Premalignant

Oral Lesions
Precancerous Oral Lesions
 Precancerous Lesion
It is a benign, morphologically
altered tissue that has a greater
than normal risk of malignant
transformation.
Leukoplakia
Erythroplakia

Erythroleukoplakia
 Leukoplakia
(leuko-white; plakia-patch)
Oral leukoplakia is defined by the WHO as
a white patch or plaque that can not be
characterized clinically or pathologically as
any other disease.
Thus a diagnosis by exclusion.
The term is strictly a CLINICAL one and
does not imply a specific histopathologic
tissue alteration.
Leukoplakia is the most common oral
precancer.
 Leukoplakia: Why is it
White?
The clinical color (white) results
from a thickened surface keratin
layer (which appears white when
wet) or a thickened spinous layer,
which masks the normal vascularity
(redness) of the underlying
connective tissue.
 Leukoplakia: A
Premalignant or
Precancerous Lesion
Although leukoplakia is not
associated with a specific
histopathologic diagnosis, it is
considered to be a premalignant
lesion for the risk of malignant
transformation is greater in a
leukoplakic lesion than that
associated with normal or unaltered
mucosa.
 Leukoplakia
Despite the fact that leukoplakia is a
premalignant lesion it should be noted
that not every lesion shows
histopathologic evidence of epithelial
dysplasia or frank malignancy
(squamous cell carcinoma).
In fact, dysplastic epithelium or invasive
carcinoma is found in only 5 to 25 % of
the biopsy samples of leukoplakia.
 Leukoplakia:
Malignant Transformation
Potential
Overall, the malignant
transformation potential of
leukoplakia is 4 % (estimated
lifetime risk).
However, specific clinical subtypes
are associated with much high
potential malignant transformation
rates (as high as 47 %).
Leukoplakia: How Common
Is It?
Leukoplakia is by far the most common oral
precancer, accounting for 85 % of such
lesions. (Note: this statement is not saying
that leukoplakia has the highest malignant
transformation risk of the premalignant group
of lesions for erythroplakia [erythroplasia]
does).
Leukoplakia is also a relatively common lesion
for it is estimated that approximately 3 % of
all white adults will be affected at some time.
 Leukoplakia: Who
Develops It?
There is a strong male predilection
(70%), except in parts of the country
where females use tobacco products
more than males.
Overall, there has been a slight decrease
in the proportion of males affected over
the past few decades.
In general, leukoplakia is diagnosed
more frequently now than in the past,
probably because of enhance awareness.
 Leukoplakia: Etiology
The cause of leukoplakia remains
unknown.
Over the years the following have
been considered: tobacco, alcohol,
sanguinaria, ultraviolet radiation,
microorganisms and trauma.
 Etiology of Leukoplakia:
The Role of Tobacco
The habit of tobacco smoking appears most
closely associated with leukoplakia
development.
80 % of patients with leukoplakia are smokers.
Smokers are much more likely to have
leukoplakia than non-smokers.
Heavier smokers have greater numbers of and
larger lesions than light smokers.
A large proportion of leukoplakias in persons
who stop smoking either disappear or become
smaller soon after discontinuing the habit.
 Etiology of Leukoplakia:
The Role of Alcohol and
Sanguinaria
Alcohol, which seems to have a strong
synergistic effect with tobacco in oral cancer
development, has not been associated with
leukoplakia.
Sanguinaria (blood root) is a herbal extract that
has been used in toothpaste and moutwash.
Over 80 % of the patients with
vestibular/maxillary alveolar leukoplakias have
a history of using a sanguinaria containing
product as compared to 3 % of the normal
population; some lesions have persisted after
the patient stopped using the product.
 Etiology of Leukoplakia:
The Role of Ultraviolet
Radiation
Ultraviolet radiation has been
associated with leukoplakia of the
vermilion of the lower lip.
This leukoplakia is usually
associated with actinic cheilosis.
 Etiology of Leukoplakia:
The Role of
Microorganisms
Treponema pallidum has been
implicated in leukoplakia of the
dorsal surface of the tongue in
patients with syphilis.
Candida albicans has been
demonstrated histologically in the
hyperplastic/dysplastic epithelium of
lesions termed candidal leukoplakia
and candidal hyperplasia.
 Etiology of Leukoplakia:
The Role of
Microorganisms
Human papillomavirus (HPV),
particularly subtypes 16 and 18,
have been identified in some oral
leukoplakias.
However, HPV has also been
demonstrated in normal oral
epithelial cells.
 Etiology of Leukoplakia:
The Role of Trauma
Several keratotic lesions, which until
recently have been viewed as variants of
leukoplakia, are now considered not to be
premalignant.
Included in this group are lesions termed
nicotine stomatitis and frictional keratosis.
The keratosis are readily reversible after
the elimination of the trauma or chronic
irritation.
 Leukoplakia: Clinical
Features
Leukoplakia usually affects people
over the age of 40 years (average
age is 60 years).
Prevalence increases rapidly with
age particularly in males.
Approximately 8 % of the males over
the age of 70 years are reportedly
affected.
 Leukoplakia: Clinical
Features
Approximately 70 % of the oral
leukoplakias are found on the lip
vermilion, buccal mucosa and
gingiva.
Note: Lesions of the tongue, lip
vermilion and floor of the mouth
account for more than 90 % of those
that show dysplasia or carcinoma
upon histologic examination.
 Leukoplakia: Clinical
Features
Individual lesions vary in clinical
appearance and tend to change over time.
Early/mild lesions usually appear as
slightly elevated gray or gray-white
plaques, which may appear translucent,
fissured or wrinkled and are typically soft
and flat.
Early/mild lesions are usually well
demarcated but may blend into the
surrounding normal mucosa.
 Leukoplakia: Clinical
Features
Early/mild thin leukoplakia, which
seldom shows dysplasia on biopsy, may
disappear or continue unchanged.
If the cause (s) of the lesion are not
removed, many lesions will gradually
become thicker and larger.
The clinical appearance (s) of
leukoplakia and the anticipated
underlying histopathologic changes are
presented in the following diagram.
 Proliferative Verrucous
Leukoplakia (PVL)
PVL is a special high risk form of leukoplakia.
It is characterized by multiple keratotic plaques
with rough surface projections although initially
beginning as a simple flat hyperkeratosis.
PVL plaques tend to spread slowly, yet
progressively.
PVL usually transforms into a squamous cell
carcinoma within about 8 years.
PVL has a strong female predilection (1:4 male to
female) and minimal association with tobacco
usage.
 Leukoplakia:
Histopathologic Features
Leukoplakia is characterized by a
thickened keratin layer
(hyperkeratosis) with or without a
thickened spinous layer (acanthosis).
Some leukoplakias show surface
hyperkeratosis but with atrophy or
thinning of the underlying epithelium.
Variable numbers of chronic
inflammatory cells are typically noted
within the underlying connective tissue.
 Leukoplakia:
Histopathologic Features
While most leukoplakias show no
dysplasia on biopsy, some 5 to 25 %
of the cases do show evidence of
epithelial dysplasia (or squamous
cell carcinoma).
The histopathologic alterations of
dysplastic epithelial cells are
outlined in the next slide.
Histopathologic Alterations
of Dysplastic Epithelial
Cells
Enlarged nuclei and cells.
Large and prominent nucleoli.
Increased nuclear-cytoplasmic ratio.
Hyperchromatic (dark-staining) nuclei.
Pleomorphic (abnormally shaped) nuclei
and cells.
Dyskeratosis (premature keratinization)
Increased mitotic activity and abnormal
mitotic figures
Histopathologic Alterations
of Dysplastic Epithelium
Continued
Bulbous or teardrop-shaped rete
ridges.
Loss of polarity (lack of progressive
maturation toward the surface).
Keratin or epithelial pearls.
Loss of typical epithelial cell
cohesiveness.
 Leukoplakia:
Treatment and Prognosis
Leukoplakia represents a clinical diagnosis
and therefore the first step in treatment is to
arrive at a definitive diagnosis via biopsy and
histologic examination of the tissue.
Treatment depends upon the diagnosis and
any leukoplakia exhibiting moderate epithelial
dysplasia or worse warrants complete
removal if possible. Treatment of lesions
exhibiting less severe changes is guided by
the size of the lesion and its response to more
conservative measures such as eliminating
tobacco use.
 Leukoplakia:
Treatment and Prognosis
Leukoplakia not exhibiting dysplasia often
is not excised but clinical evaluation every
6 months is recommended.
Additional biopsies are recommended if
smoking continues or if clinical changes
increase in severity.
The following diagram represents the
various clinical appearance of oral
leukoplakia and the anticipated underlying
associated histopathologic changes.
 Leukoplakia:
Treatment and Prognosis
Complete removal of oral leukoplakia can
be accomplished with equal effectiveness
by surgical excision, electrocautery,
cryosurgery or laser ablation.
Long-term follow-up after removal is
mandatory because of recurrence potential
and because new leukoplakias may occur.
Malignant transformation potential is
related to clinical appearance and the
degree of dysplasia present.
Erythroplakia: Definition
Erythroplakia is defined as a red
patch that can not be clinically or
pathologically diagnosed as any other
condition.
Erythroplasia is occasionally used as
a synonym for erythroplakia although
it was originally used by Queyrat to
describe a precancerous red lesion of
the penis.
 Erythroplakia
Almost all true erythroplakias
demonstrate significant epithelial
dysplasia, carcinoma in situ or
invasive squamous cell carcinoma.
The cause (s) of erythroplakias are
unknown but presumed to be the
same as those associated with
squamous cell carcinoma.
 Erythroplakia
Erythroplakia is far less common than
leukoplakia but has a much greater
potential to be severely dysplastic at
the time of biopsy or to develop
invasive malignancy at a later time.
Erythroplakia can occur in conjunction
with leukoplakia and has been found
concurrently with a large proportion
of early invasive oral carcinomas.
 Erythoplakia: Clinical
Features
It is predominantly a disease of older males
with a peak prevalence between the ages of
65 and 74 years.
The floor of the mouth, tongue and soft
palate are the most commonly involved sites.
Multiple lesions may occur.
Early erythroplakias appear as well-
demarcated erythematous macules or
plaques with a soft velvety texture.
Unfortunately, it is usually asymptomatic.
 Erythroplakia:
Histopathologic Features
Approximately 90 % of these lesions
represent either severe epithelial
dysplasia, carcinoma in situ, or
superficially invasive carcinoma.
Typically the epithelium shows a lack of
keratin production and is often atrophic.
This lack of keratinization, coupled with
epithelial thinness allows the underlying
microvasculature to show through
imparting the red appearance.
 Erythroplakia:
Treatment and Prognosis
As with leukoplakia, the treatment is
guided by the definitive diagnosis
obtained by biopsy.
Lesions exhibiting moderate dysplasia
or worse must be completely
removed.
Recurrence and multifocal oral
mucosal involvement necessitates
long-term follow-up.
 Erythroleukoplakia
This term is used for lesions that
have both a red (Erythroplakia) and
white (Leukoplakia) component.
Formerly called either speckled
erythroplakia or speckled
leukoplakia depending upon which
(red or white) accounted for the
majority component.
 Precancerous Oral
Conditions
A precancerous condition is a
disease or patient habit that does
not necessarily alter the clinical
appearance of the local tissue but is
associated with a greater than
normal risk of a precancerous lesion
or cancer developing in that tissue.
Plummer-Vinson Syndrome
(Paterson-Kelly Syndrome)
This is an uncommon condition
characterized by an iron-deficiency
anemia with an associated glossitis
and dysphagia.
It is of significance because of its
association with a high frequency of
oral and esophageal squamous cell
carcinoma.
Plummer-Vinson Syndrome:

Clinical Features
This syndrome is most common in females
between the ages of 30 and 50 years.
It is more common in patients of Scandinavian
and northern European background.
Patients complain of a burning tongue/mouth.
Angular cheilitis and a smooth red tongue are
often presenting features.
Dysplasia (difficulty) or pain on swallowing
are often manifestations of esophageal webs
(abnormal tissue bands in the esophagus).
Plummer-Vinson Syndrome:

Clinical Features
Another sign involves the nails,
which are often spoon-shaped
(koilonychia) and may be brittle.
The symptoms of anemia such as
fatigue, shortness of breath and
weakness often lead the patient to
seek medical care.
Plummer-Vinson Syndrome:
Laboratory & Microscopic
Features
Hematologic studies show a
hypochromic, microcytic anemia
consistent with iron-deficiency anemia.
Biopsy of the oral mucosa reveals
epithelial atrophy with submucosal
inflammation.
In advanced case one may see epithelial
atypia, dysplasia, carcinoma in situ or
frank squamous cell carcinoma.
Plummer-Vinson Syndrome:
Treatment and Prognosis
Treatment centers on correcting the iron-
deficiency anemia and if this is successful,
the glossodynia and esophageal symptoms
improve.
Patients should be evaluated periodically
for oral, pharyngeal and esophageal
cancer.
The frequency of malignancy in these
patients has ranged from 5 to 50 % in the
literature.
Oral Submucous Fibrosis:
Clinical Features
Oral lesions appear as areas of
opacification with loss of elasticity.
Fibrous bands may occur.
Any region of the oral cavity may be
affected.
 Oral Submucous
Fibrosis: Cause
This lesion may be a result of a
hypersensitivity reaction to dietary
constituents such as betel nut,
capsaicin, etc.
 Oral Submucous Fibrosis:
Treatment
No treatment has been consistently
effective.
Intralesional corticosteroids,
surgical splitting or excision of the
fibrous band have been helpful in
some cases.
 Oral Submucous Fibrosis:
Significance
The greatest significance is that oral
submucous fibrosis is a high-risk
precancerous condition.
Additionally, these fibrous lesions
are not reversible restricting many
oral movements.
 Oral Lichen Planus
A chronic inflammatory disease that causes
bilateral papules, striations or plaques
May cause erythema, erosions and blisters
Found on buccal mucosa, tongue and gingiva
Female:Male ratio 1.4:1
Predominantly seen in adults over 40 years.
0.5% to 2% of general population
Affects all ethnicities
Picture 1: Plaque-like OLP Picture 2: Reticular OLP

Picture 3: Erosive OLP Picture 4: Reticular OLP

 Pathogenesis of
Reticular LP
Oral Lichen planus is a purely T cell mediated
inflammatory response.There are no B cells,
plasma cells and no deposits of immunoglobulin
or complement.
The trigger for keratinocyte apoptosis in OLP is,
for the most part, unknown. However, the
lymphocytic infiltrate in OLP is composed almost
exclusively of T cells, and the majority of T cells
within the epithelium and adjacent to damaged
basal keratinocytes are activated CD8+
lymphocytes. Therefore, it is very probable that
cytotoxic T cells trigger keratinocyte apoptosis in
OLP.
 Proposed
Immunopathogenesis
of OLP
A lichen planus-specific antigen is expressed in
conjunction with MHC class 1 molecules on
keratiocytes at the OLP lesion site.
Antigen specific CD8+ T cells are activated in the
area.
Activated antigen-specific CD8+ cytotoxic T
lymphocytes trigger keratinocyte apoptosis,
possibly by secreted TNF-.
The activated T lymphocytes undergo intra-lesional
clonal expansion and release soluble mediators
(cytokines and chemokines), which recruit
lymphocytes from the local microvasculature and
cause migration toward the epithelium.
 This hypothesis predicts that the majority of
lymphocytes recruited to the OLP lesion site are
not specific for the lichen planus-specific antigen.
However, they may contribute to the pathogenesis
of OLP by secreting MMP-9, which leads to
epithelial basement membrane disruption.
Epithelial basement membrane disruption allows
for the passage of lymphocytes into the epithelium
and denies keratinocytes a cell survival signal,
resulting in further keratinocyte apoptosis.
This hypothesis predicts that the earliest events in
OLP lesion formation are confined to the
epithelium and that basement membrane and
connective tissue changes occur secondarily.
 Clinical Presentation
Oral lesions-more persistant and
resistant to treatment than skin lesions
30-50% of pts also have cutaneous lesions
Three common types
Reticular
Erosive
Plaque

Variants of Plaque and Erosive types

Atrophic
Bullous
 Clinical Presentation
Reticular lesions
Most common type
Interlacing white kerototic lines w/
erythematous borders (Wickhams
striae)
Typically bilaterally on buccal mucosa,
mucobuccal fold and gingiva
Less common on tongue, palate and lips

Assymptomatic
 Erosive lesions
2nd most common type
Mix of erythematous and ulcerated areas
sorrounded by radiating keratotic striae
Similar appearance to candidiasis, pemphigus
and lupus
Lesions tend to migrate and often multifocal
Mostly buccal mucosa and vestibule
Symptomatic:
Sore mouth sensitive to heat, cold, spices, and
alcohol
Pain and bleeding on touch
Plaque lesions
- Resemble focal leukoplakias
- Vary from smooth flat areas to raised irregular
plaques
- Often multifocal
- Dorsum of tongue and buccal mucosa
 Variants of Erosive and Plaque
lesions
Atrophic
Diffuse, erythematous patches
Causes significant discomfort

Gingiva and buccal mucosa

Bullous
Intraoral bullae on buccal mucosa and
lateral surface of tongue
Rupture soon after appearance resulting in
classic appearance of erosive lesions
 Diagnostic tests
Clinical exam: for reticular LP with
characteristic appearance of
Wickhams striae or annular pattern
on erythematous background
Histological and Direct
Immunofluorescent examinations: for
plaque and erosive LP because they
can resemble other mucosal lesions
including malignancy
 Diagnostic tests
Histological exam
Requires biopsy
Varies based on the type of lesion
Typically: epithelial hyperplasia, orto and para
keratosis, acanthosis, atrophic areas w/ loss of
rete pegs, dense accumulation of T-lymphocytes
in the basilar cell layer
Direct Immunofluorescent examination
Requires biopsy
Differentiates between other autoimmune
conditions
Detects shaggy deposition of fibrinogen along
the basement membrane
Histology: Reticular Lichen
Planus
Consists of local areas of epithelial hyperplasia in
which the surface contains a thick layer of
orthokeratin or parakeratin.
The spinous cell layer may be thickened (acanthosis)
with shortened and pointed rete pegs. The thickened
areas are seen clinically as Wickhams striae.
Between these areas the epithelium is thinned
(atrophic), with loss of rete peg formation.
The adjacent underlying c.t. contains a thin, dense
accumulation of T lymphocytes that move through
the basement membrane and are observed in the
basilar and parabasilar cell layers of the epithelium.
 Histology: Erosive Lichen
Planus
Exhibit an extensively thinned epithelium with
areas of complete loss of rete peg formation and a
dense infiltrate of T lymphocytes.
This T lymphocyte infiltrate obscures the
basement membrane and extends well into the
middle and upper levels of the epithelium.
Liquefaction of the basement membrane and
destruction of the basal cells is present in most
areas.
Occasionally, subepithelial separation will be
present. Often, the epithelium is lost, exposing
the underlying connective tissue.
The lymphocytes are confined to a narrow zone
in the upper layers of the connective tissue.
Histology: Plaque Lichen
Planus
Plaque LP resembles the histology of reticular LP
because of the striae pattern but it lacks the
intermittent atrophic areas of the epithelium.
It consists of generalized hyperorthokeratosis or
hyperparakeratosis combined with acanthosis.
There may be loss of rete pegs at the epithelial
and connective tissue interface or alteration of
their shape into a saw-tooth pattern.
The basement membrane is noticeably thickened.
The band of T lymphocytes present in the
superficial connective tissue is more sparse than
In reticular LP, with only occasional cells found in
the lower levels of the epithelium.
 Treatment of OLP
No treatment for OLP is curative
Goal:
Reduce painful symptoms
Resolution of oral mucosal lesions
Reduce risk of oral squamous cell carcinoma
Improve oral hygiene
Eliminate exacerbating factors
Repair defective restorations or prosthesis
Remove offending material causing allergy
Diet
Eliminate smoking and alcohol consumption
Eat fresh fruit and vegetables (but avoid tomatoes and
nuts)
Reduce Stress
 Treatment of OLP
Medication
Topical corticosteroids
0.05% clobetasol proprionate gel
0.1% or 0.05% betamethasone valerate gel

0.05% fluocinonide gel

0.05% clobetasol butyrate ointment

0.1% triamcinolone acetonide ointment

Can be applied directly or mixed with

Orabase
 Treatment of OLP
Medication
Systemic Steroid Therapy
Prednisone (for 70kg adult)
10-20mg/day for moderately severe cases
As high as 35 mg/day for severe cases
Should be taken in the morning to avoid insomnia
Should be taken with food to avoid peptic ulceration
Azathioprine (Imuran) Inhibits synthesis of DNA
1mg/kg/d for 6-8 weeks
Methylprednisolone (Medrol Dosepak)
to reduce pain and inflammation
Prophylactic use of 0.12% dhlorhexidine gluconate may help reduce
fungal infection during corticosteroid therapy
Alternative Treatment of
OLP
0.1% topical tacrolimus ointment
2x/day
Tacrolimus: immunosuppresive
macrolide
Suppresses T-cell activation
Intraoral ulceration resolved after 3
months of daily application
Remission for 1 year without
maintenance
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