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27
Dysplasia, Precancer andOral Potentially Malignant Disorders
Agnieszka Frydrych and Omar Kujan
UWA Dental School, The University of Western Australia, Perth, Western Australia, Australia
27.1 Introduction
Terms such as dysplasia and precancer have been used frequently in the literature. Dysplasia
describes the disorderly growth and maturation of cells that are not normal but not malignant.
Dysplasia is often considered a sign with an increased risk of malignancy, as in cervical dysplasia,
colon polyps and Barrett’s oesophagus. In the literature, these conditions are known by terms such
as ‘pre- cancer’, ‘premalignant conditions’ and ‘intraepithelial neoplasia’. In the oral cavity, leukoplakia, erythroplakia and several other lesions with epithelial dysplastic changes have a higher risk of
transforming into squamous cell carcinoma. In 2007, the World Health Organisation Collaborating
Centre recommended replacing the term ‘precancer’ and adopted a more precise term ‘oral potentially malignant disorder’ (OPMD), because of the evidence that there is no certainty that all oral
‘precancerous lesions and conditions’ will eventually develop into oral cancer. This chapter discusses
molecular and related aspects of oral epithelial dysplasia (OED) and potentially malignant disorders.
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27.2 Oral Epithelial Dysplasia: Definition, Aetiology, Clinical
Presentation andNatural History
Oral squamous cell carcinoma (OSCC) is often preceded clinically by an OPMD, the worldwide
prevalence of which ranges from 1 to 5%(1). The disorder has been defined as ‘morphologically
altered tissue in which cancer is more likely to occur than in its apparently normal counterpart’(2).
Several lesions and conditions are included under the auspices of OPMDs, including leukoplakia,
erythroplakia, palatal lesions in reverse smokers, lichen planus, oral submucous fibrosis, lupus
erythematosus and actinic keratosis (Figure27.1)(1, 3, 4). Oral leukoplakia is the most common,
with a prevalence of 1% and reported malignant transformation rates of 2– 5%(5). Other conditions
also associated with increased cancer risk include graft- versus- host disease, HIV infection and rare
inherited genetic syndromes, namely Fanconi anaemia, dyskeratosis congenita and xeroderma
pigmentosa(3, 5, 6). Diagnosis of OPMD is based on clinical presentation and histopathology,
which may or may not include OED.
Pathological Basis of Oral and Maxillofacial Diseases, First Edition. Edited by S. R. Prabhu, Syed Ali Khurram,
Omar Kujan and Merva Soluk Tekkesin.
© 2025 John Wiley & Sons Ltd. Published 2025 by John Wiley & Sons Ltd.
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(a) (b)
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(c) (d)
Figure27.1 Clinical presentations of oral potentially malignant disorders. (a) Homogenous leukoplakia,
(b)erythroplakia, (c) lichen planus, (d) oral submucous fibrosis.
The term ‘epithelial dysplasia’ refers to abnormal epithelial growth(1, 7, 8). It is characterised by
specific cytological and architectural alterations arising from the loss of normal epithelial maturation and stratification, reflecting progressive genetic alterations with the potential to develop into
OSCC(1, 7, 8). OED may revert to normal upon removing the inciting stimulus, remain stable, or
progress to malignancy(1). The malignant transformation rate of OED ranges from 1.4 to 36%,
with most dysplastic lesions progressing to malignancy over a period of 2– 5 years but can also
transform much later(1, 3, 9).
OPMD which may harbour OED encompass leukoplakia (including proliferative verrucous leukoplakia [PVL]), erythroplakia, palatal lesions in reverse smokers, oral submucous fibrosis and
actinic cheilitis(1, 8). These vary regarding harbouring dysplasia and undergoing malignant
transformation, with the most significant risk posed by leukoplakia, erythroplakia and oral submucous fibrosis(7, 8, 10). Nearly all cases of erythroplakia harbour OED, in contrast to 1– 30% of
oral leukoplakias(1). Different intraoral sites are associated with varying risks of developing dysplastic lesions. The most common site is the lateral tongue and the least common site is the hard
palate(7).
The risk factors of OED are shared with those of OSCC, with the highest incidence occurring in
older males who use tobacco, areca/betel nut and consume alcohol(11). Other risk factors include
vaping (e- cigarettes), infections with human papillomavirus (HPV) or candida, immune dysfunction, certain genetic disorders and nutritional deficiencies (iron, vitamins A, B and C)(5, 7, 11).
Dysplasia is rare in children and young adults, and such individuals should be investigated for rare
genetic conditions(6).
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27.3 Histopathology
(a) (b)
(c)
27.3 Histopathology
Despite advances in molecular pathology, diagnosis of OED continues to rely on histopathologic
evaluation and clinical correlation (7). Scalpel biopsy is the most reliable OED diagnosis
method(12). Diagnosis is based on identifying specific architectural and cellular changes in oral
epithelia reflecting aberrations in the normal cellular proliferation and maturation(13). In the case
of large or heterogeneous lesions, multiple biopsies should be obtained(6, 7).
27.3.1 Architectural Features
Numerous architectural features have been described (Figures27.2– 27.5) in OED, including:
● Irregular Epithelial Stratification: Altered epithelial thickness and loss of normal stratification
can form bulky exophytic and endophytic proliferation(7). Epithelial thickness significantly
higher than expected for the oral subsite is suspicious for OED(7). The finding of hyperkeratosis
or parakeratosis overlying atrophic mucosa can also be a feature of OED(7).
● Loss of Polarity of Basal Cells: Loss of polarity of the basal epithelial cells has been considered
one of the most important factors in predicting the progression of OED to carcinoma(12). As
OED progresses towards cancer, basal epithelial cells lose their polarity(12).
● Drop- shaped Rete Ridges: Normal rete ridges do not have a specific shape and project in random
directions(12). In OED, loss of organised epithelial structure results in bulbous elongation of the
rete ridges and reflects lateral/downward rather than outward cell maturation and growth(6, 7).
● Increased Number of Mitotic Figures
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Figure27.2 Photomicrographs of oral epithelial dysplasia. (a) Mild dysplasia (low- grade dysplasia),
(b)Moderate dysplasia (low- grade dysplasia), (c) Moderate dysplasia (high- grade dysplasia), (d) severe
dysplasia (high- grade dysplasia).
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(d)
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Figure27.3 Photomicrograph of
mild dysplasia showing dysmature
basaloid cell hyperplasia where cells
have increased nuclear- to- cytoplasmic
ratio and increased mitotic figures.
Figure27.4 Photomicrograph of
moderate dysplasia showing
remarkable loss of cohesion, irregular
epithelial stratification and loss of
basal cell polarity.
Figure27.5 Photomicrograph of
severe dysplasia showing remarkable
nuclear pleomorphism,
hyperchromasia and high mitotic
figures.
● Abnormal Superficial Mitosis
● Premature Keratinisation in Single Cells (Dyskeratosis): Increased keratin production within the
lower immature layers of the epithelium reflects loss of normal maturation and migration
towards the surface(7).
● Keratin Pearls Within Rete Ridges
● Loss of Epithelial Cell Cohesion: Acantholytic or discohesive appearance within the basal and
parabasal layers results from loss of desmosomes and other adhesion mechanisms(7).
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● Skip Lesions: These may reflect irregular boundaries of clonal changes rather than separate satel-
lite lesions(6).
● Sharply Defined Margin to Changes: The cytologically atypical epithelium in OED generally
demonstrates a sharp distinction from adjacent normal mucosa in contrast to the uniform
appearance of reactive changes seen in inflammatory conditions or following trauma(6, 7).
Sharply defined boundaries between normal and dysplastic tissue reflect a clonal structure(6).
● Verrucous or Papillary Architecture
● Lateral Extension of Changes into Minor Gland Ducts: Usually considered to indicate severe epi-
thelial dysplasia(6).
● ‘Lichenoid’ Immune Response: This raises the possibility of mild epithelial dysplasia when no
other reason for the immune response can be identified and is associated with keratinocyte killing by induction of apoptosis(6, 7, 10).
27.4 Cytological Features
Cytological features observed in OED include:
● Abnormal variation in nuclear size and shape
● Abnormal variation in cell size and shape
● Increased nuclear cytoplasm ratio
● Increased mitotic activity
● Expanded proliferative compartment/high mitoses
● Atypical mitotic figures
● Spontaneous apoptosis
● Apoptotic mitoses
● Increased number and size of nucleoli
● Hyperchromasia
● Glycogen depletion
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Carcinogens decrease the cytoplasm’s capacity to mature. As the amount of cytoplasm constructed in relation to the nucleus is reduced, the cell size decreases(12). Increase in the size of the
nucleus has been attributed to an increase in the nuclear components needed for proliferation(12,
14). These variations increase nuclear- cytoplasmic ratio, cellular and nuclear pleomorphism and
nuclear hyperchromatism(6, 12). Chromosomal and genetic instability leads to spontaneous apoptosis and apoptotic mitoses(6).
The normal epithelium contains basal cells with larger nuclei and scanty cytoplasm(12). With
maturation, keratin production increases and the nuclear size decreases towards the surface(12).
Loss of maturation with retained larger nuclei and mitoses towards the surface indicates a lack of
appropriate maturation and expansion of the proliferative zone(12).
27.5 The Spectrum ofDysplasia andDysplasia Patterns
Although different patterns of dysplasia are described, it is essential to remember that dysplasia is
a continuum and that other types may exist within the same lesion. Different patterns of dysplasia
are associated with varying risks of malignant transformation.
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27.5.1 ‘Differentiated’ Dysplasia
A concept of ‘differentiated dysplasia’ was recently introduced, referring to a type of dysplasia having malignant potential similar to classic dysplasia in specific organs, although not usually considered dysplasia in most other organs due to excellent differentiation(15).
Oral mucosal squamous epithelium is histologically similar to that of other organs (e.g. larynx,
oesophagus, uterine cervix, vagina, etc.) and dysplasia is diagnosed based on similar histopathological
criteria. In some organs, however, organ- specific dysplasia may develop, such as HPV- related dysplasia of the uterine cervix and oropharynx(15). Differentiated- type vulvar intraepithelial neoplasia is
another example, characterised by premature keratinisation in the deeper epithelial layers and nuclear
atypia generally limited to the basal layers with often normal terminal epithelial differentiation(6, 15).
Contrary to this benign histopathological picture, this differentiated type of vulvar dysplasia is associated with a higher risk of malignant transformation than the usual- type vulvar dysplasia(6, 15).
Oral epithelial differentiated dysplasia (ODD) is a novel type of dysplasia recently introduced(15). While histologically similar to classic dysplasia, ODD exhibits certain attributes rarely
observed in classic dysplasia and, despite its seemingly benign features, has been associated with a
higher risk of malignant transformation(15). Histopathological features which have been attributed to ODD include abnormal variation in nuclear size and shape; increased number and size of
nucleoli; loss of polarity of basal cells; premature keratinisation of single cells and loss of epithelial
cell cohesion, with the last two attributes often limited to the lower half of the epithelium(15). In
fact, premature keratinisation of single cells and loss of epithelial cell cohesion (infrequent in classic dysplasia) have been identified as essential attributes of ODD(15).
ODD has been proposed as part of the broader spectrum of OED, exhibiting morphological characteristics which differ from classic dysplasia(15). Additional studies are required to characterise
further improved understanding and diagnosis of this new entity, including molecular studies and
immunohistochemistry, with some biomarkers (e.g. CK13 and CK17) already proving useful in the
diagnostic process(6, 15).
27.5.2 Basaloid Dysplasia
Basaloid dysplasia is characterised by monotonous basaloid cells with a high nucleus cytoplasm
ratio, large nuclei, drop- shaped rete ridges and minimal keratinisation(6). It usually affects the
non- keratinised epithelium of the lateral tongue and floor of the mouth(6).
27.5.3 Human Papillomavirus- associated Dysplasia
Human papilloma virus associated OED is a distinctive subset of OED(6, 10). It is characterised by
Odell etal.(6):
● Uniform replacement of most epithelial thickness by basaloid cells or cells of prickle cell
morphology
● Loss of demarcation between basal, prickle cell and maturing compartments
● Acanthosis
● Increased mitoses– often suprabasal
● Atypical cells at all levels, including apoptotic cells, apoptotic mitoses, multinucleate cells and
grossly atypical cells with karyorrhexis. The karyorrhectic cells have fragmented chromatin and
a peri- cellular halo from attachment loss to adjacent cells.
● Vertical orientation of basal and prickle cells
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● Usually, a normal- appearing basal epithelial cell layer
● Increased keratinisation
● Often, a folded epithelial architecture
While HPV- associated OED can affect any intraoral site, most cases involve the tongue and floor
of the mouth and can present as solitary or multiple lesions(6). In contrast to oropharyngeal SCC,
the prognosis of oral cavity HPV- associated dysplasia is unknown and, at present, the clinical management should follow that of other OPMDs(6, 7). In one study of 54 cases of HPV- associated
OED (predominantly associated with HPV- 16), 15% developed invasive SCC(16).
27.5.4 Dysplasia inthe Context ofPapillary andVerrucous Lesions
andProliferative Verrucous Leukoplakia
Verrucous and papillary OPMDs are known to carry a high risk of malignant transformation
despite exhibiting low grades of dysplasia(9).
Verrucous lesions show predominantly architectural changes, including(6, 7):
1) Premature even keratinisation
2) Para- or ortho- keratinisation with a corrugated or verrucous surface
3) Broad acanthotic rounded or slightly bulbous rete processes
4) The basal cell layer ranges from apparently normal to expansion to a few layers with mild cyto-
logical atypia
5) The surface keratin may dip down into rete processes (keratin ‘plugging’)
6) Frequent lichenoid immune response
7) Frequent sharp lateral demarcation and skip lesions
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Papillary and verrucous lesions can be challenging to identify as dysplastic and differentiate
from viral changes, verrucous or papillary squamous carcinoma(6). This verrucous architecture is
rare in other oral lesions. Verrucous lesions are characterised by sharp, pointed and generally regular keratinised surface projections that do not extend far from the surface (6). Papillary lesions
exhibit fronds or exophytic extensions, and most contain some cytological atypia(6). In the case of
verrucous OPMDs, the specific verrucous morphology alone, even in the absence of other atypia,
warrants a diagnosis of mild OED(6, 9). Additional atypia upstages the grade(6).
Proliferative verrucous leukoplakia is a specific type of OPMD predominantly affecting older
females and presenting as a multifocal leukoplakia with a preference for palatal and gingival
mucosa, with a poor prognosis owing to its high rate of malignant transformation of about 50%(11).
In its early stage, PVL is a flat lesion lacking atypical features(6) architectural dysplasia develops
with minimal atypia as the lesion evolves(6, 9). Cytological atypia may or may not become more
apparent in the later stages of lesion evolution and malignant transformation can occur in lesions
with only architectural atypia(6, 9).
27.5.5 Dysplasia witha Lichenoid Immune Response
‘Lichenoid’ refers to a T- cell- mediated immune response against keratinocytes and is characterised by a lymphohistiocytic band- like infiltrate, epithelial infiltration by lymphocytes and
apoptotic destruction of basal and supra- basal cells(6). Basal cell destruction disrupts normal
epithelial proliferation and maturation, usually resulting in increased and generalised premature
keratinisation(6).
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A lichenoid immune response is a common feature of OED, particularly in PVL and
differentiated dysplasia (6). Histopathologically, it can be challenging to distinguish lichen
planus, lupus erythematosus, graft- versus- host disease, contact reactions and drug eruptions
from OED with a lichenoid immune response, and clinicopathological correlation becomes
paramount(6, 9).
27.6 Grading ofOral Epithelial Dysplasia
Carcinogenesis is recognised as a multistep process arising from the accumulation of genetic
mutations. In this model, epithelial hyperplasia progresses through increasing grades of dysplasia
due to mounting genetic aberrations(1, 7, 17). Grading of OED has been used to assess the probability of malignant transformation and guide treatment planning(8). It is based on assessments
of architectural and cytological changes. Fortunately, most dysplastic lesions do not end in malignancy, and the challenge lies in identifying those lesions that will progress(6). Although numerous patient and lesion characteristics are considered, patients with low- grade dysplasias are
generally managed conservatively by managing risk factors and surveillance. In contrast, lesions
with moderate and severe dysplasia are excised(7).
Numerous classification systems of OED have been proposed to standardise reporting and facilitate management. An ideal classification system should be reproducible, reflect the malignant
potential of the lesion, indicate the timeline of malignant transformation and facilitate the allocation of patients to appropriate treatment protocols(1, 6). Since Smith and Pindborg described the
first system for grading OED in 1969, numerous other classification systems have been proposed,
none of which have thus far fulfilled all criteria of an ideal system(6). Shortfalls of the proposed
classification systems included subjectivity of assessments of microscopic features, poor reproducibility and complexity of use(7, 8). Furthermore, existing systems are not necessarily applicable to
HPV- associated dysplasia, verrucous lesions and architectural dysplasia (5, 6). Separate grading
systems may be necessary for those entities(6). Finally, epithelial trauma, irritation and infection
can produce changes that mimic OED and hamper grading(7). Accurate history and clinical
examination are essential in ensuring accurate diagnosis of OED(7).
In 1978, the World Health Organisation (WHO) defined and listed 12 characteristics of OED
and put forward its first classification system(1). Depending on whether these characteristic features were restricted to the lower, middle or upper third of the epithelium, OED was graded as
mild, moderate or severe, respectively (1). The WHO classification of OED was subsequently
modified in 2005 and 2017. The current (2017) WHO classification system is the most widely
used. It is based on assessing defined architectural and cytological changes as they progress
through the epithelial thirds, resulting in a diagnosis of mild, moderate or severe dysplasia
(Figure27.6)(12). This system, however, is also not ideal. Firstly, while supported by evidence,
the list of features presented in the 2017WHO classification is not necessarily definitive, and various other characteristics have also been proposed in the literature(6). Secondly, OPMDs encompass a wide range of lesions which exhibit significant variations in size, thickness and complexity
of rete architecture and keratinisation, making it difficult to define the levels of thirds, particularly in very thin epithelia. Lichenoid, verrucous and differentiated lesions can also be problematic in terms of portraying their actual risk of malignant transformation and in an attempt to
allow higher grades to be assigned to such lesions, the significance of architectural features and
the connective tissue interface was increased in importance, and it was noted that changes limited to the basal third could warrant a diagnosis of severe dysplasia(6). The importance of third
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Architectural changes Cellular changes
Irregular epithelial stratification
Loss of basal cell polarity
Drop-shaped rete ridges
Increased number of mitotic figures Cellular pleomorphism (abnormal variation in
Abnormal superficial mitosis Increased nuclear-cytoplasmic ratio
Dyskeratosis (premature keratinisation in single
cells)
Keratin pearls within rete ridges
Loss of epithelial cell cohesion Hyperchromasia
Cellular and architectural changes are restricted to the lower third of the epithelium.
Cellular and architectural changes are restricted to the lower two-thirds of epithelium.
Cellular and architectural changes observed in greater than two-thirds of epithelium
Anisonucleosis (abnormal variation in nuclear
size)
Nuclear pleomorphism (abnormal variation in
nuclear shape)
Anisocytosis (abnormal variation in cell size)
cell shape)
Atypical mitotic figures
Increased number and size of nucleoli
Mild
Moderate
Severe
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Figure27.6 World Health Organisation classification system of Oral Epithelial Dysplasia (2017).
grading was downgraded in the 2017 edition, and OED is no longer required to show both architectural and cytological features(6).
To further improve reproducibility and clinical utility, simplified two- tier systems were proposed, classifying OED into either low or high risk for progression to malignancy (1, 5). The
most recent classification system was proposed by Kujan etal. and is based on four architectural
and five cytological features and has demonstrated improved inter- observer agreement and
reproducibility with a similar prognostic ability compared to the three- tier WHO classification
system(1). Nankivell etal. later modified the system to four architectural features and four cytological changes required for the high- grade dysplasia diagnosis, splitting moderate dysplasias
between low and high risk, based on the number of architectural and cytological changes evident (Figure 27.7) (6, 18). This change improved the prognostic value of the binary system
slightly, but neither system convincingly prognosticated lesions in the moderate group any more
accurately(6, 18). A binary system also tends to increase false positive and negative results(6).
Nevertheless, binary grading appears to be the most successful grading system for OED thus far
regarding its reproducibility and clinical and biological relevance(9). Longitudinal studies are
required to validate further the ability of the binary system to predict the malignant transformation of OED(1).
Despite the shortcomings and imperfections of the current OED classification systems, grading
differentiates lesions with different risks of malignant transformation. It identifies lesions with the
greatest short- term risk(6, 8). In general, lesions with high- grade dysplasia tend to be associated
with a higher risk of progression to malignancy and an earlier time to transformation(6, 8).
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Binary system of grading oral epithelial dysplasia for prediction
Architectural changes Cellular changes
Irregular epithelial stratification
Loss of basal cell polarity
Drop-shaped rete ridges
Increased number of mitotic figures Cellular pleomorphism (abnormal variation in
Abnormal superficial mitosis
Dyskeratosis (premature keratinisation in single
cells)
Keratin pearls within rete ridges
(No potential susceptibility for malignant transformation)
Based on the observation of less than four architectural changes or less than four cytological
(Potential susceptibility for malignant transformation)
Based on the observation of at least four architectural changes and four cytological changes
of malignant transformation
Anisonucleosis (abnormal variation in nuclear
size)
Nuclear pleomorphism (abnormal variation in
nuclear shape)
Anisocytosis (abnormal variation in cell size)
cell shape)
Increased nuclear-cytoplasmic ratio
Increased Nuclear size
Atypical mitotic figures
Increased number and size of nucleoli
Hyperchromasia
Low-risk Lesion
changes.
High-risk Lesion
Figure27.7 The binary classification system of oral epithelial dysplasia was proposed by Kujan etal. and
modified by Nankivell etal.
27.7 Imitates ofOral Epithelial Dysplasia
Complicating the diagnosis and grading of OED is the fact that numerous benign lesions can
mimic OED. Therefore, the diagnosis of OED must also consider the lesion’s clinical presentation.
Histopathologically, abrupt transitions between normal and dysplastic epithelium and dropshaped rete ridges are typically seen in OED while absent in reactive changes(7).
27.7.1 Candidal Infection
Fungal infections elicit an inflammatory response with neutrophilic infiltrate, including micro
abscess formation(7). The organisms aggregate within parakeratotic debris and along the surface
of the mucosa, which is often hyperplastic. Fungal hyphae may or may not be present in dysplastic
lesions. In reactive lesions, inflammatory changes are typically characterised by evenly acanthotic
mucosa and abrupt transitions are not seen(7). There is also uniform enlargement of nuclei and
small and uniform nucleoli, while marked variations in nuclear size or multiple nucleoli are not
seen(7). In cases where the distinction between a reactive and dysplastic lesion is difficult, a repeat
biopsy after treatment of the fungal infection is indicated(7).
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