PRECANCEROUS LESIONS:-Premalignant lesions are morphologically

atypical tissue which appear abnormal when viewed under the

microscope, and which are more likely to progress to cancer than
normal tissue.

World Health Organization (WHO) classification for the pathological

diagnosis of oral premalignant lesions, dysplasia, which is graded as
mild, moderate or severe, and carcinoma in situ (CIS), which is a non-
invasive carcinoma, are classified as precursor lesions of oral squamous
cell carcinoma.
An oral lesion (which includes aphthous ulcers) is an ulcer that occurs
on the mucous membrane of the oral cavity. ... Oral lesions may form
individually or multiple lesions may appear at the same time. Once
formed, it may be maintained by inflammation and/or secondary
infection.
DEFINITION:

• Precancerous lesion: A morphologically altered tissue in which cancer

is more likely to occur than in its apparently normal counter
part.[WHO,1978]
• Precancerous Condition: A generalized state associated with a
significantly increased risk of cancer.[WHO,1978]
Premalignant condition

• ‘It is a group of disorders of varying etiologies, usually tobacco

characterized by mutagen associated, spontaneous or hereditary
alterations or mutations in the genetic material of oral epithelial cells
with or without clinical and histomorphological alterations that may
lead to oral squamous cell carcinoma transformation.’[WHO, 2005]
CLASSIFICATION:Premalignant Lesions:

• Leukoplakia
• Proliferative Verrucous Leukoplakia
• Intraepithelial carcinoma (Carcinoma in situ)
• Erythroplakia
• Palatal changes associated with reverse smoking
Premalignant Conditions:

• OSMF
• Lichen Planus (erosive type)
• Sideropenic dysphagia (Plummer- Vinson Syndrome)
• Syphilis – Syphilitic glossitis
• Discoid lupus erythematosus
• Xeroderma pigmentosum
• Epidermolysis Bullosa
Introduction
• Premalignant / Precancerous / Potentially malignant oral lesions
involve
• Skin lining of the mouth (known as the epithelium)
• At risk for transforming into an oral cancer
• Difficult to predict which lesions will transform and how long it will
take
Etiopathogenesis
• Salivary thiobarbituric acid reacting substance & advanced glycation
end products (Vlková et al)
• Salivary advanced oxidation products
• Vascular endothelial growth factor
• Sialotransferase and Neuraminidase
• Expression of CK8 & CK18 (Nanda et al)
• Expression of Podoplanin & ABCG2 (Feng et al)
• Prevalence of p53 mutations(Qin et al)
• Salivary IL-8 concentration(Puniyani et al )
Risk Factors
• Age group ≥ 40
• Poor oral hygiene ; Genetic theory (???)
• Habits such as :
• Tobacco (Smoking, Smokeless or inhaled)
• Pan masala, Betel nut quid
• Heavy alcohol use
• Although such lesions can also be found in younger individuals and/or
those without classic risk factors.
Clinical Features
• Lesion ≥ 14 days require a diagnostic biopsy even after irritant is removed
• Anatomical Location:
- Epithelial dysplasia rate:
Buccal mucosa -21.8%
Palate - 13.7%
Floor of the mouth -12.3%
-Leukoplakia :
Mand. Mucosa & Sulcus - 25.2%
Buccal mucosa- 21.9% (Shafer and Waldron)
Age: Mean age for diagnosis: 37 – 59
<5% : < 30 yrs
Sex: Epithelial dysplasia: Male Oral SCC
: Decrease in M:F rate
DYSPLASIA:
• Definition: It comprises a loss in the uniformity of individual cells, as
well as loss in their architectural orientation.
• It is characteristically associated with protracted chronic irritation or
inflammation.
Histomorphologicalchanges of dysplasia
• Loss of basal cell polarity
• Parabasilar hyperplasia
• Increased nuclear:cytoplasmic ratio
• Drop-shaped rete ridges
• Abnormal epithelial maturation
• Increased mitotic activity
• Mitoses in the superficial half of the surface epithelium
• Cellular pleomorphism
• Nuclear hyperchromaticity
• Enlarged nucleoli
• Loss of cellular cohesiveness
• Individual cell keratinization in the spinous cell layer
Leukoplakia
• DEFINITION: “A white patch or plaque in the oral cavity which cannot
be scrapped off or stripped off easily & more over, which cannot be
characterized clinically or pathologically as any other disease”
(WHO 1978) [Greek : – “leucos” - white &“plakia” – patch ]
• “ A predominantly white lesion of the oral mucosa that cannot be
characterized as any other definable lesion.”
(WHO,2012)
LEUCOPLAKIA
Classification of leukoplakia
• Based on CLINICAL TYPE:
Homogenous : Smooth, Furrowed, Ulcerative
Non homogenous : Ulcerative, Verrucous, Speckled
• Based on ETIOLOGY:
Tobacco associated
Idiopathic
• Based on EXTENT:
Localized
Diffuse
(Axell & Pindborg et al 1983)
Classification of leukoplakia
• Based on risk of MALIGNANT TRANSFORMATION
High risk sites
Floor of mouth
Lateral/ventral surface of tongue
Soft palate
Low risk sites
Dorsum of tongue
Hard palate
• Based on HISTOLOGY:
Dysplastic
Non dysplastic
Sharp’s staging of leukoplakia
• Stage I - Earliest lesion-non palpable, faintly translucent, white
discoloration
• Stage II - Localized or diffuse, slightly elevated plaque of irregular
outline. It is opaque white & may have a fine granular texture
• Stage III - Thickened white lesion showing induration and fissuring
Clinical presentation
• Solitary or multiple, “White patches”
• Varies from a non-palpable faintly translucent white area to a thick
fissured, papillomatous or indurated Lesion
• 70% in buccal mucosa, commissural areas, followed by lower lip, floor
of the mouth, palate & gingiva
SYMPTOMS
• Feeling of increased thickness of mucosa
• Ulcerated or nodular type: c/o burning sensation
• Enlarged cervical lymph nodes (metastasis)

Homogeneous/ Leukoplakia Simplex

Speckled/Nodular
Ulcerative
Histopathological features
• Keratinization pattern
• Thickness of epithelium
• Changes in underlying connective tissue

Waldron & Shafer (1975)

-80% lesions show benign hyperkeratosis with/without acanthosis
-Dysplastic changes typically begin in basal & parabasal zones of
epithelium
Conservative management
• Elimination of etiological factor
• Restraining from smoking or chewing tobacco
• To remove sharp broken down teeth
• Correction & replacement of overhanging or faulty metal restorations
with a metal bridge
CHEMOPREVENTION
1) Isoretinoin / 13- cis- retinoic acid
2) Beta carotene -30mg TID
3) Topical Bleomycin – 0.5-1% solution/2wks
4) 5-Fluorouracil & Cisplatin
Surgical Excision:
• entire lesion excised if it is >1cm in size, following modalities used:
a) Scalpel – surgical stripping
b) Cryosurgery – with liquid nitrogen
c) Electrocautery
d) Laser ablation
Erythroplakia
• DEFINITION: “Any lesion of the oral mucosa that presents as a bright
red velvety patch or plaque, which cannot be characterized clinically
or pathologically as any other recognizable condition. [WHO].
Reported by Querat in 1911
CLASSIFICATION
• Clinical variants
1. Homogenous erythroplakia
2. Erythroplakia interspersed with patches of leukoplakia
3. Granular or Speckled erythroplakia

- Smooth and granular/nodular, well defined

- May have an irregular, red granular surface interspersed with white or
yellow foci
- Soft on palpation
Management
• Biopsy should be performed
• Treatment guided by histopathologic diagnosis
• Recurrence , multifocality common
• Careful long term follow up
Intraepithelial carcinoma (Ca in Situ)
• Most severe stage of epithelial dysplasia
• Striking feature – dysplastic epithelial cells do not invade into
connective tissue
• Common among elderly, with a male predilection
• Present as white plaques or ulcerated, & reddened areas
• Site – floor of the mouth, tongue, lips
• Has combined features of leuko & erythroplakia
Treatment
• No accepted treatment
• Surgical excision, irradiation & cauterization
Oral lichen planus
• Definition : “A common chronic immunologic inflammatory
mucocutaneous disorder that varies in appearance from keratotic
(reticular or plaque like) to erythematous and ulcerative, affecting the
stratified squamous epithelium”
• Coined by E Wilson ( British physician) 1869
• Lichen – latin for primitive plants (symbiotic algae & fungi)
• Planus – latin for flat
Etiology & pathogenesis
• Both antigen-specific & non-specific mechanisms may be involved in
pathogenesis of OLP
• Antigen-specific mechanisms: –
antigen presentation by basal keratinocytes and
antigen-specific keratinocyte killing by CD8 + cytotoxic T-cells
• Non-specific mechanisms: –
mast cell degranulation and matrix metalloproteinase (MMP)
activation
These mechanisms may combine to cause
• T-cell accumulation in superficial lamina propria
• Basement membrane disruption
• Intra-epithelial T-cell migration &
• Keratinocyte apoptosis
Clinical features
• Lesions usually symmetrical
• Frequently affects buccal mucosa, tongue, gingiva, lip and palate
• Extra-oral mucosal involvements - anogenital area, conjunctivae,
oesophagus/larynx
• Approx 1.2% - 5.3% lesions undergo malignant changes
• Hence regular follow up mandatory
On skin
• Flat-topped purple polygonal & pruritic papular rash
Oral Cavity
Asymptomatic
• Reticular – Wickham’s striae + discrete erythematous border
• Plaque-like – Resemble leukoplakia, common in smoker
Clinical features
Symptomatic
• Atrophic – Diffuse red patch, peripheral radiating white striae
• Erosive – Irregular erosion covered with a pseudomembrane
• Bullous – Small bullae / vesicles that may rupture easily
Histology
• Shklar -3 classic microscopic features of OLP
• Overlying hyperkeratinization
• A band like layer of chronic inflammatory cells within underlying
connective tissue
• Liquefaction degeneration of basal cell zone
Diagnosis
• Oral biopsy
• Direct Immunofluorescence
Management
• Reticular type is asymptomatic & treatment often unnecessary
• Erosive type presents significant management problems
• All patients should optimize oral hygiene
• Oral candidiasis should be excluded/treated
• Cortico steroids, is the treatment of choice eg: Fluocinonide or Clobetasol
gel for 2 weeks, with 3months follow-up
• In symptomatic patients with apparent contact dental factor, patch test
with replacement of amalgam
• In those with no apparent contact factor, topical or intralesional steroid -
first line treatment. A short course of systemic steroid for more rapid
control
Oral submucousfibrosis
• DEFINITION: “It is an insidious chronic disease affecting any part of
the oral cavity and sometimes the pharynx. Although occasionally
preceded by or associated with vesicle formation ,it is always
associated with juxta-epithelial inflammatory reaction followed by a
fibro-elastic changes of the lamina propria with epithelial atrophy
leading to stiffness of the oral mucosa and causing trismus and
inability to eat.”
(J.J Pindborg and Sirsat 1966). First described by Joshi (1952) and by
Schwatz among East Indian Women.
Clinical presentation
• Common site – buccal mucosa, retromolar area, uvula, palate, etc
• Initially, pain and a burning sensation upon consumption of hot &
spicy foods
• Vesicle & ulcers
• Excessive or reduced salivation & defective gustation
• Hearing loss
• Depapillation & atrophy of tongue and uvula
• Depigmented & loss of stippling over gingiva
• Nasal tone in the voice
• Difficulty in deglutition
• Impaired mouth movements (eg, eating, whistling, blowing, sucking)
Prodromal symptoms
• Mortality/morbidity
• High rate of morbidity - progressive inability to open mouth, resulting
in difficulty eating & consequent nutritional deficiencies
• Significant mortality rate - can transform into oral cancer, particularly
SCC (7.6%)
Clinical stages
• Three stages based on physical findings:
• Stage 1: Stomatitis includes erythematous mucosa, vesicles, mucosal
ulcers, melanotic mucosal pigmentation & mucosal petechiae
• Stage 2: Fibrosis occurs in ruptured vesicles & ulcers when they heal,
hallmark of this stage
• Stage 3: Sequelae of OSMF
Leukoplakia is found in more than 25% of individuals with OSMF
Speech and hearing deficits may occur because of involvement of
the tongue and the eustachian tubes
RANGANATHAN K (2001)
• Group I : Only Symptoms, No mouth opening
• Group II : Mouth opening > 20mm
• Group III : Mouth opening < 20mm
• Group IV: Limited mouth opening, precancerous & cancerous
changes throughout mucosa
Histopathology
• Hyperkeratinized, atrophic epithelium with flattening & shortening of
rete pegs
• Nuclear pleomorphism & severe inter-cellular edema
• Finely fibrilar collagen & increased fibroblastic activity in early stage
showing dilated & congested blood vessels with areas of
haemorrhage
• Advanced stage shows “homogenization” and “hyalinization” of
collagen fibers (important feature)
• Degeneration of muscle fibers and chronic inflammatory cell
infiltration in the connective tissue
Management
• 1. Behavioral therapy
• - Patient counseling, Stoppage of habit
• 2. Medicinal therapy
• -Hyaluronidase: Topically, shown to improve symptoms more quickly
than steroids alone
• - Mild cases – intralesional inj. Dexamethasone 4 mg to reduce
symptoms & surgical splitting / excision of fibrous bands
• - Recent study – intralesional inj. of gamma interferon 3 times a week,
improves mouth opening significantly
Emerging Trends
• HPV 16 and 18 : Cervical Carcinoma (90%)
• Oncogenes
• E6 and E7 (Tumor Supressor Proteins)
• Degradation
• (-) Apoptotic pathway in these cells
• Overproliferation
OPPORTUNITIES & BARRIERS TO PROGRESS
• Validating Histopathological criteria/ biomarkers
• Identifying C/F of premalignancy that predict higher probability of
malignant change
• Clarifying premalignant risk of lichen planus
• Comparing efficacy of conventional scalpel excision with laser excision
for control of oral leukoplakias
• Identifying an accurate biomarker for premalignant state would aid in
diagnosis
SUMMARY
• Patient presenting with Potentially malignant disorders should
undergo a careful examination to identify any causative factors, which
are best eliminated at the first stage of the treatment. However, many
patients may not have any obvious causative factor. A biopsy of the
lesion is necessary to demonstrate the histological features of the
lesion and detect any existing invasive carcinoma. Frequent
monitoring of histopathological changes is essential to obtain an
accurate assessment of histological activity of the lesion and to try to
predict its future behavior. The subsequent management of the
patient depends on how “high risk” the lesion is
REFERENCES:
• Textbook of Oral Pathology, Shafers, 1st edition.
• Dr. R.V. Subramanyam. Classification of oral lesions.
• Neville BW et al. Oral cancer and Precancerous lesions. CA Cancer J
Clin 2002;52:195215.
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