1. Keratoses and related disorders of oral mucosa II
 Leukoplakia:
 Definition:
 Leukoplakia = white patch
 WHO original definition "a white patch which can NOT be
characterized clinically or histopathologically as any other disease"
 Definition slightly modified in 1994 to: "a predominantly white
lesion of the oral mucosa that can NOT be characterized as any
other definable lesion"
 Therefore leukoplakia is a clinical diagnosis arrived at by exclusion
 Leukoplakias can NOT be scrapped/wiped off
 It indicates NO particular histopathological change or behavior. However, a small percentage is
premalignant and some may be invasive carcinomas at presentation
 It is impossible to predict which lesions are likely to become malignant, but certain clinical and
histopathological features are recognized as being associated with an increased risk of malignancy
 Incidence:
 There's a worldwide variation from less than 1% to more than 10%
 Difficulties in standardization of diagnostic criteria make comparison of the prevalence in different
areas somewhat difficult
 Marked variation in incidence, sex, site, and age groups affected occur between different cultural and
ethnic groups, reflecting variations in the possible etiological factors
 Leukoplakias involving ventral tongue and/or Flour of the mouth (sublingual keratosis) have a
higher risk of malignant transformation
 Previous studies in Western Europe & North America reported leukoplakia as being:
- Predominant in males (since they smoke more)
- Affecting older people (cumulative effect of smoking)
- Affecting mostly Flour of the mouth & buccal mucosa
 Recent studies in the same areas indicate that:
- M:F ratio is becoming almost equal
- Incidence in younger adults is increasing
- This possibly reflects changes in smoking habits
 In areas where smoking habits are common, leukoplakia is common too
 Clinical Features:
 Size  small well-defined to extensive
 Color  white, whitish-yellow, or grey
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2.  Surface appearance  Homogeneous vs. Non-homogeneous:
o Homogeneous lesions:
- Flat, uniform & predominantly white plaques "ONLY white in color"
- Some may show shallow cracks/fissures producing tessellated appearance )
o Non-homogeneous lesions:
- Irregular in outline
- Maybe speckled with areas of Erythroplakia "areas of redness" (speckled leukoplakia)
- Maybe ulcerated, nodular/thickened, or sometimes take Verrucous "warty" surface
(Verrucous leukoplakia)
- Non-homogeneous lesions have a worse prognosis
 Erythroplakia:
o Definition = "a bright red velvety plaque on the
oral mucosa which can NOT be categorized clinically or
histopathologically as being due to any other condition"
o Clinically:
- Maybe homogeneous "ONLY red in color" with a well-
defined but irregular outline
- Or maybe intermingled with patches of leukoplakia
(the so-called speckled leukoplakia or
erythroleukoplakia)
o Histopathologically:
- May represent carcinoma-in-situ or even invasive carcinoma
- No hyperkeratosis
- Atrophic epithelium
o Development of Erythroplakia in a previously uniform white lesion is an important clinical
sign (sinister change) of malignant transformation!
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3.  Some clinical features that may indicate malignant change in leukoplakia/Erythroplakia:
1. Development of Erythroplakia in a previously uniform white lesion
2. Fixation to surrounding structures
3. Induration (being filled with cells and firm to palpation)
4. Ulceration
5. Lymphadenopathy (enlarged/swollen lymph nodes)
6. Bone destruction if it overlies bone
7. Other clinical features of malignancy (rapid growth, irregular margins…)
 Etiology:
 By definition, leukoplakia is idiopathic
 Etiology is likely to be multifactorial
 Some predisposing (BUT NOT CAUSATIVE) factors can be identified in some patients, e.g.:
** Predisposing means factors that do NOT cause but increase risk of leukoplakia
1. Tobacco:
o Tobacco use is a major factor and it is the most common factor identified in patients with
leukoplakia
o Higher prevalence of leukoplakia has been found among smokers
o Prevalence increases with the amount of tobacco & duration of smoking
o Any part of the mucosa may be involved
o Distribution of lesions may vary with the particular type of habit, e.g.:
- Cigarettes smokers: leukoplakia maybe diffuse on cheeks, lips and tongue
- Reverse smoking: wide variation of changes (white patches, red areas, or ulceration)
- Smokeless tobacco (chewing tobacco, snuff dipping and areca nut "betel nut"):
leukoplakia maybe in the lower buccal sulcus
** Reverse smoking refers to a smoker putting the lit end of a cigarette into his mouth.
The smoker then inhales the smoke from the lit end!!
** In those patients whose tobacco-associated keratosis regresses on cessation of the
habit, the lesion should NOT be classified as leukoplakia
** In leukoplakia, tobacco may be a predisposing factor for the changes taking place
BUT it is NOT the cause that if removed the lesion would regress
2. Alcohol:
o No clear evidence for its importance, but it may have a role
o Many heavy smokers are also heavy drinkers so smoking may help alcohol in its effects
(synergistic effect)
3. Candida:
o Candida can be demonstrated in Candidal leukoplakia (chronic hyperplastic candidosis)
which is a white patch caused by fungal infection and this means it is NOT an idiopathic
leukoplakia (which doesn't have a recognizable cause)
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4. ** Candidal leukoplakia affects mainly commissure of the
lip, found mainly in smokers, and it is a premalignant lesion
that carries a risk for malignant transformation
o Candida may be associated with idiopathic leukoplakia, BUT it is NOT clear yet whether it
is the cause or the result (we don’t know yet whether Candida causes the dysplastic changes
in the lesion or it only colonizes the lesion after getting dysplastic!!)
** It is thought that Candida likes to live in altered or dysplastic tissues
4. Viruses:
o Human Papilloma Virus (HPV):
- Type 16 & 18 may be found in leukoplakia as well as in
some healthy mucosa
- Their role in the pathogenesis is uncertain
o Epstein-Barr Virus (EBV):
- EBV can be demonstrated in hairy leukoplakia which is a
white patch caused by viral infection and this means it is
NOT an idiopathic leukoplakia (which doesn't have a recognizable cause)
** Hairy leukoplakia is NOT a premalignant lesion & it is more common in AIDS patients
5. Oral epithelial atrophy:
o Atrophy weakens the mucosa and increases its sensitivity to chemicals & traumatic agents
o Any condition that may cause epithelial atrophy increases the risk for leukoplakia e.g.:
- Iron deficiency
- Some vitamin deficiencies (folic acid, vitamin B12 …)
- Submucous fibrosis (which is a premalignant condition characterized by epithelial
inflammatory reaction and progressive fibrosis of the submucosal tissues "lamina
propria and deeper connective tissues". The condition is linked to areca nut chewing habit)
- Tertiary syphilis
- Sideropenic dysphagia (also known as Patterson-Kelly or Plummer-Vinson
syndrome) in which patients develop iron-deficiency anemia, dysphagia (difficulty in
swallowing) and esophageal webs (thin membranes that make swallowing painful)
Orally it is associated with epithelial atrophy, leukoplakia or carcinomas
6. Tumor suppressor genes:
o These genes are important for the cell cycle regulation
o Mutations in tumor suppressor genes, mainly p53 on chromosome 17p, result in uncontrolled
cell proliferation, and such mutations are seen in a wide range of malignancies, and in some
Leukoplakias ESPECIALLY those present with dysplasia or in heavy smokers or drinkers
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5. 7. Sanguinaria-associated leukoplakia:
o Sanguinaria Canadensis (a type of flowers) has been found to be
effective against plaque build up and gingivitis
o Sanguinaria-associated leukoplakia is a unique form of oral
leukoplakia attributed to the chronic use of oral rinses and
toothpastes containing the extract of the plant
o It is usually located on the attached gingiva & the alveolar mucosa
of the maxillary vestibule
o Preparations containing Sanguinaria should be avoided until the risk
for malignant transformation is determined
 Histopathology of leukoplakia, Epithelial Dysplasia:
 Leukoplakias histologically show a wide variation in histological appearances with variable
degrees of :
o Keratosis (Orthokeratosis, Parakeratosis, or both)
o Epithelial thickness (could be acanthotic or atrophic)
** Areas of Erythroplakia (clinically) are often associated with epithelial atrophy (histologically)
o Epithelial dysplasia
** NOT all Leukoplakias are dysplastic
** Dysplasia can be mild, moderate or severe
** Severe dysplasias have higher risk for malignant transformation
o Chronic inflammation in the lamina propria as a result of being invaded
** In some Leukoplakias, keratosis & change in epithelial thickness are the only abnormal
features
** While other cases may show features of epithelial dysplasia
- It is NOT necessary to see all the dysplastic features in one case
- The junction between normal and abnormal epithelium may be abrupt or there may be
gradual transition
** It is important to remember that Leukoplakia is a clinical diagnosis arrived at after exclusion
and is NOT based on any specific histopathological features
** There are two histological features which are highly suggestive of
smoking as a predisposing factor:
1- The presence of chevron peaks in keratin {e.g. V-shaped keratin}
2- The presence of melanin incontinence {increased melanin
production in basal keratinocytes and leakage of melanin into the
underlying connective tissue}
This may give the lesion grey colour
clinically
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6.  The degree of dysplasia is subjectively assessed into mild, moderate and severe based on the
thickness of the epithelium involved with the dysplastic features:
o Mild (grade I) dysplasia  Proliferation of atypical basal cells above the para-basal region BUT
NOT extending beyond the lower third of the epithelium
o Moderate (grade II) dysplasia  demonstrates a similar proliferation into the middle one-third
of the epithelium
o Severe (grade III) dysplasia  Abnormal proliferation from the basal layer into the upper third
of the epithelium
** It is NOT possible to predict the presence and severity/grade of dysplasia from clinical
appearance of the lesion
** Although it is NOT possible to predict the presence and severity of dysplasia from clinical
appearance lesion, Erythroplakias and non-homogeneous Leukoplakias are more likely to be
dysplastic (or even malignant) than homogeneous Leukoplakias
** Several studies showed:
- Only about 10% of homogeneous Leukoplakias tend to be dysplastic
- About 50% or more of non-homogeneous types tend to be dysplastic
- Speckled Leukoplakias show a very high incidence of dysplasia, which approaches
100% as speckling increases and as the clinical features more closely resemble
Erythroplakia
 The individual cellular changes (cellular atypia) seen in dysplastic epithelium reflect abnormalities
in proliferation, maturation, and differentiation of epithelial cells
 Features of epithelial dysplasia (changes affecting the tissue
as a whole):
1- Abnormal mitoses or increased (and it is NOT only
limited to the basal layer but it extends beyond)
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7. 2- Basal cell hyperplasia
3- Drop-shaped rete ridges (wider in deep parts than superficial)
4- Disturbed polarity of basal cells or loss of cellular orientation (no definable long axis of cells)
5- Increase in nuclear/cytoplasmic ratio
6- Nuclear Hyperchromatism (intense color)
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8. 7- Prominent and enlarged nucleoli (to synthesize more proteins for cell division)
8- Irregular epithelial stratification (disruption in the maturational changes of cells as they pass
from deep to superficial layers)
9- Nuclear and cellular pleomorphism (showing different sizes and shapes)
10- Dyskeratosis (abnormal keratinization that is present below the surface layer forming keratin pearls)
11- Loss or reduction of intercellular adhesion
 Prognosis:
 Leukoplakias have unpredictable tendency to undergo malignant transformation
 Marked variation in reported rates from different countries due to differences in diagnostic criteria
and etiological factors
 Transformation times vary from one to several years
 Combining results from several studies, a rate of ~14% over a period of up to 20 years has been
reported
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9.  Potential for malignant transformation is greater in high risk
sites (ventral tongue, flour of mouth and lingual aspect of
lower alveolar mucosa)
** Lesions in these areas are designated as sublingual keratosis
to draw attention to these sites
** 25% of these show invasive carcinoma in initial biopsies,
and 25% of them develop carcinoma later when followed up
 Dysplastic lesions carry an increased risk of malignant transformation (<10% - >30%)
 The more severe the dysplastic features, the greater the risk, BUT NO clear correlation
 The majority of dysplastic lesions remain unchanged during observation period
 A proportion of these will improve or regress
 Speckled and other non-homogeneous types have increased rate of malignant transformation (~30%)
 Erythroplakia (alone or as part of speckled leukoplakia) shows invasive carcinoma or carcinoma in
situ on ~ 50% of initial biopsies, and most of the remaining show severe dysplasia
 Candidal leukoplakia has a high incidence of dysplasia or malignant transformation (~30%)
 Malignant transformation likely to be due to progressive accumulation of genetic changes over time
 Recent studies show that Leukoplakias with abnormal DNA content of epithelial cells are more
likely to undergo malignant transformation
 This may become an important prognostic indicator in the future
 At present, risk assessment is based on:
o Size
o Site
o Clinical appearance
o Degree of epithelial dysplasia
 Some clinical presentations indicate poorer prognosis:
1. Leukoplakias involving ventral tongue and/or floor of the mouth and the lingual aspect of
lower alveolar mucosa (sublingual keratosis) are more likely to be dysplastic and have a higher
risk of malignant transformation
2. Erythroplakias and non-homogeneous Leukoplakias are more likely to be dysplastic (or even
malignant) than homogeneous Leukoplakias
3. Presence and severity of dysplasia (the more severe the dysplastic features, the greater the
risk for malignant transformation)
4. Presence of Abnormal DNA content
- Normal cells have two copies of each chromosome (they are diploid, 5%)
- Malignant and premalignant cells usually show abnormal number of chromosomes due
to mutations in the genes controlling cell cycle and DNA replication
- Reduplication of chromosomes prior to mitosis results in polyploidy (tetraploid, 50%) cells
- Abnormal segregation (separation) of chromosomes during mitosis give
unequal/abnormal number of chromosome in cells; the so-called (aneuploid, 80%)
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