נגעים לבנים ואדומים - שיעור 2 ת-א PDF

White and Red Lesions
in the oral mucosa
Dr. Avraham Hirshberg MD, DMD

Dept. Oral Pathology & Medicine
Tel-Aviv University

in the oral mucosa
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The mucosa on the dorsal surface of the tongue has two types of papillae (upfolding of the
epithelia).
The filiform papillae most numerous and have a conical shape. They do not contain taste buds and
are often partly keratinized.
Fungiform papillae are less numerous, resemble mushrooms (fungi) and have scattered taste buds
on their upper surface. The epithelia covering these papillae are not keratinized.
The mucosa on the dorsal surface of the tongue has two types of papillae (upfolding of the
epithelia).
The filiform papillae most numerous and have a conical shape. They do not contain taste buds and
are often partly keratinized.
Fungiform papillae are less numerous, resemble mushrooms (fungi) and have scattered taste buds
on their upper surface. The epithelia covering these papillae are not keratinized.
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The taste buds within the papillae are ovoid structures with paler-staining
columnar cells that are sensory cells and support cells. There are microvilli
on the surface of these cells and the sensory cells sense the contents of
the oral cavity via a small pore.
The circumvallate papillae - are the largest and least numerous papillae,
and are surrounded by a deep cleft.
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Aggregates of serous glands open into the base of the circumvallate clefts,
these glands are called von Ebner's glands. They empty into the cleft and
continually wash the taste buds to move foodstuffs. The taste buds are more
numerous on the the circumvallate papillae and are deep in the cleft and along
the lateral margins of the papillae.
The body of the tongue consists of a mass of interlacing bundles of

skeletal muscle fibers
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in the oral mucosa
Fordyces granules
Congenital lesions
White sponge nevus
Aquired lesions Candidiasis
Lichen planus
Dermatoses
DLE
Self inflicting lesions Frictional hyperkeratosis
Idiopathic Leukoplakia
Physical injuries
Physical and chemical induced lesions
Nicotine stomatitis

in the oral mucosa
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Developmental (congenital) lesions
FORDYCES GRANULES
Sebaceous gland on the oral mucosa
80% of the population
Multiple yellowish papules
Asymptomatic
Buccal mucosa,
Vermillion of the upper lip
Retromolar area, ant. Pillar
Adults > children (hormonal factors)

FORDYCES GRANULES
Asymptomatic
Buccal mucosa,
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FORDYCES GRANULES
Asymptomatic
Buccal mucosa,

White Sponge Nevus
Genodermatosis – genetically determined skin disorder
Autosomal dominant - Appear at birth, or early childhood rarely at adolescence
Mutaion in keratin 4 and 13 genes
Defect in normal keratinization of the oral mucosa
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White Sponge Nevus
Rare - Asymptomatic
Symmentric, thickened corrugated or velvety, diffuse plaques
Buccal mucosa
Tongue, labial mucosa soft palate, alveolar mucosa, FOM
Extraoral sites are less common – upper ADT, anogenitaal.

White Sponge Nevus
Hyperkeratosis, acanthosis
Vacuolated cells
Dense keratinized cells (condensed keratin filaments)
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Gingival cyst of the newborn
“Dental lamina cysts of the newborn"

"Epstein's pearls"
Small (2-3mm) superficial keratin-filled
cysts on the alveolar mucosa of infants.
Remnants of the dental lamina
50% of newborns
Disappear spontaneously (rupture)

“Dental lamina cysts of the newborn"

"Epstein's pearls"
Small (2-3mm) superficial keratin-filled
cysts on the alveolar mucosa of infants.
Remnants of the dental lamina
50% of newborns
Disappear spontaneously (rupture)
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Epstein pearls Bohn’s nodule
Small cysts on the palate of newborn infants – 60% of infants
“inclusion cysts” or epithelial remnants of minor salivary glands
Leukoedema
A common condition of unknown cause

Blacks > White
In 70-90% in blacks, in 50% in black children
Diffuse, grayish-white, milky opalescent bilaterally- buccal mucosa
Surface – folded, wrinkles
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Oral Candidiasis
Candidosis
Oral Thrush
Moniliasis
Oral Candidiasis
Yeasts are single-celled budding organisms
C. albicans may exist in two forms – Dimorphism
Yeast form
Hyphe form
Pseudohyphae Hyphae
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Oral Candidiasis
Candida albicans
Found in 30-50% of normal human beings.
Mouth, gut, and vagina.
60% of dentate patients carrying the organism in
their mouth without any clinical evidence of disease
C. Tropicalis
C. Guilliermondi
C. Krusei
C. Parapsilosis
Oral Candidiasis
Candida albicans
For this human commensal organism to
become a pathogen, interruption of normal
defense mechanisms is necessary
Oppotunistic infection
naturally - diabetes mellitus
iatrogenic - antibiotics
indwelling intravenous catheters
Inhaled steroids
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Oral Candidiasis
Broad spectrum antibiotics
Antibiotics suppress normal bacterial flora and allow
Candida organisms to proliferate, especially in the GI tract.
Sulfonamides decrease neutrophil Candida intracellular

killing, and tetracycline, doxycycline, and aminoglycosides
have been shown to decrease neutrophil phagocytosis
Oral Candidiasis
Diagnosis
Fungal cells have rigid walls of glucans and often chitin.
In the tissue all fungal cell walls are

stained mainly by
Periodic acid–Schiff (PAS) stain the

polysaccharide in the cell wall.
Gomori methenamine-silver
Gram stain (most fungi, except

Candida, remain unstained).
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Oral Candidiasis
Candidal infection may range from mild,
superficial mucosal involvement to fatal,
disseminated disease in severely
immunocompromized patients.
Oral Candidiasis
Clinical forms
– Pseudomembranous candidiasis (Thrush)
– Erythematous candidiasis
– Central papillary atrophy
– Chronic multifocal candidiasis
– Angular cheilitis
– Denture stomatitis
– Chronic hyperplastic candidiasis
– Mucocutaneous
– Endocrine-candidiasis syndromes
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Pseudomembranous candidiasis
Oral Thrush
• Broad spectrum antibiotics - Acute
• Immune dysfunction: leukemia, AIDS - Chronic
• Infants
Oral Thrush
• White plaques (cottage cheese, curdled milk)
can be removed by scrapping
Symptoms: burning pain,

altered taste sensation
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Oral Thrush
• White plaques (cottage cheese, curdled milk)
can be removed by scrapping
Can affect infants

The mouth of normal newborn infants
has a low pH which may promote the
proliferation of C. albicans
The infections are usually acquired
during the birth process from mothers
who had vaginal thrush during
pregnancy.
Clinical symptoms may persist until a
balanced oral flora has been
established
Erythematous candidiasis
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• Acute atrophic candidiasis (antibiotic sore mouth)

Follows broad spectrum antibiotics
Burning sensation
Diffuse loss of filiform papillae
• Central papillary atrophy of the tongue,

median rhomboid glossitis
In the past: developmental defect

Failure of the tuberculum impar to be covered by the lateral swelling of
the tongue
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• Chronic multifocal candidiasis (palate, mouth angles)
kissing lesions
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Angular cheilitis - Perlech
Angles of the mouth - erythema, fissuring and scaling
Part of chronic multifocal candidiasis
Alone – eldery
Diminished vertical dimention
20% - c. albicans alone
60% - combined infection:
c. albicans + staph aureus
20% - staph aureus alone
Angular cheilitis - Perlech

Angles of the mouth - erythema, fissuring and scaling
Part of chronic multifocal candidiasis
Alone – eldery
Diminished vertical dimention
20% - c. albicans alone
60% - combined infection:
c. albicans + staph aureus
20% - staph aureus alone
Cheilocandidiasis – angular cheilitis and peri-oral skin (ch. Lip licking..)
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Denture stomatitis
Chronic atrophic candidiasis
(a form of erythematous candidiasis)
Erythema and petechial hemorrahge,

localized to the denture-bearing areas
Usually asymptomatic
Denture stomatitis
Chronic atrophic candidiasis
(a form of erythematous candidiasis
Biopsy – seldom show candidal infection

Extensive colonization of the denture
(sabouraud’s agar)
DD:
Unfitted denture, pressure on the mucosa
Allegry
Inadequate curing of the acrylic denture
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Chronic hyperplastic candidiasis
Candidal leukoplakia
White patch that cannot be removed by scraping

White patch that cannot be removed by scraping
Usually on the anterior buccal
mucosa. Sometimes
associated with angular
chielitis. Antifungal therapy
? Leukoplakia with
superimposed candidiasis
→ Biopsy
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Histology
Mucocutaneous candidiasis
Chronic mucocutaneous candidiasis
Heterogeneous group of Candida infections of
the skin, mucous membranes, hair, and nails
that have a protracted and persistent course
despite what is usually adequate therapy.
Associated with immunologic defect (usually T-cell
defects)
Childhood
Lesions resemble ch. hyperplastic candsidiasis –
thick white plaques
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Mucocutaneous candidiasis
Endocrine candidiasis syndrome
hypothyroidism, hypoparathyroidism, Addisin’s disease,
diabetes mellitus
Iron deficiency anemia
The endocrine abnormalities may develop months or

even years after the onset of the candidal infection
Candidiasis and HIV

The most common intra-oral manifestation of HIV infection
Not diagnostic for AIDS
AIDS in 2 years
In 90% of AIDS patients
Pseudomembranous
Erythematous
Angular cheilitis
Exfoliative cheilitis
Candida-associated palatal papillary hyperplasia
Hyperplastic
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Candidiasis and HIV
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Lichen Planus
Chronic inflammatory disorder affecting
stratified squamous epithelia
• Oral mucosa
• Skin
• Vulvar and vaginal mucosa
• Glans penis
• Scalp (resulting in alopecia)
• Nails
Lichen Planus
Skin:
Purple, pruritic papules
Flexor surfaces of the extermities
Wickham’s striae – fine, lacelike
network of white lines
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Lichen Planus
Erasmus Wilson 1869 lichen = ‫חזזית‬
Oral Lichen Planus

T cell-mediated autoimmune disease –
Auto-cytotoxic CD8+ T cells trigger apoptosis of oral epithelial cells
Unknown Antigenic stimulus
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Oral Lichen Planus
Antigenic stimulus
Exogenous, endogenous
Langerhans cells and Factor XIIIa dendrocytes increase

Associated with antigenic challenge
Endothelium upregulates adhesion molecules (ICAM, ELAM)

Induced by resident macrophages, langerhans cells and dendrocytes
T-lymphocytes recruited
Through receptors to endothelial adhesion molecules
Basal keratinocytes neoexpress ICAM and lymphocytes attach

Through lymphocytes receptors to ICAM
Basal keratinocytes undergo apoptosis

Through lymphocytes- derived cytokines
Hyperkeratosis
Enhanced membrane adhesion – reduced desquamation
Oral Lichen Planus

Prevalence rate 0.5% - 2.2%
Age: 30 - 60 years (middle-aged adults)
Women > Men (3:2)
In the majority of instances:

Cutaneous lesions are self-limiting
Oral lesions are chronic, rarely undergo
spontaneous remission, are potentially
premalignant and are often a source of morbidity.
Furthermore, oral lesions, unlike cutaneous
lesions, are difficult to palliate
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Oral Lichen Planus
Histopathology
Normal epithelial maturation pattern
Jagged, spindly rete

ridges
Basal cell liquefaction

degeneration
Superficial band-like infiltrate of T

lymphocytes
Classic LP
Compatible with LP – Lichenoid lesion
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Oral Lichen Planus
Clinical Features:
Reticular
Erythematous (atrophic)
Erosive (ulcerated, bullous)
Posterior buccal mucosa
Tongue (mainly the dorsum)
Gingiva
Labial mucosa, and vermilion of the lower lip
Oral Lichen Planus

Reticular
A network of connecting and overlapping lines, papules or plaques

Widespread disease.
Asymptomatic
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Oral Lichen Planus
Reticular
Papular Keratotic Lichen Planus
Plaque like lesions
Oral Lichen Planus

Reticular
Papular Keratotic Lichen Planus
Plaque like lesions
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Oral Lichen Planus
Erythematous (atrophic)
Oral Lichen Planus

Erosive (ulcerated, bullous)
The erosive lesions hardly ever remit

spontaneously and may lead to
confusion with other autoimmune
mucosal, vesiculo-erosive diseases,
which share similar clinical features
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Oral Lichen Planus
Gingival Lichen Planus
Up to 10% of patients with OLP have the disease confined to the
gingiva, typically with atrophic and erosive lesions resulting in
desquamative gingivitis
Oral Lichen Planus

Extraoral manifestations
15% - develop cutaneous lesions
develop within several months after the appearance of the oral
lesions, and the severity of the oral lesions does not seem to
correlate with the extent of cutaneous involvement
Genital lesions developing in 20% of women with
OLP (vulvovaginal-gingival syndrome)
Penogingival syndrome
Scalp – alopecia
Esophageal LP
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Oral Lichen Planus
Association with hepatitis C virus
(HCV)
HCV infection is more frequently found in
patients with erosive OLP than in patients
with non-erosive OLP.
HCV was shown to occasionally replicate in
oral lichen planus tissue
Oral Lichen Planus

Diabetics who develop OLP have an
increased frequency of atrophic erosive
lesions and a greater proportion of lesions
on the tongue
Psychological factors, anxiety, depression, psychic
disorders
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Oral Lichen Planus
Oral lichenoid reactions
Eruptions in the oral cavity that have an identifiable

etiology and that clinically and histologically
resemblance

Dental restorative materials including
amalgams, composite resins, cobalt and gold,
Drug-induced oral lichenoid reactions

(NSAID,ACE…)
Chronic graft-versus-host disease (cGVHD)
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Graft-versus-host disease - GVHD
GVHD arises in recipients of allogeneic
hematopoietic stem cell or bone marrow
transplantation.
Due to donor T-lymphocytes’ reaction to minor
histocompatibility tissue antigen expression by
recipient cells.
Lichenoid reactions and GVHD can not be differentiated from

OLP on a histologic basis
GVHD – Oral lichenoid lesions in 80% of patients
Increased risk for developing oral SCC
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Propanolol
Approach
• Allergy - testing to identify agent
• Eliminate local factors, replace
restorations
• Replace suspected medication
Isothiazide
• Topical treatment as in OLP
Oral Lichen Planus
Malignant potential
Squamous cell carcinoma
Around 1% over 5 years
Independent of the clinical type of OLP and
therapy administered
Lichenoid dysplasia, a premalignant condition
with lichenoid features. Often display
erythematous and erosive lesions clinically
identical to OLP lesions
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Oral Lichen Planus
Malignant potential
Given the uncertainty of the premalignant nature of
OLP and the fact that early detection of oral
cancer results in improved survival, it seems
prudent to monitor all patients with OLP carefully
and over the long-term
Oral Lichen Planus

Diagnosis
Biopsy
to confirm the clinical diagnosis
to exclude dysplasia and malignancy.
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Oral Lichen Planus
Treatment
• Follow-up
• Corticosteroids
• Immunosuppressive agents
• Retinoids
• Phototherapy
Relief can be achieved in the majority of patients with

topical corticosteroids alone or in combination with other
immunomodulatory topical agents
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Lupus Erythemathosus
LE is a multisystem autoimmune disease
Young women
Ranges from mild cutaneous lesions and ⁄ or
arthritis to renal failure or intense nervous,
cardiac and haematological disturbances
• Systemic lupus erythematosus (SLE)
• Cutaneous lupus erythematosus
Chronic CLE (Discoid LE)
Subacute CLE
Acute CLE
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Systemic lupus erythematosus
SLE is an autoimmune disease in which organs and cells
undergo damage mediated by tissue-binding
autoantibodies and immune complexes.
Women of child-bearing years 90%
Circulating autoantibodies –
Antinuclear antibodies – 98%
Anti double strand DNA – 70%
Etc.
Systemic Lupus Erythemathosus

95% Systemic: Fatigue, malaise, fever, anorexia, weight loss
95% Arthralgias/myalgias
60% Nonerosive polyarthritis
80% Cutaneous
40% Oral ulcers
85% Hematologic
25% Nephrotic syndrome
60% Neurologic
60% Cardiopulmonary
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Classic symptom of lupus is a
“butterfly” facial rash
Doctors in the 1800s named the
disease lupus, meaning “wolf,”
because they thought the hallmark
facial rash looked like the bite of a
wolf. The rash is red or pink, and it
can be raised or flat. It generally
covers both cheeks and crosses the
nose. It may extend to the chin and
ears. While this rash has led to the
disorder's name, it only occurs in
20% of patients. Rashes may also
appear on the arms, hands, chest, or
other areas exposed to the sun
A. Systemic lupus erythematosus showing prominent, scaly, malar erythema.

Involvement of other sun-exposed sites is also common. B. Acute LE on the
upper chest demonstrating brightly erythematous and slightly edematous
papules and plaques.
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5-25% develop oral lesions - mild
Palate, Buccal mucosa, Gingiva, Cheilitis
Ulceration, erythema, keratosis
Discoid Lupus Erythematosus

Chronic Cutaneous LE
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Predilection sites of cutaneus lupus erythematosus
Chronic Cutaneous Lupus Erythematosus
This chronic, indolent skin disease is
characterized by sharply marginated, scaly,
infiltrated, and later atrophic red ("discoid")
plaques, usually occurring on habitually
exposed areas
This disorder, in most cases, is purely
cutaneous without systemic involvement.
However, CCLE lesions may occur in SLE.
AGE OF ONSET: 20-45

Females > males.
Can be precipitated by sunlight.
Lesions last for months to years. Usually no
symptoms, sometimes slightly pruritic or smarting
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Oral manifestations
Erythematous eroded plaques

Oral manifestations
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Course and Prognosis
Lesions may heal spontaneously in one area and appear in another

Healing – atrophy, scarring, hypo/hyperpigmentation
1 to 5% may develop SLE

with localized lesions, complete remission occurs in 50%
with generalized lesions, remissions are less frequent <10%
CCLE lesions may be the presenting cutaneous sign of SLE.
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Frictional keratosis
Chronic mechanical irritation
Normal hyperplastic response
Reversible after elimination of trauma
Frictional keratosis is not a premalignant lesion
Chronic mechanical irritation
Normal hyperplastic response
Reversible after elimination of trauma
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Chronic cheek bite
Morsicatio Buccarum
Linea alba
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Smokeless tobacco keratosis
Snuff pouch
Snuff dipper’s lesion
Spit tobacco keratosis
Ready absorption of nicotine and other molecules through the oral mucosa

Painless loss of gingival
and periodontal tissues
Dental caries
Occlusal wear
Stain
Develops in 1-5 years of use

Confined to the area in direct contact
Typically – thin gray or gray-white (translucent) plaque with borders bland into
the surrounding mucosa, sometimes – peripheral erythema
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Streching the mucosa reveal a pouch (snuff pouch)

Histopathology;
Nonspecific
The epithelium is hyperkeratinized and
acanthotic with or without inta-cellular
edema of the glycogen-rich superficial
cells.
Epithelial dysplasia- uncommon or mild

Malignant potential – low (X4 than non-users)
Without microscopic evidence of dysplasia keratosis are not treated
Habit cessation lead to normal mucosa appearance (within 2-6 weeks) in 98%
of the cases.
Whenever the lesion remains it should be considered as leukoplakia
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• X 4.2 risk than in non-users

BUT
• Lower risk than in smoking- related leukoplakia
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Concept of precancer
In longitudinal studies, areas of tissue with certain
alterations in clinical appearances identified at the first
assessment as precancerous’ have undergone
malignant change during follow-up.
Some of these alterations, particularly red and white
patches, are seen to co-exist at the margins of overt oral
squamous cell carcinomas.
A proportion of these may share morphological and
cytological changes observed in epithelial malignancies,
but without frank invasion.
Some of the chromosomal, genomic and molecular
alterations found in clearly invasive oral cancers are
detected in these presumptive precancer’ or
premalignant’ phase[s]..
Epithelial precursor lesions

World Health Organization. World Health Organization Classification of
Tumours. In: Barnes L, Eveson JW, Reichart P, Sidransky D, eds.
Pathology & Genetics. Head and Neck Tumours. Lyon: International
Agency for Research on Cancer (IARC) IARC Press, 2005; 177–9.
Potentially malignant disorders

S. Warnakulasuriya, Newell. W. Johnson, I. van der Waal.
Nomenclature and classification of potentially malignant disorders of
the oral mucosa. J Oral Pathol Med. 2007
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Precancerous lesion is ‘a morphologically altered
tissue in which oral cancer is more likely to occur than
in its apparently normal counterpart’
Precancerous condition is ‘a generalized state

associated with a significantly increased risk of cancer’.

Precancerous lesions Precancerous conditions
Leukoplakia Submucous fibrosis
Erythroplakia Actinic keratosis
Palatal lesion Lichen planus
associated with Discoid lupus
reverse smoking erythematosus
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Leukoplakia
WHO 1997
A predominantly white lesion of the oral mucosa that
cannot be characterized as any other definable lesion.
Clinicians extend that definition by adding that leukoplakia is “nonwipeable,”
which facilitates the distinction between leukoplakia and pseudomembranous
candidiasis
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Leukoplakia
S. Warnakulasuriya, Newell. W. Johnson, I. van der Waal.
J Oral Pathol Med. 2007
The term leukoplakia should be used to recognize white
plaques of questionable risk having excluded (other)
known diseases or disorders that carry no increased risk
for cancer.
Leukoplakia
Clinical types
Homogeneous
Thin
Thick
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Leukoplakia
Clinical types
Homogeneous
Thin
Thick
Non-homogeneous
Leukoplakia
Non-homogeneous leukoplakia
Speckled: mixed, white and red, but retaining
predominantly white - Erythroleukoplakia
Nodular: small polypoid outgrowths, rounded red or white
excrescences;
Verrucous: wrinkled or corrugated surface appearance.
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Leukoplakia
Epidemiology
Global prevalence of 2–3%.
Leukoplakia
Clinical features
Age: >40 years (average 60y)
Male>Female (3:1)
Tobacco use
Location:
25% buccal mucosa,
20% on the lower gingiva,
10% on the tongue and floor of mouth,
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Leukoplakia
Leukoplakia is a clinical term
It must be noted that oral epithelial dysplasia has no

specific clinical appearance and the term should not be
used as a clinical descriptor of a white lesion.
Oral Leukoplakia
Histologic spectrum
Hyperkeratosis
Dysplasia
Carcinoma in situ Invasive cancer
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Leukoplakia
Hyperplasia (hyperkeratosis) - Increased cell number
in the spinous layer – acanthosis
in the basal/suprabasal layer – basal cell hyperplasia
Regular stratification, no atypia
Leukoplakia
Dysplasia, architectural
disturbances accompanied by
cytologic atypia
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Leukoplakia
Dysplasia
basal-cell hyperplasia
bulbous rete ridges
loss of polarity of basal cells
abnormal keratinocyte stratification
Increased nuclear:cytoplasmic ratio
nuclear hyperchromatism
pleomorphism
abnormal keratinization
abnormally increased numbers of
mitoses and suprabasal mitoses
Leukoplakia
Mild dysplasia
Architectural disturbance limited to the lower third of the epithelium
accompanied by cytological atypia
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Leukoplakia
Moderate dysplasia
Architectural disturbance extending into the middle third of the epithelium
accompanied by cytological atypia.
Leukoplakia
Severe dysplasia
Architectural disturbance associated with cytological atypia extending
greater than two thirds of the epithelium.
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Leukoplakia
Carcinoma in-situ
Full thickness of architectural abnormalities associated with pronounced
cytological atypia. Atypical mitotic figures and abnormal superficial
mitoses.
Malignant transformation has occurred but invasion is not present
Hyperplasia – hyperkeratosis – 80%

Dysplasia – 12%
Carcinoma in-situ and invasive cancer – 8%
65
The recognition of these features is subjective.
There is wide variation in the degree of
interexaminer agreement and intraexaminer
reproducibility in the diagnosis
Oral leukoplakia
Outcome
40% will reduce in size or disappear, an event
often, but not always, associated with cessation
of tobacco use.
Develop OSCC a rate of less than 2% per annum.
66
Oral leukoplakia
malignant transformation
Size
Oral subsite
Clinical subclassification
Degree of epithelial dysplasia
Oral leukoplakia
Size
67
Oral leukoplakia
Size
Oral subsite
High-risk site
Non high-risk site
Oral leukoplakia
Size
Oral subsite
High-risk site
68
Oral leukoplakia
Size
Oral subsite
Homogenous Non-
Non-homogenous
Oral leukoplakia
Size
Oral subsite
Degree of epithelial dysplasia
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Oral leukoplakia
4.4-17.5% 3-6%
• gender – women
• age - older patients
• nonsmokers
• type - idiopathic non homogenous
• long duration
• site - ventral tongue, floor of mouth
• histology - epithelial dysplasia
• candida ?
Oral leukoplakia
In the floor of the mouth

16-
16-39%
ventral tongue
+
women 47%
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Erythroplasia - Erythroplakia
The oral mucosal lesion with the greatest potential for
malignant transformation in the mouth.
A fiery red patch that cannot be characterized clinically or pathologically as
any other definable disease.
Almost all cases - significant epithelial dysplasia
carcinoma in-situ, and invasive cancer
71
Floor of mouth, tongue, and soft palate
Proliferative verrucous leukoplakia

PVL is an aggressive form of oral leukoplakia with considerable
morbidity and strong predilection to malignant transformation
The condition develops initially as leukoplakia that progressively
becomes a wide multifocal disease with gross exophytic features.
Age – average – 62 years

Women (ratio, 4:1)
Multiple oral sites are affected
High recurrence rate and histologic
progression
Many cases are resistance to all
forms of treatments
72
Aids in Diagnosis
• Toluidine blue – Vital stainig

• Exfoliative cytology
• Brush biopsy
• Light-based detection systems
• Molecular markers
• Biopsy
Multistep hypothesis
Of oral tumorgenesis
Hyperkeratosis
Dysplasia
Carcinoma in situ
Invasive cancer
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Multistep hypothesis Tobacco
Of oral tumorgenesis Initial genetic insult
EGFR, telomerase
3p, 9p LOH activation
COX-2 upregulation
RAR-b, p16 promoter methylation
Genomic instability
4q, 8p, 11q, 13q, 14q, 17p LOH
Cyclin D1
overexpression
P53 mutation Increased proliferation

8q, 13p, 18q
LOH
Increased frequency of
mutations
Califano J et al. Cancer Res 56: 2488-2492. 1996

Lippman SM, Sudbo J, Hong WK. J Clin Oncol 23(2): 346-56. 2005
Vital stain - Toluidine blue
Toluidine blue (also known as tolonium chloride) is a vital dye that

may stain nucleic acids and abnormal tissues
74
Vital stain - Toluidine blue
Protocol for staining

1% Toluidine Blue, 30 sec
Rinse with tap water
2% acetic acid
Rinse with tap water
Exfoliated cytology
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Brush biopsy – Oral CDx
Atypical Negative
Positive
Follow-
Follow-up
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Brush biopsy – Oral CDx
Several reports, however, raised the issue of the low specificity
because of the large number of false positive cases. In addition,
reports of false negative have also been published, which raise
the concern that the use of the brush will delay diagnosis.
Absence of cellular atypia does not exclude the malignant
potential of the lesion. The brush biopsy is based solely on
morphological changes; therefore, false negative can be
anticipated.
Sudbo J, Kildal W, Risberg B, Koppang HS, Danielsen HE, Reith A DNA content as a
prognostic marker in patients with oral leukoplakia. N Engl J Med 2001; 344:1270–1278.
DNA content
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Ploidy and cancer
Alterations in the number of chromosomes which is defined
as aneuploidy, is consistently observed in virtually all
cancers and is shown to be the earliest and most distinctive
pre-neoplastic genotype
Multicolour-fluorescence in situ hybridization of an aneuploid

non-small cell lung cancer. Metaphase chromosomes are
stained in 23 different colours
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Light-based detection
systems
Tissue reflectance (ViziLite Plus, MicroLux DL)
Narrow-emission tissue fluorescence (VELscope)
Chemiluminescent lighting
ViziLite- new technology
80
systems
systems
81
Chemiluminescent lighting
ViziLite- new technology
Improve visualization of mucosal abnormality
Detection of early transformation
When used as a screening adjunct with standard visual oral
examination, provides additional visual information.
Studies underway to explore clinical significance, predictive
value
Kerr AR, Sirois DA, Epstein Clinical evaluation of chemiluminescent lighting: an adjunct for oral mucosal
examinations.J Clin Dent. 2006;17(3):59-63
Needs to be validated!
Oral leukoplakia
Treatment
Arrive at a definite diagnosis, clinical and histopathological
Biopsy should be taken from the clinically most suspicious area
Sometimes, multiple biopsies are required
Simple hyperkeratosis and Mild dysplasia – follow-up every 6 months

Moderate dysplasia and severe dysplasia – complete surgical removal
Long-term follow-up
Smoking cessation
82
Oral leukoplakia
Treatment
Smoking cessation
Chemoprevention - topical bleomycin, systemic cisretinoic acid,
and systemic lycopene
To date there is no evidence of effective nonsurgical treatment in

preventing progression of dysplastic lesions to SCC. Some
treatments were at least temporarily effective
83
Oral Submucous Fibrosis
Chronic progressive, scarring

of the oral mucosa
India, South-East Asia
Etiology: quid chewing (pan
masala genetic, nutritional,
autoimmune
Does not regress with habit
cessation
Chronic progressive, scarring

of the oral mucosa
India, South-East Asia
Etiology: quid chewing (pan
masala genetic, nutritional,
autoimmune
Does not regress with habit
cessation
Quid: areca nut, slacked lime, tobacco, sweeteners wrapped in betel leaf
84
Mucosal rigidity caused by fibroelastic
hyperplasia and modification of the
superficial connective tissue.
Clinical features:
Trismus
Oral burning
Buccal, retromolar, soft palae
Diffuse hyalinization of subepithelial

stroma with few, small fibroblastic
nuclei and with pigment
incontinence from the overlying
epithelial melanin

Malignant transformation
In India
• 10y follow up - 2-3%
• 15y follow up - 4.5%
• >17y follow up - 7.6%
85
Hairy Leukoplakia
EBV-associated disease that typically occurs on the lateral
border of the tongue of HIV-infected individuals as a consequence of
reactivation of the virus. Also in other immunocompromized patients
Rarely in immunocompetent individuals
Prevalence of OHL of HIV-infected adults varies from 0.42 to 38%
Male > Female
86
Hairy Leukoplakia
EBV-associated disease that typically occurs on the lateral
border of the tongue of HIV-infected individuals as a consequence of
reactivation of the virus. Also in other immunocompromized patients
Rarely in immunocompetent individuals
Prevalence of OHL of HIV-infected adults varies from 0.42 to 38%
Male > Female
PAS
Hairy Leukoplakia
The occurrence of OHL is usually associated with a low CD4+ count
and high HIV viral load
Candida with no Baloon cells

inflammation
87
Hairy Leukoplakia
Asymptomatic
No malignant potential
Rarely requires treatment
Antiviral therapy
Candida with no Baloon cells

inflammation
88
Nicotine Stomatitis
Smoker’s Palate
Reddened area and slowly progresses to a white, thickened, and fissured

appearance. The palate has numerous minor salivary glands. They become
swollen and the orifices become prominent, giving the tissue a speckled
white and red appearance. Patients are usually asymptomatic.
Nicotine Stomatitis
Smoker’s Palate
almost exclusively observed in individuals who smoke tobacco

in pipe and reverse cigarette smokers and less often in cigarette and cigar
smokers.
asymptomatic or mildly irritating
89
Nicotine Stomatitis
it is generally not
associated with dysplastic or
malignant changes.
The exception to this is in individuals who reverse smoke.

Reverse smoking is common in some parts of the Caribbean and
Southeast Asia. The concentrated heat and chemicals increase the
potential for malignant change.
90
Geographic Tongue
Benign Migratory Glossitis
A common benign condition affecting mainly
the tongue
Multiple, well demarcated zones of erythema
Atrophy of the filiform papillae, surrounded
by slightly elevated scalloped border
1-3% of the population
Female>male (2:1)
Usually asymptomatic
Sometimes burning sensation
Geographic Tongue
Migrating lesions
Solitary and multiple lesions
91
Geographic Tongue
Association with fissured tongue
Geographic Tongue
Histology:
Hyperparakeratosis
Spongiosis
Acanthosis
Elongation of the rete-ridges
Collection of neutrophils (Munro abscess)
Psoriasiform mucositis
92
Migratory Stomatitis
Erythema Migrans
Geographic Stomatitis
Very infrequently erythema migrans may
occur on oral mucosa other than the
tongue
Asymptomatic
Erythema Migrans
Not to be mistaken with –
Erythema chronicum migrans

Lyme disease is spread by the bite of the tiny tick
Infectious disease - Borrelia
Most people who get Lyme disease will show a rounded red
rash at the place the tick bit them within a month.
The rash is called erythema migrans (formerly erythema
chronicum migrans). The rash may be solid red, form a ring or
multiple rings called a "bulls-eye" appearance. The rash is
commonly about four inches across when seen, but often covers
large areas of the body.
Erythema migrans can last for a few days or for more than a
month
Lyme disease include flu-like symptoms, malaise, low-grade
fever, fatigue, headaches and muscle or joint aches and pains
93
Psoriasis
A chronic condition characterized by an
eruption of sharply demarcated,
erythematous papules and plaques with
overlying silvery scale.
The classic distribution is on the scalp,
elbows, and knees.
Genetic predisposition.
Environmental triggers:
dry, cold weather, infection (HIV, strep
throat), trauma to the skin (Koebner’s
phenomenon), drugs (lithium, beta-blockers,
NSAIDs), and emotional stress
Psoriasis
Increased epidermal proliferation
where skin cell turnover is increased
sevenfold.
The cells in the stratum corneum
that are usually shed do not have
time to shed properly and their
accumulation leads to the physical
finding of scaling on the
lesions. Nuclei are retained in the
stratum corneum due to decreased
keratinocyte transit time with
shortening of cell cycle time.
94
Psoriasis
Nonspecific tongue lesions are significantly more
frequent in psoriatic cases
Geographic tongue
Fissured tongue
BMC Dermatology 2004, 4:16
95
White Hairy Tongue
Marked accumulation of keratin on the filliform

papillae.
Increase keratin production
Decrease normal keratin desquamation
0.5% of adults
Black Hairy Tongue

Prevalent in heavy smokers
Antibiotic therapy
Poor oral hygiene
General debilitaion
Radiation therapy
Oxidizing mouthwashes, antacids
Overgrowth of fungal or bacteria
Black hairy tongue – the result of pigment producing bacteria, tobacco stain
Biopsy not indicated
96
Various white and red lesions
97
Physical Injuries
Physical Injuries
Mechanical
Chemical
Thermal
Hematomas in the floor of the mouth following periodontal surgery
98
Measles – Rubeola
‫חצבת‬
Koplik spots, early
small, white spots (often on a
reddened background) that occur
on the inside of the cheeks early
in the course of measles
Buccal, labial mucosa
Pharyngitis (measles)
Macular Hemangioma
Vascula hamartoma Telangiectasia tongue and lips
99
Purpura, Petechia, Ecchmosis
Patient with AML
Purpura, Petechia, Ecchmosis
Palatal petechiae, erosions and a greyish exudate in a patient with

infectious mononucleosis
100
101

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White and Red Lesions

in the oral mucosa

Dr. Avraham Hirshberg MD, DMD

White and Red Lesions

The body of the tongue consists of a mass of interlacing bundles of

Aquired lesions Candidiasis

Self inflicting lesions Frictional hyperkeratosis

White and Red Lesions

Developmental (congenital) lesions

Developmental (congenital) lesions

Developmental (congenital) lesions

“Dental lamina cysts of the newborn"

Developmental (congenital) lesions

“Dental lamina cysts of the newborn"

A common condition of unknown cause

Sulfonamides decrease neutrophil Candida intracellular

In the tissue all fungal cell walls are

Periodic acid–Schiff (PAS) stain the

Gram stain (most fungi, except

Symptoms: burning pain,

Can affect infants

• Acute atrophic candidiasis (antibiotic sore mouth)

• Central papillary atrophy of the tongue,

In the past: developmental defect

• Central papillary atrophy of the tongue,

• Central papillary atrophy of the tongue,

Angular cheilitis - Perlech

Cheilocandidiasis – angular cheilitis and peri-oral skin (ch. Lip licking..)

Erythema and petechial hemorrahge,

Biopsy – seldom show candidal infection

Chronic hyperplastic candidiasis

The endocrine abnormalities may develop months or

Candidiasis and HIV

Oral Lichen Planus

Langerhans cells and Factor XIIIa dendrocytes increase

Endothelium upregulates adhesion molecules (ICAM, ELAM)

Basal keratinocytes neoexpress ICAM and lymphocytes attach

Basal keratinocytes undergo apoptosis

Oral Lichen Planus

In the majority of instances:

Normal epithelial maturation pattern

Jagged, spindly rete

Basal cell liquefaction

Superficial band-like infiltrate of T

Compatible with LP – Lichenoid lesion

Oral Lichen Planus

A network of connecting and overlapping lines, papules or plaques

Oral Lichen Planus

Oral Lichen Planus

The erosive lesions hardly ever remit

Oral Lichen Planus

Oral Lichen Planus

Eruptions in the oral cavity that have an identifiable

Oral lichenoid reactions

Drug-induced oral lichenoid reactions

Chronic graft-versus-host disease (cGVHD)

Lichenoid reactions and GVHD can not be differentiated from

GVHD – Oral lichenoid lesions in 80% of patients

Increased risk for developing oral SCC

Oral Lichen Planus

Oral Lichen Planus

Relief can be achieved in the majority of patients with

Systemic Lupus Erythemathosus