral lichenoid
lesions has subsequently been reported in several case studies
4 | CO N D ITI O N S N E W LY A D D E D I N 2 0 2 0 (Demarosi et al., 2005; Frydrych et al., 2019; Hashimoto et al., 2019;
C L A S S I FI C ATI O N Mawardi et al., 2011). Atsuta et al., (2014) analyzed a database of
17,545 adult recipients of an allogeneic stem cell transplantation be-
4.1 | Oral lichenoid lesions (OLL) tween 1990 and 2007 in Japan. Multi-system chronic graft-versus-
host disease (GVHD) was a significant risk factor for the development
Oral lichenoid lesions (OLL) lack the typical clinical or histological ap- of all solid tumors (RR = 1.8, p < .001), significantly higher for oral
pearance of OLP, that is, they may not be symmetrical and could be cancer (RR = 2.9, p < .001) among patients after 1-year post-trans-
unilateral. According to van der Meij and van der Waal, (2003), OLL plant. The possible role of immunosuppressant therapy for chronic
would be those disorders that do not present the clinical and/ or histo- graft-versus-host disease on the development of oral squamous cell
pathological characteristics considered typical (but compatible) with carcinoma needs consideration (de Araújo et al., 2014).
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- 5 | D I S O R D E R S W ITH LI M ITE D O R
tionship to a dental restoration, often amalgam, referred to as oral li- I N S U FFI C I E NT E PI D E M I O LO G I C A L
chenoid contact reactions (OLCR) (Al-Hashimi et al., 2007; McParland E V I D E N C E FO R M A LI G N A NT P OTE NTI A L
& Warnakulasuriya, 2012), (c) lichenoid drug reactions (LDR) (Al-
Hashimi et al., 2007), (e) oral lesions following intake of food or some The current literature refers to three other disorders that are prob-
substances, such as cinnamon, and (f) oral lesions of graft-versus-host ably associated with an increased frequency of oral cancers, epi-
disease. Furthermore, lichenoid contact reactions to betel quid (BQ) dermolysis bullosa, chronic hyperplastic candidosis, and exophytic
are reported among BQ users (Reichart & Warnakulasuriya, 2012). verrucous hyperplasia.
It is a diagnostic challenge to clinically distinguish OLL from OLP. We describe here the available evidence and highlight the con-
Recently, Aguirre-Urizar et al., (2020) proposed grouping OLP and troversies surrounding these disorders:
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 Disorders with limited epidemiological evidence of
disease. Oral lichenoid diseases encompass both OLP and OLL and malignant potential.
characteristically show white papules (and reticular formation) and
are sometimes accompanied by other types (erosive-ulcerative, atro-
phic, plaque, and bullous). Gonzalez-Moles et al. (2019) also argues
for abandoning the term OLL as defined by van der Meij and van der 5.1 | Oral epidermolysis bullosa
Waal, (2003). The evidence from their systematic review suggests
that patients with OLL, have more or less similar malignant potential Epidermolysis bullosa was included as a potentially malignant dis-
to OLP (Gonzalez-Moles et al., 2019). order in our 2007 classification of OPMDs. A specific potentially
malignant oral lesion associated with epidermolysis bullosa is not specific causes and the Working Group noted that candidal leuko-
well characterized in the literature. Squamous cell carcinomas are plakia was now a deprecated term.
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- 5.3 | Exophytic verrucous hyperplasia/Oral
viduals with severe generalized RDEB. verrucous hyperplasia
Verrucous hyperplasia of the oral mucosa—a relatively unrec-

Disorders with insufficient epidemiological evidence. ognized entity that may resemble verrucous carcinoma both
clinically and histologically was first described by Shear and
The Working Group reviewed the available evidence on the following Pindborg, (1980). VH was considered a precursor of verrucous
disorders and found insufficient evidence for their malignant poten- carcinoma (Batsakis et al., 1999). A new entity was proposed by a
tial. At present, these are not recommended for inclusion within the group of South Asian pathologists to describe a “mass type” lesion
OPMD group of disorders. 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-
5.2 | Chronic hyperplastic candidosis (CHC) agnosed with OPMDs (Wang et al., 2009), and the name proposed
by these authors was oral verrucous hyperplasia. A second cohort
CHC presents as an adherent white patch caused by a chronic fun- was described later by the same group among which 6 (10%) devel-
gal infection, usually Candida albicans (Farah et al., 2019). The clinical oped an oral cancer (Wu et al., 2018). This disorder can present in
presentation is thick white plaques, or mixed red and nodular non-ho- two forms: (a) as an exophytic, fleshy verruco-papillary outgrowth
mogenous white patches most commonly involving the anterior buc- with a white and/or pink surface color or (b) as a white, plaque-
cal mucosae and commissures or on the dorsum of the tongue (Dilhari like exophytic verrucous lesion. It typically manifests as a discrete
et al., 2016). There is some experimental evidence that Candida or solitary lesion and may co-exist in patient presenting with oral
causes epithelial hyperproliferation (Rast et al., 2016; Sitheeque & submucous fibrosis. The clinical presentation could masquerade
Samaranayake, 2003). It is known that C. albicans dramatically modifies as a squamous cell carcinoma or verrucous carcinoma. Absence of
the clinical and histological aspects of oral white plaques commonly deep induration is a cardinal feature.
referred to as candida leukoplakia. Candida is frequently present in the Hsue et al., (2007) reported on a group of 1,458 Taiwanese
biopsies of moderate and severe dysplasia, and significant dysplastic patients with OPMDs and based on clinical and histopathologi-
changes are noted in the epithelium of candida Leukoplakia harbor- cal criteria 324 (22%) were classified as oral verrucous hyperpla-
ing Candida species (McCullough et al., 2002; Shukla et al., 2019). It sia: 10 patients developed malignancies during a mean follow-up
is postulated that Candida-related oral carcinogenesis could arise time of 43 months. Wang et al., (2014) reporting on 5,071 south-
from acetaldehyde production from alcoholic beverages by specific ern Taiwanese patients from Kaohsiung city diagnosed with
Candida isoforms (Alnuaimi et al., 2016). Candidalysin—a cytolytic OPMDs, described the clinical presentation of 869 OVH patients,
peptide toxin secreted by C. albicans—by interacting with epithelial 59 of whom (6.79%) developed cancer in a follow-up period of
growth factor receptors (EGFR) could activate human EGF pathways 33.5 months. Cancers were found mostly on the buccal mucosa,
to produce increased cell proliferation (Ho et al., 2019). but the lower lip, dorso-lateral surfaces of the tongue, soft palate,
The distinction between candida leukoplakia and chronic hy- and gingiva were also affected. The clinical and histological diag-
perplastic candidosis is not clear and most authors consider these nostic criteria for oral verrucous hyperplasia aka oral exophytic
two terms synonymous. The first description of candidal leuko- verrucous hyperplasia (OEVH) are outlined by Zain et al., (2016). A
plakia was published by Cawson and Lehner, (1968) and reviewed high proportion of these disorders in Taiwanese subjects demon-
by Sitheeque and Samaranayake, (2003). Both sets of authors strated OED at the initial histopathological investigation and a pro-
emphasize that the lesions responded readily to antifungal treat- portion developed oral cancer at the sites of the presenting lesion.
ment, which supports a causal relationship. Nevertheless, it must Recent reports on exophytic/oral verrucous hyperplasia proposed
be noted that while many cases improve with antifungal treatment, that this disorder be regarded as an OPMD (Hsue et al., 2007;
they do not disappear completely. The current Working Group Patil et al., 2016; Wang et al., 2009, 2014; Wu et al., 2018; Zain
noted that it is important to have consistency in the way we use et al., 2016). Several cases presented at a workshop held in Kuala
these two terms and that antifungal treatment should be part of Lumpur (Zain et al., 2016) have provided new evidence that these
the diagnostic process. may arise as a secondary lesion in patients with oral submucous
A recent systematic review on “candida leukoplakia” (Shukla fibrosis (Shah et al., 2019). Having considered the recent publica-
et al., 2019) identified 3 studies quoting malignant transformation tions describing these disorders, the Working Group was of the
ratios of 2.5%, 6.5%, and 28.7%: such a wide range implies incon- opinion that it would be desirable to obtain more follow-up data
sistent diagnostic criteria. The definition of leukoplakia excludes from several countries in regions where betel quid chewing is
common. The Working Group recommends the term OEVH rather marker usually associated with malignant disease would signify a
than OVH for this apparent entity. 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.
6 | C A RC I N O M A S A R I S I N G I N PATI E NT S Currently, available adjunctive tools (Kerr, 2020; Rashid &
W ITH O PM D s Warnakulasuriya, 2015) have not been adequately researched to
test whether the new optical devices are able to identify these oc-
The most common histopathological diagnosis reported for a cancer cult lesions within field changes. However, evidence for field change,
arising in a patient with an OPMD is a conventional squamous cell based on a variety of markers (e.g., cytokeratins, p53, and markers
carcinoma. OPMDs are a heterogeneous group and have variability of angiogenesis), has been identified within biopsies of clinically nor-
in their ratios of progression to cancer (1.4%–49.5%) over a follow- mal mucosa from oral cancer patients (El-Gazzar et al., 2005; Ogden
up period ranging from 12 months to 20 years) (Iocca et al., 2020). et al., 1993, 1997), and by Ogden (1997) using exfoliative cytology
Predicting the risk of transformation remains a significant challenge (e.g., cytomorphology, cytokeratins). However, a reliable marker
even in specialist practice. At one end of the spectrum, patients di- that can predict future malignant change in every case has yet to
agnosed with PVL and erythroplakia show high frequencies of can- be found. Future molecular techniques might make these invisible
cer development (close to 30%–50%), and on the other hand, oral changes detectable but further research is needed.
lichen planus (OLP) show lower frequencies of cancer development
(1%–2%). Oral leukoplakia has a variable risk with non-homogene-
ous forms showing higher risk compared with homogeneous leuko- 8 | S Y N D RO M E S TH AT M AY P OTE NTI ATE
plakia. The presence and grade of epithelial dysplasia have shown C A N C E R D E V E LO PM E NT I N TH E O R A L
prognostic utility in stratifying the risk of cancer development. In a C AV IT Y
meta-analysis, Mehanna et al., (2009) have shown that higher grades
of dysplasia have significantly higher frequencies of cancer devel- Close to 20 familial cancer syndromes are described and people
opment. Techniques such as ploidy assessment when combined born with inherited genetic predispositions develop hematological
with dysplasia grading may refine the prediction of risk (Alaizari malignancies and solid cancers at a younger age and with a relatively
et al., 2018). Accompanying publications in this volume discuss in high frequency. Important examples are Fanconi anemia, xeroderma
greater detail cancer development in patients with OPMDs, pathol- pigmentosum, Li Fraumeni syndrome, Blooms's syndrome, ataxia-
ogy tools, biomarkers and how ploidy analysis may assist in stratify- telangiectasia, and Cowden syndrome.
ing risk. The biomarkers currently investigated for predicting the risk Many of these syndromes are caused by alterations in tumor
are not in routine clinical use anywhere in the world. 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
7 | C A RC I N O M A A R I S I N G FRO M incidence of oral cancer in inherited cancer syndromes and whether
C LI N I C A LLY N O R M A L M U COS A the genes that are known to be relevant to the pathogenesis of these
cancer syndromes also play a role in the development and behavior
Malignancy can arise from an area of “normal-looking” mucosa of oral cancer. These authors provide a comprehensive list of gate-
without the patient or a clinician being aware of an OPMD being keeper genes associated with several hereditary cancer syndromes
present earlier at the site. This is consistent with the concept of a (Prime et al., 2001).
field change, that apparently normal mucosa may contain significant Of the many familial cancer syndromes described, Fanconi ane-
molecular aberrations that increase the likelihood of cancer (Farah mia has the strongest evidence for a predisposition for oral cancer
et al., 2018; Farah, Shearston, et al., 2019; Nikitakis et al., 2018; and a short description appears below:
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 8.1 | Fanconi anemia (FA)
et al., (1953)—not least in ensuring common terminology (Ogden &
Hall, 1997). Field cancerization is characterized by phenotypic and An increased susceptibility of Fanconi anemia (FA) patients to
genetic changes in the neighboring areas of frank carcinomas, while early-onset OSCCs—largely in the absence of known lifestyle risk
the term “field change” should be reserved for alterations in tissues factors—has been observed for decades. Fanconi anemia (FA) is a
that show no evidence of disease clinically or histologically (Ogden rare autosomal recessive disorder of DNA repair genes in which the
et al., 1990). A proliferating field that gradually displaces the nor- defect(s) lie in the repair of DNA crosslinks. It is characterized by
mal mucosa have been detected on the basis of mutations in TP53, physical congenital anomalies (skeletal malformations), aplastic ane-
whereas they are usually not detected by routine diagnostic tech- mia, and then progressive pancytopenia. FA may lead to bone mar-
niques (Braakhuis et al., 2003, 2005). Thus, the identification of a row failure, leukemia, and/or solid tumors, including head and neck
cancers, with oral squamous cell carcinoma being the most common 10 | I M PLI C ATI O N S FO R R E S E A RC H
type. Recently, there has been renewed interest among researchers
on development of OSCCs in FA. Masserot et al., (2008) described • The complete natural history of the individual OPMDs is yet to be
head and neck squamous cell carcinoma in 13 patients (8 in oral cav- confirmed.
ity) with Fanconi anemia after hematopoietic stem cell transplanta- • There is a need for further research to identify the potential risk
tion. In a systematic review, Furquim et al., (2018) identified a total of of cancer in patients with different OPMDs based on strict clini-
121 individuals affected by FA and OSCC among 47 published from copathological diagnostic criteria.
1970 to 2016. The tongue was the most affected site. The overall • There is a need to better understand the number of oral cancer
risk was estimated to increase 500- to 700-fold for head and neck cases developing from apparently normal oral mucosa.
cancer in FA patients compared to the general population (Kutler • There is a need to elucidate the role (if any) of Candida infection
et al., 2003) and the majority developed carcinomas at an early age. in dysplastic tissues.
Therefore, young people who develop HNSCC must receive FA diag- • The role of immunosuppression in GVHD toward the develop-
nostic tests. Patients with FA can present with potentially malignant ment of oral cancer needs study.
disorders, especially oral leukoplakia (Amenábar et al., 2019). Among • There is a need to identify molecular differences between ho-
138 Brazilian patients with FA who had not undergone hematopoi- mogenous and non-homogenous Leukoplakia, and dysplastic and
etic stem cell transplantation (HSCT), 16 cases (12%) were diagnosed non-dysplastic Leukoplakia.
with oral leukoplakia, with a median age of 16.5 years (Cavalcanti • There is a need to identify reliable molecular predictive and prog-
et al., 2015). 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
8.2 | Plummer-Vinson syndrome observed mucosal changes.
• The Working Group reiterates the need for good quality longitu-
Plummer-Vinson (Paterson-Kelly) syndrome (PVS)—a constellation dinal studies, assembling cases by the precise clinicopathological
of symptoms relating to postcricoid esophageal webs, atrophic glos- criteria defined here, gathering extensive metadata on demogra-
sitis, koilonychia, and dysphagia considered to be caused by micro- phy and risk factors, and analyzing follow-up data appropriately.
cytic hypochromic anemia—was linked to predisposition to upper Studies with inconsistent designs should not be pooled.
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) 11 | CO N C LU S I O N S
and could be a co-factor among people with OPMDs and deserves
attention in future research. This paper provides an update on the 2007 WHO Collaborating
Centre's classification of oral potentially malignant disorders. The
Working Group identified sufficient evidence on oral lichenoid le-
9 | OTH E R TE R M I N O LO G I E S sions and oral graft-versus-host disease that merit their addition to
the classification proposed in 2007. The natural history and the bio-
It has recently been suggested to replace the term OPMD with: “po- logical behavior of many OPMDs remain unknown and there was
tentially premalignant oral epithelial lesion (PPOEL)” (Nikitakis, 2018; consensus that further research on these disorders is warranted. A
van der Waal, 2018). The terminology, oral potentially malignant dis- global research consortium to study OPMDs is needed to establish
orders, is now well established in the literature with over 750 publi- multi-site longitudinal studies with well-defined clinicopathological
cations and the Working Group could not see any reason for change. diagnostic criteria to address questions and characterize their natu-
Both in the 2007 paper, and here, we argue distinction between the ral history and possibly to prevent development of oral cancer in
terms “potentially malignant” and “premalignant”: the former indi- patients diagnosed with these disorders.
cates an unknown potential for the later development of a malignant
tumor; the latter an inevitability given sufficient time. “Potentially AC K N OW L E D G E M E N T S
premalignant” may indicate lack of premalignancy. Moreover, We thank the Royal College of Physicians and Surgeons (RCPSG) for
changes observed in histology are not limited to epithelium, and providing logistic support for holding this expert symposium and
therefore, “epithelial lesion” is inappropriate. Epithelial-connective Henry Schein Cares for an educational grant for travel expenses of
tissue interactions are fundamental to homeostasis and disease some invited experts who attended the workshop.
and connective tissue changes are a striking component of many
disorders (Johnson, 2020; Vucicevic Boras et al., 2018), including C O N FL I C T O F I N T E R E S T
in oral lichen planus and oral submucous fibrosis (OSMF) (Arakeri The authors filed detailed disclosure of potential conflicts relevant
et al., 2018; Lodi et al., 2005). to the workshop topics, and none were declared.
AU T H O R C O N T R I B U T I O N S Journal of Oral Pathology and Medicine, 47(2), 97–103. https://doi.

org/10.1111/jop.12603
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Received: 20 September 2020 | Revised: 21 October 2020 | Accepted: 25 October 2020

Oral potentially malignant disorders: A consensus report from

Saman Warnakulasuriya1 | Omar Kujan2 | José M. Aguirre-Urizar3 |

1862 | © 2020 Wiley Periodicals LLC wileyonlinelibrary.com/journal/odi Oral Diseases. 2021;27:1862–1880.

Medical Sciences, Newcastle University,

observed in superficially invasive carcinomas; and some of the chro-

TA B L E 1 Recommended definitions for OPMDs

Disorder Definition Source

Clinical conditions to exclude in the

Clinical conditions to exclude in the

3.5 | Oral lichen planus

3.7 | Palatal lesions in reverse smokers 3.9 | Dyskeratosis congenita

Verrucous hyperplasia of the oral mucosa—a relatively unrec-

AU T H O R C O N T R I B U T I O N S Journal of Oral Pathology and Medicine, 47(2), 97–103. https://doi.

You might also like

Oral Diseases - 2020 - Warnakulasuriya - Oral Potentially Malignant Disorders A Consensus Report From An International

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Document Informationclick to expand document information

Copyright:

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Oral Diseases - 2020 - Warnakulasuriya - Oral Potentially Malignant Disorders A Consensus Report From An International

Uploaded by

Document Information

Original Title

Copyright

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Oral Diseases - 2020 - Warnakulasuriya - Oral Potentially Malignant Disorders A Consensus Report From An International

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Copyright:

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Received: 20 September 2020 | Revised: 21 October 2020 | Accepted: 25 October 2020

Oral potentially malignant disorders: A consensus report from

Saman Warnakulasuriya1 | Omar Kujan2 | José M. Aguirre-Urizar3 |

1862 | © 2020 Wiley Periodicals LLC wileyonlinelibrary.com/journal/odi Oral Diseases. 2021;27:1862–1880.

Medical Sciences, Newcastle University,

observed in superficially invasive carcinomas; and some of the chro-

TA B L E 1 Recommended definitions for OPMDs

Disorder Definition Source

Clinical conditions to exclude in the

Clinical conditions to exclude in the

3.5 | Oral lichen planus

3.7 | Palatal lesions in reverse smokers 3.9 | Dyskeratosis congenita

Verrucous hyperplasia of the oral mucosa—a relatively unrec-

AU T H O R C O N T R I B U T I O N S Journal of Oral Pathology and Medicine, 47(2), 97–103. https://doi.

You might also like

1862 | © 2020 Wiley Periodicals LLC wileyonlinelibrary.com/journal/odi Oral Diseases. 2021;27:1862–1880.