3. Potentially Malignant Disorders (1)

Oral Potentially Malignant Disorders
CONTENTS
• INTRODUCTION
• TERMINOLOGIES
• CLASSIFICATION
• INDIVIDUAL DISORDERS
- DEFINITION
- ETIOPATHOGENESIS
- CLINICAL FEATURES
- DIFFERENTIAL DIAGNOSIS
- INVESTIGATIONS
- MANAGEMENT
 REFERENCES
INTRODUCTION
• Several attempts to produce internationally accepted terminologies

and definitions of ‗oral precancer‘ have appeared in the literature.
• World Health Organizations (WHO) in 1972 subdivided
‗precancer‘ into ‗lesions‘ and ‗conditions‘ with their definitions.
World Health Organization proposed in 1978-
a) A precancerous lesion is a morphologically altered tissue in which

oral cancer is more likely to occur than in its apparently normal
counterpart.
b) A precancerous condition is a generalized state associated with a
significantly increased risk of cancer.
c) Recent working group of WHO (2005) is not in favor of such
subdivision and recommended the use of the term ‗oral potentially
malignant disorder (OPMD)‘.
d) This is mainly attributed to the recent advancement in molecular
and genetic aspects of ‗oral precancer‘.
e) But efforts to define OPMDs are few in the literature. ‗Oral
precancer‘ is ultimately colligated to oral squamous cell carcinoma
(OSCC).
f) According to the recent concepts, not all the disorders will
transform into OSCC but there are disorders among which some
may have an increased potential for malignant transformation.
g) Hence, word ‗potential‘ was recommended in the most recent
workshop of WHO held in London in 2005.
h) The word ‗potential‘ literally means ‗capable of being but not yet
in existence‘, ‗having possibility, capability or power‘, ‗the
inherent ability or capacity for growth, development or coming into
being‘.
Oral Potentially malignant disorders
• It conveys that not all lesions and conditions described under this
term may transform to cancer, rather that there is a family of
morphological alterations amongst which some may have an
increased potential for malignant transformation.
• Potentially malignant disorders of the oral mucosa are also
indicators of risk of likely future malignancies elsewhere in
(clinically normal appearing) oral mucosa and not only site-
specific predictors.
• The terminologies and concepts discussed till date in the literature

regarding OPMD are related to transformation of ‗oral mucosa‘ to
OSCC.
• To be more particular, OPMDs are directly or indirectly related to
stratified squamous epithelium of lining, masticatory or
specialized mucosa of the oral cavity.
• In another way, the OPMDs can be termed as ‗oral mucosal
potentially malignant disorders‘.
• The concept of denoting some lesions or disorders of the oral
mucosa as ‗precancerous‘ is based on the evidence that:
1. 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
2. Some of these alterations, particularly red and white patches, are
seen to co-exist at the margins of overt OSCCs
3. A proportion of these may share morphological and cytological
changes observed in epithelial malignancies, but without frank
invasion
4. Some of the chromosomal, genomic and, molecular alterations
found in clearly invasive oral cancers are detected in these
presumptive ‗precancer‘ or ‗premalignant‘ phase.
Classification of precancerous lesions and conditions (WHO 1978)

1. High Risk
1.1. Erythroplakia.
1.2. Leukoplakia.
1.3. Oral Submucous Fibrosis (OSF).
1.4. Erosive Lichen Planus.
2. Life-style Related
2.1. Smokeless Tobacco Keratosis.
2.2. Reverse Smoker‘s Palate.
2.3. Actinic Cheilitis
3. Infections
3.1. Hyperplastic Candidiasis.
3.2. Viral (HPV, HIV, EBV, HBV, HSV).
3.3. Tertiary Syphilis.
4. Immunodeficiency
4.1. Solid Organ Transplantation.
4.2. Graft Versus Host Disease.
4.3. Chronic Cutaneous Lupus Erythematous.
5. Inherited Disorders
5.1. Xeroderma Pigmentosum.
5.2. Dyskeratosis Congenita.
5.3. Epidermolysis Bullosa.
5.4. Bloom Syndrome.
5.5. Fanconi‘s Anemia.
RED AND WHITE LESIONS WITH DEFINED OR UNCERTAIN

PRECANCEROUR POTENTIAL
• Leukoplakia and erythroplakia

• Oral lesions associated with use of tobacco and alcohol
• Electrogalvanically induced oral white lesions
• Carcinoma in situ
• Oral submucous fibrosis
• Atinic keratosis ,Elastosis and Chelitis
• Discoid lupus erythematosus
• Dyskeratosis congenita
• Lichen Planus
• Lichenoid Reactions
▼ PREMALIGNANT LESIONS
Oral Leukoplakia and Erythroplakia
Oral Submucous Fibrosis
▼ IMMUNOPATHOLOGIC DISEASES
Oral Lichen Planus
Drug-Induced Lichenoid Reactions
Lichenoid Reactions of Graft-versus-Host Disease
Lupus Erythematosus
▼ ALLERGIC REACTIONS
Lichenoid Contact Reactions
Reactions to Dentifrice and Chlorhexidine
▼ TOXIC REACTIONS
Reactions to Smokeless Tobacco
Smoker‘s Palate
Oral Leukoplakia
 Leukoplakia (white patch) is the most common potentially

malignant lesion of the oral mucosa.
 Leukoplakia should be used to recognize white plagues of
questionable risk having excluded (other) known diseases or
disorders that carry no increased risk for cancer.
 Furthermore leukoplakia is a clinical term and the lesion has no
specific histology.
 It may show atrophy or hyperplasia (acanthosis) and may or may
not demonstrate epithelial dysplasia.
 It has a variable behavioural pattern but with an assessable
tendency to malignant transformation.
 In other words, leukoplakia denotes a negative diagnosis based on
exclusion criteria.
 It represents an area localized in distribution, hyperkeratotic in
nature and white in appearance due to wetting of the keratotic
patch while in contact with saliva.
 It should be stressed that the diagnosis of leukoplakia denotes
mainly, that :
• The mucosa is irritated by either mechanical, chemical or galvanic
means, and
• The mucosa is trying to adapt to the noxious stimuli by undergoing
hyperkeratinization of its surface
• Since leukoplakia is an adaptive response, offered by a viable and
healthy oral mucosa against some forms of sustained, low-grade
irritant, it is irrational to consider it as a disease entity (hence its
assumption of a negative diagnostic state).
Definable White Lesions
Hyperplastic candidiasis (candidal leukoplakia).

• When dealing with a hyperplastic epithelial lesion in which the
presence of Candida albicans is demonstrated, it is referred to as
candida-associated leukoplakia or others prefer the term
hyperplastic candidiasis.
• In the absence of clinical re-sponse to antifungal treatment, it
seems preferable to con-sider such lesion as leukoplakia (van der
Waal, 1997).
Hairy leukoplakia (Greenspan lesion).

The term ‗hairy leukoplakia‘ is a misnomer due to several reasons.
• First of all, hairy leukoplakia is a definable lesion.
• Furthermore, the lesion is not premalignant in nature.
• Therefore, the use of the term should be abandoned.
• As an alternative, the term ‗Greenspan lesion‘ has been suggested.
Tobacco-induced white lesions.

 Smoker‘s palate (leukokeratosis nicotina palati), palatal keratosis
in reverse smokers and snuff dippers lesions are clearly related to
tobacco use and, therefore, are usually listed as ‗tobaccoinduced le-
sions‘.
• These lesions are being regarded as ‗definable le-sions‘ and are
traditionally not described as leukoplakia.
• Nevertheless, some of these lesions may transform into cancer.
Tobacco-associated leukoplakia.
 The etiological role of tobacco in patients who smoke cigarettes,
cigars or pipes is less obvious.
• Therefore, preference has been given to the term ‗tobacco-
associated leukoplakia‘ (leukoplakia in smokers) over the term
‗tobacco-induced white lesions‘.
Idiopathic leukoplakia.
 One also recognizes nontobacco-associated leukoplakia
(leukoplakia in nonsmokers), often referred to as idiopathic
leukoplakia.
Viadent Leukoplakia (Sanguinaria-associated Keratosis)

• Viadent leukoplakia is a white patch or plaque, which is associated
to sanguinaria mouth rinse.
• Sanguinaria extract is a mixture of benzophenanthridine alkaloids
derived from bloodroot plant.
• According to Damm et al an increased prevalence of leukoplakia
has been observed in the maxillary alveolar mucosa in patients
using sanguinaria mouthwash.
• It seems that sanguinaria extract has a carcinogenic effect.
• Therefore, viadent leukoplakia should be considered a
premalignant lesion and mouth rinses containing sanguinaria
should be avoided until the risk for transformation into malignancy
is determined.
Epidemiology
• The prevalence of oral leukoplakia varies among scientific studies.

• A comprehensive global review points at a prevalence of 2.6%.
• Most oral leukoplakias are seen in patients over the age of 50 and
infrequently encountered below the age of 30.
• In population studies, leukoplakias are more common in men, but a
slight majority for women was found in reviews of referred
materials.
• The prevalence of this lesion in Ernakulam district (Kerala, India)
was 17 per 1,000; it was highest (61 per 1,000) among people with
mixed habits.
• The annual age adjusted incidence rate was 2.1 per 1,000 among
men and 1.3 per 1,000 among women; the highest incidence (6.0
per 1,000) was among men who both chewed and smoked.
 In two studies from India (Gupta PC et al, 1980, Silverman S et al,
1976), rather low annual malignant transformation rates of oral
leukoplakia have been reported, 0.3% and 0.06%,respectively.
 In reports from western countries, usually based on hospital
material, somewhat higher figures have been mentioned (Axell T,
1987).
 One must take the following into account, when studying
percentages of malignant transformation rates of oral leukoplakia:
• The length of observation period
• The type of study population
• The therapeutic approach.
 On the basis of the lowest reported annual malignant
transformation rate of oral leukoplakia, it can be calculated that
patients with oral leukoplakia carry a five fold higher risk of
developing oral cancer than controls.
 Recently the role(s) of dietary factors in determining the
precancerous nature of oral leukoplakia among tobacco habitues
revealed interesting results (Gupta PC et al, 1998).
• A population-based case control study in the Bhavnagar district,
Gujarat, India estimated nutrient intake in blinded, house-to-house
interviews.
• Among 5,018 male tobacco users, 318 were diagnosed as cases.
• Malignant transformation of oral leukoplakias has been reported in
the range of 1 to 20% over 1 to 30 years.
• Based on a recent review of available European epidemiologic
data, the incidence has been calculated not to exceed 1% per year.
• Sixteen to 62% of oral carcinomas have been reported to be

associated with leukoplakia at the time of the diagnosis, and in an
• Indian house-to-house survey, 80% of oral cancers were reported
to be preceded by oral precancerous lesions or conditions.
• Until biomarkers are developed, management of oral leukoplakias
and erythroplakias has to rely on traditional clinical and
histopathologic criteria.
• Homogeneous oral leukoplakia entails less risk for malignant
transformation than do nonhomogeneous leukoplakias and
erythroplakias.
Etiology and Pathogenesis
• The development of oral leukoplakia and erythroplakia as

premalignant lesions involves different genetic events.
• This notion is supported by the fact that markers of genetic defects
are differently expressed in different leukoplakias and
erythroplakias.
• Activation of oncogenes and deletion and injuries to suppressor
genes and genes responsible for DNA repair will all contribute to a
defective functioning of the genome that governs cell division.
• Following a series of mutations, a malignant transformation may
occur.
• For example, carcinogens such as tobacco may induce
hyperkeratinization, with the potential to revert following
cessation, but at some stage, mutations will lead to an unrestrained
proliferation and cell division.
• Leukoplakia occurs more frequently in smokers of tobacco than in
nonsmokers.
• There is a dose-response relationship between tobacco usage and
the prevalence of oral leukoplakia.
• Reducing or cessation of tobacco use may result in the regression
or disappearance of oral leukoplakia (Gupta et al, 1995).
• On the other hand, disappearance of oral leukoplakia has
occasionally been reported in patients who continued to smoke
(Silverman and Rozen, 1968).
• Tobacco was most often chewed as an ingredient in betel quid
(smokeless tobacco or paan) in India.
• The paan-chewers‘ lesion consists of a thick, brownish-black
encrustation on the buccal mucosa at the site of the placement of
betel quid.
• It is often seen in heavily addicted betel quid chewers.
• It could be scraped off with a piece of gauze (leukoplakia); it

regresses spontaneously when the habit is discontinued.
• Due to these reasons the paan-chewer‘s lesion does not deserve the
designation of leukoplakia.
• This is a specific entity and rarely progresses to leukoplakia.
• Whether the use of alcohol by itself is an independent etiological
factor in the development of oral leukoplakia, is still questionable.
• Its effect, at best, may be synergistic to other well-known
etiological factors (physical irritants).
• The role of Candida albicans as a possible etiological factor in
leukoplakia and its possible role in malignant transformation is still
unclear.
• About 10% of oral leukoplakias satisfy the clinical and histological
criteria for chronic hyperplastic candidiasis (candidal leukoplakia).
• Epithelial dysplasia is reported to occur four to five times more
frequently in Candida leukoplakia than in leukoplakia in general.
• However, this change is more common in the speckled variant than
in homogeneous leukoplakia and carcinomatous change is more a
characteristic of the speckled lesion than that of candidal
superinfection.
• Various kinds of evidence has been presented to justify an etiologic
role for candida in neoplastic transformation, which includes,
among others, the catalytic transformation in vitro of the
carcinogenic nitrosamine, N-nitrosobenzyl-methylamine, by
strains of C. albicans demonstrated to be selectively associated
with leukoplakia.
• The possible contributory role of viral agents (human papilloma
virus strains 16, 18) in the pathogenesis of oral leukoplakia has
also been discussed, particularly with regard to exophytic
verrucous leukoplakia (Palefsky JM et al, 1995).
• In a study from India, serum levels of vitamin A, B12, C, beta-
carotene and folic acid were significantly decreased in patients
with oral leukoplakia compared to controls, whereas, serum
vitamin E was not (Ramaswamy G et al, 1996).
• Relatively little is yet known with regard to possible genetic
factors in the development of oral leukoplakia.
• Electro-galvanic reaction between unlike restorative metals.
• Ultraviolet radiation from sunlight – associated with lip lesions.
• Chronic inflammation or irritation from sharp teeth or chronic
cheek-bite (tissue modifiers rather than true carcinogens).
Clinical Aspects
• Preleukoplakia is defined as a low-grade or very mild reaction of

the oral mucosa, appearing as a gray or grayish-white, but never
completely white area with a slightly lobular pattern and with
indistinct borders blending into the adjacent normal mucosa
(Pindborg et al, 1968).
Various forms of leukoplakia and subdivisions recommended

(WHO, 1980)
Clinical features
• The typical homogeneous leukoplakia is clinically characterized

as a white, well-demarcated plaque with an identical reaction
pattern throughout the entire lesion.
• The surface texture can vary from a smooth thin surface to a
leathery appearance with surface fissures sometimes referred to as
―cracked mud.‖
• The lesions are asymptomatic in most patients.
• The nonhomogeneous type of oral leukoplakia may have white

patches or plaque intermixed with red tissue elements .
• The adjective ‗nonhomogeneous‘ is applicable both to the aspect of
color, i.e. mixture of white and red changes (erythroleukoplakia)
and to the aspect of texture, i.e. exophytic, papillary (nodular), or
verrucous.
• With regard to the latter lesions, no reproducible clinical criteria
can be provided to distinguish (proliferative) verrucous leukoplakia
from the clinical aspect of verrucous hyperplasia or verrucous
carcinoma.
• The clinical manifestation of the white component may vary from
large white verrucous areas to small nodular structures.
• Both homogeneous and nonhomogeneous leukoplakias may be
encountered in all sites of the oral mucosa.
• The homogeneous type is usually otherwise asymptomatic,
whereas the nonhomogeneous (mixed white and red) leukoplakia
are often associated with mild complaints of localized pain or
discomfort.
• In the presence of redness or palpable induration, malignancy may
already be present
• Oral leukoplakia may be found at all sites of the oral mucosa.

• Nonsmokers have a higher percentage of leukoplakias at the border
of the tongue compared with smokers.
• The floor of the mouth and the lateral borders of the tongue are
high-risk sites for malignant transformation .
• These sites have also been found to have a higher frequency of loss
of heterozygosity compared with low-risk sites.
• However, the separation into high- and low-risk sites has recently
been questioned.
Proliferative Verrucous Leukoplakia and its Related Lesions:
• Proliferative verrucous leukoplakia (PVL) and verrucous

hyperplasia (VH) are two related oral mucosal lesions.
• The terms; however, are not clinically or pathologically
interchangeable.
• The term PVL is preferably a clinical one, but the diagnosis of
VH, on the other hand, must be made histologically.
• Proliferative verrucous leukoplakia (PVL) : First described by
Hansen et al, in 1985, PVL continues to be recognized as a
particularly aggressive form of oral idiopathic leukoplakia that has
a considerable morbidity and a strong potential for malignant
transformation.
 Oral leukoplakias, where the white component is dominated by
papillary projections, similar to oral papillomas, are referred to as
verrucous or verruciform leukoplakias.
 Diagnosis is often made late in the protracted course of PVL with
the disease in an advanced stage when it is especially refractory to
treatment.
 PVL is usually encountered in older women, and the lower gingiva
is a predilection site.
• The malignant potential is very high, and verrucous carcinoma or
squamous cell carcinoma may be present at the primary
examination.
• As the common surface reaction pattern is similar to what is seen
in oral papillomas, the PVL has been suspected to have a viral
etiology, although no such association has been confirmed.
 The histologic spectrum that is seen in PVL are:

• Verrucous hyperplasia (VH), a histologically defined lesion
• Varying degrees of dysplasia
• Three forms of squamous cell carcinoma: Verrucous, conventional
and according to some, papillary squamous cell carcinoma.
Verrucous hyperplasia (VH)

• This is a forerunner of verrucous carcinoma and the transition is so
consistent that the hyperplasia, once diagnosed, should be treated
like verrucous carcinoma.
Histopathological Aspects
• It should be emphasized that leukoplakia is a clinical term, and its

use carries no implications with regard to the histological findings.
• However, it is recommended that a histological report should
always include a statement on the presence or absence of epithelial
dysplasia, and if present, the assessment of its severity.
• The hallmarks of the histopathological aspects of leukoplakia are
epithelial hyperplasia and surface hyperkeratosis.
• Epithelial dysplasia, if present, may range from mild to severe.
• In some instances, carcinoma in situ and even squamous cell
carcinoma are encountered histologically.
Histopathological features of epithelial dysplasia (Krammer et al.,

1978)
1. Loss of polarity of the basal cells

2. Presence of more than one layer of cells having a basaloid appearance
3. Increased nuclear cytoplasmic ratio
4. Drop-shaped rete processes
5. Irregular epithelial stratification
6. Increased number of mitotic figures (a few abnormal mitoses may be
present)
7. Presence of mitotic figures in the superficial half of the epithelium
8. Cellular pleomorphism
9. Nuclear hyperchromatism
10. Enlarged nucleoli
11. Reduction of cellular cohesion
12. Keratinization of single cells or cell groups in the prickle layer.
Grading of Epithelial Dysplasia
• Epithelial dysplasia is usually assessed subjectively and

considerable interobserver variability exists in its interpretation.
• Principally, what is lacking in this exercise is objectivity and lack
of reproducibility.
• A consensus decision is, by and large, adopted in the management
of individual lesions and based on the presence of dysplastic
features, epithelial dyplasia is usually divided into three categories:
mild, moderate and severe.
• It is recommended that the histological report of a leukoplakia
should include a statement on the absence or presence of epithelial
dysplasia and an assessment of its severity.
• The practical value of the grading of epithelial dysplasia is
questionable.
• The clinical significance of human papilloma virus-associated
epithelial dysplasia, so-called ‗koilocytic dysplasia‘ remains to be
investigated.
• The term ‗lichenoid dysplasia‘ is sometimes used when the
dysplastic epithelium may show features that, to some extent,
resemble those of lichen planus.
• The term ‗chevron‘ type of keratinization is used when it is
associated with use of tobacco.
• Microabscesses may be observed in the superficial layers of the
epithelium in the presence of C. albicans and inflammatory cell
infiltration is commonly seen.
• Some of the exophytic, verrucous or papillomatous lesions, in spite
of the absence of epithelial dysplasia, may in time progress to
squamous cell carcinoma and that long-term follow-up should be
considered.
Modified Classification and Staging System for Oral

Leukoplakia
 A proposal for a modified classification and staging system for oral

leukoplakia (OLEP) has been presented by Van der Waal et al,
2000 in which the size of the leukoplakia and the presence or
absence of epithelial dysplasia are taken into account.
 Altogether four stages are recognized:
• L1 — Size of leukoplakia <2 cm

• L2 — Size of leukoplakia 2–4 cm
• L3 — Size of leukoplakia >4 cm
• Lx — Size not specified
• P — Pathology
• P0 — No epithelial dysplasia
• P1 — Distinct epithelial dysplasia
• Px — Dysplasia not specified in the pathology report.
OLEP Staging System
• Stage I — L1 P0
• State II — L2 P0
• Stage III — L3 P0 or L1 L2 P1
• Stage IV — L3 P1
• The proposed system should facilitate uniform reporting of
treatment or management results of OLEPs in which a biopsy has
become available.
• The system can easily be adjusted by replacing the
histopathological criteria of epithelial dysplasia by a clinical
subdivision in homogeneous and nonhomogeneous leukoplakia for
cases in which no biopsy is available.
• It also could serve as a means for epidemiological studies.
Disorders that need exclusion to diagnose leukoplakia Disorder
Biopsy
• In homogeneous leukoplakia, the value of histological examination

might, to some extent, be questioned.
• The occurrence of epithelial dysplasia is rather low in this clinical
subtype, as is the risk of future malignant transformation.
• However, this cannot be taken as the dictum in all cases since at
least in few cases it proves to be otherwise.
• Therefore, the taking of a biopsy in homogeneous leukoplakia
should be the standard rule.
• Incisional biopsy with scalpel and histopathological examination of
the suspicious tissue is the gold standard.
• Punch biopsy is a useful alternative and can be used in multiple
• and diffuse mucocutaneous lesions; incisional biopsy is done for
large (more than 1.0 cm), multiple, or diffuse lesions.
• If treatment consists of CO2-laser evaporation, it is mandatory to
have a biopsy taken prior to such treatment.
• In nonhomogeneous leukoplakia, biopsy should be taken at the site
of symptoms, if present, and/or at a site of redness or induration.
• Diagnostic methods other than histological examination, such as
the use of toluidine blue staining or Lugol’s iodine and
exfoliative cytology are of limited value when dealing with

leukoplakia.
• Toluidine blue, Lugol‘s iodine, and whitening of the oral mucosa
induced by acetic acid have been used to help to identify and
demarcate potentially malignant mucosal lesions, but subjective
interpretations make them unreliable and there is no convincing
evidence available to support their use in clinical practice.
• Oral transepithelial brush biopsy with computer-assisted analysis
(OralCDx®, CDx DiagnosticsTM, Suffern, USA) helps to
differentiate between precancerous and cancerous cells, and has
52% sensitivity and 29% specificity.
• The drawback is that if it is positive or inconclusive then a tissue
biopsy is indicated.
• It can also be used as a follow-up tool but its usefulness in
everyday practice is limited.
• Optical diagnostic techniques detect a change in the optical
property at a molecular level, and an alteration in the interaction
between light and tissue is used to differentiate normal from
malignant tissue.
• These techniques overcome some of the limitations of standard
techniques (being invasive and time consuming, and lacking
uniformity in reporting) by offering objective data analysis, which
may reduce variations in pathological diagnosis.
• They also provide real-time assessment of tissue structure and
metabolism through a minimally invasive approach.
• The benefits of optical technologies are limited in current daily
clinical use, but with developing technological advances they have
the potential to revolutionise the diagnosis and surveillance of
precancerous and cancerous lesions at the early stage of
development.
• Autofluorescence spectroscopy and imaging systems can
differentiate normal oral mucosa from abnormal tissue (82–100%
sensitivity, 63–100% specificity) but there is a lack of evidence to
support their ability to distinguish different types of lesions.
• When probed, the cancerous and precancerous lesions show less
green fluorescence than the surrounding normal mucosa.
• A study by Awan et al.showed that autofluorescence had 84.1%
sensitivity and 15.3% specificity for detecting dysplastic lesions,
but they also commented that it could not be used for screening,
and could not dictate the biopsy site in a large and heterogeneous
lesion.
• Multispectral imaging systems (fluorescence, narrow band
imaging, orthogonal polarised reflectance) and trimodal
spectroscopy (fluorescence spectroscopy, elastic scattering

spectroscopy, Raman spectroscopy) have been shown to diagnose
precancerous or cancerous tissue accurately.
• Even though they can diagnose precancerous lesions reliably, they
can be expensive and time consuming, which limits their efficacy
in daily clinical practice.
Diagnosis
Management
• Oral leukoplakia is a lesion with an increased risk of malignant

transformation, which has great implications for the management
of this oral mucosal disorder.
• Since alcohol and smoking are well-established risk factors for the
development of oral squamous cell carcinomas, measures should
be taken to influence the patients to discontinue such habits.
• Cold-knife surgical excision, as well as laser surgery, is widely
used to eradicate leukoplakias but will not prevent all premalignant
lesions from malignant development.
• The reported cure rates after laser surgery vary between 33.9% and
82%, and recurrence between 7.7% and 66%.
• Another large retrospective study reported cure rates of 82%, local
recurrence of 9.9%, and 1.1% malignant transformation. On the
contrary, surgery has been strongly questioned as squamous cell
carcinomas are almost equally prevalent in non–surgically treated
patients as in patients subjected to surgery.
• This may be explained by genetic defects in clinically normal
mucosa and is supported by a concept referred to as field
cancerization.
• Field cancerization is caused by simultaneous genetic instabilities
in the epithelium of several extralesional sites that may lead to
squamous cell carcinomas.
• However, in the absence of evidenced-based treatment strategies
for oral leukoplakias, surgery will remain the treatment for oral
leukoplakias.
• The use of antioxidant nutrients and vitamins have not been
reproducibly effective in management.
• Programs have included single and combination dosages of
vitamins A, C, and E; beta carotene; analogues of vitamin A; and
diets that are high in antioxidants and cell growth suppressor
proteins (fruits and vegetables)
• Carotenoids (Beta-Carotene 360mg Once weekly for 1 year) and
lycopene 4mg –BD for 3months ) : Beta-carotene is a vitamin A
precursor and Lycopene is a carotenoid without provitamin A
action , have antioxidant action.
• Systemic Vit A – 2-300,000 IU /week for 1 year
• Topical Vit A – 0.05 % 3/day for 2 weeks
• Topical Isotretinoin 0.1 % 3/day for 2 weeks
Fenretinide (200mg/day for 3 months) : vitamin A analogue , inhibit

cell growth
through the induction of apoptosis with mechanisms that may be both
receptor-dependent and receptor-independent
The carotenoids are a group of extremely hydrophobic molecules with
little or no solubility in water
Anti-neoplastic agents:
• Bleomycin: Topical bleomycin is used in dosages of 0.5%-1%
/day for 12 to 15 days or 1%/day for 14 days for treatment of
leukoplakia.
• 5-Fluorouracil: affect the cell cycle and induce apoptotic death of
cancer cells
• Photodynamic therapy (Aminolevulenic acid 10-20 %) : Twice a

week for 3 months
Polyphenols as chemo-preventive agents

• Curcumin 4,000–8,000 mg 500 mg of synthetic curcumin per
capsule
• Green Tea
According to Cochrane review–
 None of the treatments are effective in preventing malignant

transformation of leukoplakia
 Although some treatments were effective in healing Leukoplakia,
they did not prevent relapse & malignant change
 Regular follow up required irrespective of any treatment
modalities.
 There is no satisfactory treatment for Leukoplakia.
 Presently, no consensus has been developed regarding management
and follow-up of oral leukoplakias.
• A general recommendation may be to reexamine the premalignant
site irrespective of surgical excision every 3 months for the first
year.
• If the lesion does not relapse or change in reaction pattern, the
follow-up intervals may be extended to once every 6 months.
• New biopsies should be taken if new clinical features emerge.
• Following 5 years of no relapse, self-examination may be a
reasonable approach.
• Despite advances in molecular biology, there are no reliable
markers to predict the malignant transformation of oral
leukoplakia.
• It has been reported that a few markers such as Ki-67(Mib-1) and
bromodeoxyuridine, and the combined biomarker score of
chromosomal polysomy, p53, and loss of heterozygosity might be
strong predictors for malignant transformation, but this is not
generally adopted in clinical practice.
• The molecular events that induce a premalignant lesion to progress
to carcinoma are still unknown, and the overexpression (or under-
expression) of biomarkers alone adds little predictive value over
standard histological analysis.
• The detection of dysplastic lesions using oral cytological
examination is promising, but has been limited so far by variable
false-positive and false-negative results.
Prognosis
• Although clinical appearance such as non-homogeneous oral

leukoplakia or erythroplakia, and anatomical site (notably the floor
of the mouth and the ventral tongue) can help to identify lesions
with a high risk of transformation, there are no reliable ways to
predict the behaviour of individual lesions or to guide clinical
management without biopsy examination.
• Patients with multiple oral precancerous lesions and extensive
areas of mucosa that may show signs of dysplastic change are
particularly difficult to manage.
• Modern concepts of carcinogenesis have emphasised the existence
of molecularly altered preneoplastic fields from which multiple
lesions can develop.
• Widespread lesions have been shown to have higher rates of
malignant transformation than those that are more localised.
• A study by Holmstrup et al. identified 2 factors that are of
prognostic value: size and type of lesion.
• Logistic regression analysis showed that other factors that
characterise lesions were insignificant in most instances.
• Non-homogeneous leukoplakia had an odds ratio of 7.0 for cancer
to occur compared with homogeneous leukoplakia.
• There is no substantial reported evidence for the size of the lesions
to develop into cancer but this study showed that in those that
exceeded 200mm2 the odds ratio for cancer to occur was 5.4 as
opposed to smaller lesions.
• There was no correlation between histological features and clinical
outcome, which may be explained by the biopsy site not being
representative of the entire lesion.
• The risk of malignant transformation has been reported to be
between 6.6% and 36.4%, although a recent meta-analysis
indicated a rate of 12.1%.
• A recent study reported a relatively high malignant transformation
rate (22%) at 5 years among patients diagnosed with oral epithelial
dysplasia.
• Factors such as not smoking, lateral tongue site, and non-
homogeneous appearance were all associated with a 5- year
malignant transformation rate of around 40% or more.
• The study showed that the lesions on the lateral border of the
tongue had the highest rate of malignant transformation (53% at 5
years) and the floor of the mouth was the commonest site of
epithelial dysplasia (44%) with a malignant transformation rate of

8% at 5 years.
• Recurrence of oral leukoplakia after surgical treatment has been
reported in 10–35% of cases,6 and development of cancer after
operation in 3–9% of cases3; 2.6–9% were after laser surgery.
• Several reports have suggested that operation does not seem to
prevent premalignant lesions from developing malignancy.
• The only significant factors associated with malignant
transformation are clinical type and size of lesion.
• Other factors including site, demarcation, presence of any type of
epithelial dysplasia, smoking, and operation seem to be
insignificant with respect to future development of malignancy.
• The lack of success of surgical treatment may be because of a
multiclonal origin of the affected areas as seen in field
cancerisation.
• Such a concept includes the persistence of cells invaded by cancer
outside the removed lesions.
• This hypothesis is supported by studies on the DNAcontent in
cells of oral leukoplakia, which showed karyotypic changes in the
oral mucosa other than those visible clinically and histologically.
• Based on the evidence presented :
• Advancing age was found to be an important risk factor.
• Due to the heterogeneity of the age group classification across the
reviewed studies, it was difficult to derive a conclusion on the
involvement of age as a risk factor.
• Although OL is relatively uncommon among females compared to
males, the malignant transformation was found to be significantly
higher among females.
• leukoplakia exceeding 200 mm2
• Non-homogenous leukoplakia (erythroleukoplakia) was found to
have a higher risk in malignant transformation.
• The higher grades of dysplasia although in three studies, the
dysplasia grade did influence the risk for transformation.
ERYTHROPLAKIA
• Erythroplakia has been defined as a ―bright red velvety plaque or

patch which cannot be characterized clinically or pathologically as
being due to any other condition.‖
• Erythroplakia is almost always associated with premalignant
changes histologically and is, therefore, the most important
precancerous lesion.
• Fournier and Darier first described erythroplasia as a malignant

dyskeratosis with unknown etiology in 1893 and designated it as
épithéliome papillaire.
• The word is an adaptation of the French term ―erythroplasie de
Queyrat,‖ which describes a similar-appearing lesion of the glans
penis with a comparable premalignant tendency.
• WHO defined oral erythroplakia or erythroplasia during the years
as follows:
1. Bright red, velvety plaques which cannot be characterized
clinically or pathologically as being due to any other
condition.
2. Red areas that cannot be diagnosed as any other definable
lesion.
3. A predominantly red lesion of the oral mucosa that
cannot be characterized as any other definable lesion.
• Erythroplakic lesions are easily overlooked, and the true
prevalence of the condition is unknown.
• The point prevalence rate of erythroplakia in the oral cavity has
been estimated to be 1 per 2500 adults.
• The lowest prevalence of erythroplakia was reported to be 0.01%
by Lumerman et al and the highest was 0.2% according to Hashibe
et al.
• The prevalence has been estimated to be in the range of 0.02 to
0.1%.
• Erythroplakia is far less common than leukoplakia in most
histopathologic series, but this reflects the fact that leukoplakias
are more likely to have biopsies performed on them and
emphasizes the lack of appreciation of the clinical significance of
erythroplakia since it has been proposed that most erythroplakic
lesions are precursors of oral squamous cell carcinoma.
• A number of studies have shown that the majority of erythroplakias
(particularly those located under the tongue, on the floor of the
mouth, and on the soft palate and anterior tonsillar pillars) exhibit a
high frequency of premalignant and malignant changes.
• Over the years, it has been suggested that DNA content (DNA
ploidy) is an important predictor of the malignant potential of
erythroplakia.
Etiology
• The development of oral erythroplakia as premalignant lesions

involves different genetic events.
• This notion is supported by the fact that markers of genetic defects

are differently expressed in different leukoplakias and
erythroplakias.
• Activation of oncogenes and deletion and injuries to suppressor
genes and genes responsible for DNA repair will all contribute to a
defective functioning of the genome that governs cell division.
• Although the etiology of erythroplakia is uncertain, most cases of
erythroplakia are associated with heavy smoking, with or without
concomitant alcohol abuse.
• Information on role of HPV on erythroplakia is limited. Study has
shown that HPV may be an etiologic co-factor.
Clinical Features
• Several clinical variants of erythroplakia have been described, but

there is no generally accepted classification.
• Shear described ―homogeneous erythroplakia, erythroplakia
interspersed with patches of leukoplakia, and granular or speckled
erythroplakia‖; most authors consider this last category to be
identical to speckled leukoplakia.
• Many of these lesions are irregular in outline, and some contain
islands of normal mucosa within areas of erythroplakia, a
phenomenon that has been attributed to the coalescence of a
number of precancerous foci.
• Erythroplakia occurs predominantly in older men, in the sixth and
seventh decades of life.
• The gender distribution is reported to be equal by some authors.
• Erythroplakias are more commonly seen on the floor of the mouth,
the ventral tongue, the soft palate, and the tonsillar fauces, all
prime areas for the development of carcinoma.
• Multiple lesions may be present.
• These lesions are commonly described as erythematous plaques
with a soft velvety texture.
• Almost all of the lesions are asymptomatic and therefore unlikely
to be drawn to the dentist‘s attention by the patient.
• Clinically, Shear erythroplakia is classified into three types:
homogeneous, granular, and speckled.
1. Homogeneous erythroplakia – lesion that appeared flat, velvety,
with uniformly red appearance.
2. Granular erythroplakia – red lesions with granular surface.
3. Speckled erythroplakia / erythroleukoplakia predominantly red
lesion speckled with white spots.
• A special form of erythroplakia has been reported that is related to

reverse smoking of chutta, predominantly practiced in India.
• The lesion comprises well-demarcated red areas in conjunction
with white papular tissue structures.
• Ulcerations and depigmented areas may also be a part of this
particular form of oral lesion.
ERYTHROPLAKIA WITH ULCERATION
• Another rare but high-risk premalignant lesion is the chronic

erythematous change associated with constantly recurring erosive
changes.
• These lesions are often mistaken for recurrent aphthous stomatitis
of the herpetiform variety or nonspecific inflammatory
immunopathologic vesiculoerosive disease.
Histopathologic Features
• The epithelium shows lack of keratin production and is often

atrophic, but it may be hyperplastic.
• This lack of keratinization, especially when combined with
epithelial thinness, allows the underlying microvasculature to show
through, thereby causing the red color.
• The underlying connective tissue often demonstrates chronic
inflammation.
• Different studies have demonstrated that 80 to 90% of cases of
erythroplakia are histopathologically severe epithelial dysplasia,
carcinoma in situ, or invasive carcinoma.
Differential Diagnosis
• In view of the clinical significance of erythroplakia, its

differentiation from other red inflammatory lesions of the oral
mucosa is critical.
• Clinically similar lesions may include erythematous candidiasis,
areas of mechanical irritation, denture stomatitis, vascular lesions,
and a variety of nonspecific inflammatory lesions.
• Because localized areas of redness are not uncommon in the oral
cavity, areas of erythroplakia are likely to be disregarded by the
examiner, and they are often falsely determined to be a transient
inflammatory response to local irritation.
• Differentiation of erythroplakia from benign inflammatory lesions

of the oral mucosa can be enhanced by the use of a 1% solution of
toluidine blue, applied topically with a swab or as an oral rinse.
• Although this technique was previously found to have limited
usefulness in the evaluation of keratotic lesions, prospective studies
of the specificity of toluidine blue staining of areas of early
carcinoma contained in erythroplakic and mixed leukoplakic-
erythroplakic lesions reported excellent results, with false-negative
(underdiagnosis) and false-positive (overdiagnosis) rates of well
below 10%.
Lesion Description
Erythematous • Poor oral hygiene

candidiasis • Diffuse border
• Hard palate/ dorsum of tongue-
common site
• Steroid inhalation
• Broad spectrum antibiotic
Atrophic Lichen • Erythematous area with peripheral
Planus radiating striae
• No known etiology
Denture induced • Denture wearer

stomatitis • Denture bearing palatal mucosa
Traumatic erythema • H/o trauma
• Tender mucosa
Treatment and Prognosis
• According to Shafer and Waldron, 51% of eryt-hroplakias

transformed into SCC, 40% were carci-noma in situ and 9%
showed mild to moderate dysplasia.
• Because of 90% malignant transformation rate, early detection and
immediate surgical excision are recommended.
• The treatment of erythroplakia should follow the same principles
outlined for that of leukoplakia.
• Observation for 1 to 2 weeks following the elimination of
suspected irritants is acceptable, but prompt biopsy at that time is
mandatory for lesions that persist.
• The toluidine blue vital staining procedure may be redone
following the period of elimination of suspected irritants.
• Lesions that stain on this second application frequently show
extensive dysplasia or early carcinoma.
• Epithelial dysplasia or carcinoma in situ warrants complete
removal of the lesion.
• Actual invasive carcinoma must be treated promptly according to
guidelines for the treatment of cancer.
• Most asymptomatic malignant erythroplakic lesions are small; 84%
are ≤ 2 cm in diameter, and 42% are ≤ 1 cm.
• However, since recurrence and multifocal involvement is common,
longterm follow-up is mandatory.
ORAL SUBMUCOUS FIBROSIS
• Oral submucous fibrosis (OSF) is a slowly progressive chronic

fibrotic disease of the oral cavity and oropharynx, characterized by
fibroelastic change and inflammation of the mucosa, leading to a
progressive inability to open the mouth, swallow, or speak.
• This condition was described first by Schwartz (1952) while
examining five Indian women from Kenya, to which he ascribed
the descriptive term ―atrophia idiopathica (tropica) mucosae
oris‖.
• Later in 1953, Joshi from Bombay (Mumbai) redesignated the
condition as Submucous Fibrosis of the palate and pillars,
implying predominantly its histological nature.
• The first report among non-Indians was from Taiwan by Su16 in
1954 and referred it as ―Idiopathic scleroderma of the mouth‖.
• Other names that have been suggested are diffuse oral submucous
fibrosis, idiopathic palatal fibrosis and sclerosing stomatitis.
DEFINITIONS
• Pindborg and Sirsat in 1966 :An insidious chronic disease

affecting any part of the oral cavity and sometimes the pharynx.
Although occasionally preceded by and or associated with vesicle
formation, it is always associated with a juxta-epithelial
inflammatory reaction followed by a fibroelastic change of the
lamina propria with epithelial atrophy leading to stiffness of the
oral mucosa and causing trismus and inability to eat.
• WHO (1978) OSF is a slowly progressive disease in which fibrous
bands form in the oral mucosa ultimately leading to severe
restriction of movement of the mouth, including the tongue.
Epidemiology
• Numerous published reports on OSF allow an informed appraisal

of its geographic distribution, together with data on the percentage
prevalence.
• It occurs almost exclusively in inhabitants of Southeast Asia,
especially the Indian subcontinent.
• Areca nut–derived products have several hundred million
consumers in the southern parts of Asia.
• Regional variations exist regarding the preference of the areca nut
use, which also accounts for variation in the affected sites.
• Oral complications are most commonly observed on the lips,

buccal mucosa, retromolar area, and soft palatal mucosa.
• The habit of chewing betel quid, containing fresh, dried, or cured
areca nut, and flavoring ingredients is widespread in India,
Pakistan, Bangladesh, and Sri Lanka and in immigrants coming
from these regions.
• Tobacco is often used in conjunction with betel quid. The habit is
more common among women in some geographic areas, which is
also reflected in the gender distribution of submucous fibrosis.
• The global incidence of submucous fibrosis is estimated at 2.5
million individuals.
• The prevalence in Indian populations is 5% for women and 2% for
men.
• It seems as if age groups below 20 years of age more often contract
submucous fibrosis.
• There seems to be a rather wide age range, although a majority of
patients are between 20 and 40 years of age.
• Paymaster finds, however, that younger persons usually arc
affected.
• The youngest affected person that we saw was an g-year-old Indian
boy in Singapore.
• This is reflected in the advertisement of areca nut products, which
is directed against younger age groups.
• Following the introduction of this marketing strategy, the incidence
of submucous fibrosis has increased 10 times between 1980 and
1993.
• An epidemiological assessment of the prevalence of OSF among
Indian villagers, based on baseline data, recorded a prevalence of
0.2% (n 10,071) in Gujarat, 0.4% (n 10,287) in Kerala, 0.04% (n
10,169) in Andhra Pradesh, and 0.07% (n 20,388) in Bihar.
• It is interesting to note that the prevalence of submucous fibrosis is
higher in southern India, in Trivandrum, than in northern
India.(Pindborg 1966)
• Mehta et al (1972) The prevalence among 101,761 villagers in the
state of Maharashtra (central India) was 0.03%.
• In a 10-year follow-up study of oral precancer, Gupta et al, in
1980, calculated the incidence rate of OSF in Ernakulam, Kerala: 8
for men and 19 for women per 100,000.
• Variations in the prevalence figures are common between different
studies, probably because of differences in the clinical criteria for
diagnosis.
• While some investigators adhere to the earlier signs and symptoms,
others looked for fibrous bands as the diagnostic criterion.
• According to Pindborg 1989, if only the fibrous band was the

criterion for diagnoses, the prevalence rate would have been about
1.6%.
• Prevalence by gender varies widely in the different published
studies.
• The general female preponderance may be related to factors like
oral habits, deficiency states of iron, vitamin B complex among
many other conditions prevalent in Indian women.
• No caste or religious community is especially affected.
ETIOLOGY
• Even though the etiopathology is incompletely understood, several

factors are believed to contribute to the development of OSF,
including general nutritional and vitamin deficiencies and
hypersensitivity to certain dietary constituents such as chili
peppers, Areca nut , chewing tobacco, etc.
• However, the primary factor is the habitual use of betel and its
constituents, which include the nut of the areca palm (Areca
catechu), the leaf of the betel pepper (Piper betle), and lime
(calcium hydroxide).
• There is a dose dependence between areca quid chewing habit and
the development of this oral mucosal disorder.
• Areca nuts contain alcaloids, of which arecoline seems to be a
primary etiologic factor.
• The frequency of this habit in population affected by OSF ranged
from 34–100% (Bhonsle RB et al, 1987).
• This has been reported to be higher among OSF patients than in the
general population.
• In a study of 100,000 villagers in Maharashtra (India), 4.2% of
females who chewed areca nut and did not use tobacco suffered
from OSF.
• Thus chewing areca nut may be an important factor in the etiology
of OSF.
• The suspicion that chilly is an etiologic agent arose on the basis of
ecological observations and was strengthened by the clinical and
histologic characteristics of this condition.
• Capsaicin, which is vanillylamide of 8-methyl-6-nonenic acid, is
the active ingredient of chillies.
• OSF is found mostly among Indians and other population groups
who use chillies to spice their food.
• The reason for OSF cases coming from low socioeconomic group
might be due to poor quality of food, low vitamins, iron deficiency
and use of more spices and chillies to make the food tasty, coupled
with lack of health consciousness.
• Autoimmunity: is considered as one of the etiologic factor and
hence various authors studied OSF from the immunological points
of view.
• Phatak AG etal (1978) observed that these patients had
significantly elevated levels of serum globulin and
immunoglobulin IgG and Binnie and Cowson (1972) reported that
OSF and progressive systemic sclerosis (scleroderma), share a
defect of collagen maturation which gives rise to a clinically and
histologically similar presentation of both.
• A significantly higher positive ANA (23.9%), SMA (23.9%), and
GPCA (14.7%) in OSF patients has been seen (Chiang et al 2002)
Genetic susceptibiiity :
• Only an estimated 1-2% of the population who have an areca nut
chewing habit may develop the disease.
• This suggests a possible genetic predisposition in the affected
people A genetic predisposition is also supported by association-
specific human leukocyte antigen (HLA) molecules, such as HLA-
A10, -B7, and -DR3.
• Further HLA-typing done by the use of the polymerase chain
reaction (PCR) also demonstrates significantly increased
frequencies of HLA-A24, DRB1-11 and DRB3-0202/3 antigens in
21 OSF patients when compared with the English controls (Saeed
B et al, 1997).
Role of infections : HPV, HSV, EBV (Abnormal CD4/CD8 ratio)
• When betel is chewed, it produces mild psychoactive and

cholinergic effects.
• Betel use is also associated with oral leukoplakia and squamous
cell carcinoma.
• OSF is regarded as a potentially malignant disorder, and many
cases of oral cancer have been found coexisting with submucous
fibrosis.
• Cases of submucous fibrosis have been reported in many Western
countries, especially in individuals who have immigrated from the
Indian subcontinent.
Pathogenesis
• OSF reactions may be the result of either direct stimulation from
exogenous antigens like Areca alkaloids or changes in tissue
antigenicity that may lead to an autoimmune response.
• The inflammatory response releases cytokines and growth factors
that promote fibrosis by inducing the proliferation of fibroblasts,
up-regulating collagen synthesis and down-regulating collagenase
production.
• Arecoline has the capacity to modulate matrix metalloproteinases,
lysyl oxidases, and collagenases, all affecting the metabolism of
collagen, which leads to an increased fibrosis.
• During the development of fibrosis, a decrease in the water-
retaining proteoglycans will occur in favor of an increased collagen
type I production.
• There is also evidence of a genetic predisposition of importance for
the etiology behind submucous fibrosis.
• Polymorphism of the gene, which is coding for tumor necrosis
factor a (TNF-a), has been reported to promote the development of
the disorder.
• Fibroblasts are stimulated by TNF-a, thereby participating in the
development of fibrosis.
• Aberrations of other cytokines of importance are transforming
growth factor b and interferon-c, which may lead to increased
production and decreased degradation of collagen.
• Previous studies on the pathogenesis of OSF have suggested that
the occurrence may be due to:
• Clonal selection of fibroblasts with a high amount of collagen
production during the long-term exposure to areca quid ingredients
(Meghji S et al, 1987).
• Stimulation of fibroblast proliferation and collagen synthesis by
arecanut alkaloids (Harvey W et al, 1986).
• By fibrogenic cytokines secreted by activated macrophages and T

lymphocytes in the OSF tissues (Haque MF et al,2000).
• By decreased secretion of collagenase (Shieh TY et al, 1992).
• Deficiency in collagen phagocytosis by OSF fibroblasts (Tsai CC
et al, 1999).
• By production of collagen with a more stable structure (collagen
type I trimer) by OSF fibroblasts (Kuo MYP et al, 1995).
• By stabilization of collagen structure by catechin and tannins from
the areca nut (Scutt A et al, 1987).
• And by an increase in collagen cross-linkage as caused by
upregulation of lysyl oxidase by OSF fibroblasts (Ma RH et al,
1995).
• Arecoline is the main alkaloid found in AN in addition to
arecaidine, guvacine and guvacoline.
• It is apparent that fibrosis and hyalinization of sub epithelial tissues
account for most of the clinical features encountered in this
condition.
• It is likely that the normal regulatory mechanisms are either down
regulated or up regulated at different stages of the disease by the
areca alkaloids.
• Effects of arecoline in the pathogenesis of OSF include -
Ø Fibroblastic proliferation and increased collagen formation.
Ø Influence on deposition of extracellular matrix
Ø Initiation of buccal mucosal fibroblast contraction
Ø Cytotoxicity of cells.
• It was suggested that arecoline stimulates fibroblasts to increase the
production of collagen by 150%.
Mechanisms of pathogenesis of oral submucous fibrosis
• Changes in the extracellular matrix : Arecoline appears to be

involved in the pathogenesis of OSF causing fibroblastic
proliferation and increased collagen formation.
• Involvement of connective tissue growth factor (CTGF) in
fibrosis in many human tissues is well established.
• Deng et al have shown that arecoline stimulated CTGF production
in buccal mucosal fibroblasts through generation of reactive
oxygen species (ROS), and by the activation of NF – kappa B, JNK
and p38 MAPK pathways.
• It is also known that NF- kappa B, JNK and p38 are strongly
activated by ROS.
• Arecoline influences deposition of extra cellular matrix (ECM) by

increasing the production of TIMP-1 and the effect is enhanced
when fibroblasts are co cultured with keratinocytes.
• Interaction of arecoline and keratinocytes may induce the
differentiation of myofibroblasts from fibroblasts.
• Another study proposed that areca alkaloids induce buccal mucosal
fibroblast contraction and persistent fibroblast contraction may
induce fibrotic process in OSF.
• The fact that arecoline influences ECM was further supported by
the evidence for Transglutaminase-2 (TGM – 2) over expression
in OSF and its regulation by arecoline.
• TGM – 2 stabilizes ECM protein by cross linking and has been
implicated in several fibrotic disorders
• Reduced vascularity is another hallmark of OSF.
• It is observed that prolonged exposure to arecoline (0.1mM)
significantly suppress endothelial cell proliferation.
• Also the exposure to>0.2 mM arecoline decreases the proportion
of endothelial cells residing in S phase but increases the cells
arresting in G2/M phase.
• These findings suggest that the anti-proliferative and cytotoxic
effects of arecoline are possibly associated with the alteration of
specific cell cycle regulatory proteins.
• Loss of vascularity may lead to atrophy of the epithelium and the
resulting hypoxic environment may predispose the tissue to
carcinogenesis.
• In addition to arecoline, arecanut contains more active components
including other alkaloids (arecaidine, guvacine, guvacoline and
arecolinidine), polyphenols (catechin, flavanoids, flavan3:4-diols,
leucocyanidins, hexahydroxyflavans and tannins) and trace
elements (sodium,magnesium, chlorine calcium, vanadium,
manganese, copper and bromine).
• Polyphenols of arecanut such as flavanoid, catechin and tannins
cause collagen fibers to crosslink, and thereby make them less
susceptible to collagenase degradation.
• The resulting decrease in collagen breakdown in turn leads to
increased fibrosis which is the mainstay of the pathogenesis of
OSF
Matrix metalloproteinases and Tissue inhibitors of matrix

metalloproteinases (MMPs and TIMPs)
• Since MMP-1, is the main human enzyme that degrades fibrillar

collagen, its downregulation may lead to a reduction in collagen
degradation.
• In addition, stronger intensity of TIMP-1 in fibroblasts of OSF
than in normal oral mucosa suggested improper regulation of
proteolytic equilibrium as one of the main factors responsible for
the excessive fibrosis in OSF.
• The fibroblasts in OSF have a reduced replicative life span as they
accumulate senescent cells during the progression of the disease.
• This is due to the increased amount of ROS and DNA double
strand breaks (DDBs) produced intrinsically by damaged
mitochondria.
• Endogenous collagenase activity in OSF tissues is shown to be 3-5
folds less than that in normal oral mucosa, which may also be
responsible for collagen accumulation.
Copper and related structural changes of collagen
• Copper dependant enzyme lysyl oxidase is critical for collagen

cross linking and organization of ECM.
• Salivary copper is found to be higher in arecanut chewers.
• This finding indicates that soluble copper found in arecanut is
released into the oral environment and its buccal absorption may
contribute to fibrosis of oral tissues where copper is deposited.
• This observation suggested a possible local effect of copper in the
aetiopathogenesis of OSF.
• Serum copper levels in OSF is also raised suggesting a systemic
effect and increase in serum copper level has been shown with the
advancement of the clinical stage.
Morphological features of ECM Remodelling in OSF
• Stage specific alterations in ECM have been reported.

• In the early stages of OSF over expression of tenascin, perlecan,
fibronectin and collagen type III may be found in the lamina
propria and submucosa while extensive and irregular deposits of
elastin were found around muscle fibres in the intermediate stage,
together with the above molecules.
• In the advanced stage collagen type I appears to dominate the
ECM.
• Their gene expression levels were varied with the progression of

fibrosis.
• This pattern of ECM remodeling steps in OSF is similar to normal
granulation tissue formation and maturation process.
• Difficulty in opening the mouth may be related to loss of various
ECM molecules such as elastin and replacement of muscle by
collagen type I.
• Heat shock protein (HSP) 47 , a known collagen specific
molecular chaperone involved in the processing and/or secretion of
procollagen is significantly upregulated in OSF.
• Treating fibroblast with arecoline was found to elevate HSP 47 m-
RNA expression in a dose dependent manner through MEK, PI3K
and COX-2 signal transduction pathways.
• Cystatin C, a non glycosylated basic protein is increased in a
variety of fibrotic diseases.
• Cystatin C was found to be upregulated both at m – RNA and
protein levels in OSF and arecoline is responsible for this
enhancement in a dose dependent manner.
• Malondialdehyde (MDA) is a lipid peroxidation end product with
the potential to stimulate fibroblasts and to increase collagen
production.
• MDA is significantly elevated as the grading of OSF progressed.
Inflammatory cytokines and Growth factors
• Upregulation of various cytokines namely, TGF β1, TGF β1p,

THBS1, SPP1, TIG1, TGM2 and CTGF and down regulation of
BMP7 which is a known negative modulator of fibrosis has been
reported.
• TGF β is implicated as one of the main triggers for the increased
collagen production and decreased matrix degradation pathways in
OSF.
• Treatment of cells with arecanut water extract consisting of
polyphenols and alkaloids, has shown that 64% of the differentially
regulated genes found in test samples matches with the TGF β
induced gene expression profile.
• Further, studies have revealed that keratinocytes secrete TGF β
through αvβ6 integrin expression
• Same authors have illustrated loss of TGF β expression using the
drug tropicamide that blocks αvβ6 integrin confirming that OSF is
an epithelial driven connective tissue disease.
• Phosphorylation of SMAD -2 was observed following treatment of
keratinocytes by catechin, tannin and alkaloids, hence the authors
state that arecanut mediated activation of p-SMAD – 2 involves

upregulation and activation of TGF β.
• CTGF/CCN2 and COX-2 were found to be over expressed in OSF.
The CCN2 synthesis in buccal mucosal fibroblasts is stimulated by
TGF β1 and this reaction is mediated via ALK5, JNK and p38
MAPK pathways.
• Epigallocatechin-3- gallate (EGCG) in turn can completely block
TGF β1 induced CCN2 synthesis by suppressing JNK and p38 in
buccal mucosal fibroblasts, which may be useful in controlling
OSF.
• Loss of adipose tissue in OSF was found to be due the ability of
TGF β to cause lipodystrophy.
• b-FGF is increased in fibroblasts and in endothelial cells in early
disease, and in advanced fibrosis b-FGF expression was noted
more in stroma.
• IGF-1 expression is significantly upregulated in OSF both at m-
RNA and protein levels and arecoline had been responsible for this
elevation in a dose dependant manner.
• TNF-may play a role in pathogenesis of OSF through modulation
of collagen metabolism.
• With the available literature on growth factors and cytokines, TGF
β appears to be the main mediator of the disease and others such as
TNF-α, IGF-1, b-FGF and CTGF may contribute to continuous
accumulation of collagen with activation of signaling pathways
such as ALK5, JNK, and p38 MAPK.
Epithelial–mesenchymal transition (EMT)
• Epithelial–mesenchymal transition (EMT) has gained significant

attention due to its implication in cancer and fibrosis.
• Cell injury caused by areca nut extract produces ROS which in turn
triggers both MAPK and NF-κB pathways involved in EMT of
OSF.
• Thereby exposure to areca nut extract causes alterations of normal
keratinocyte morphology and induces the cell cycle arrest at G1/S
phase and the senescence-associated phenotypes.
• Keratinocytes secrete a variety of inflammatory mediators such as
PGE2, IL-6, TNF–α and most importantly TGF-β, in response to
injury.
• Hif-1 α enhances the EMT in vitro and promotes fibrogenesis by
increasing expression of extracellular matrix–modifying factors
and lysyl oxidase genes.
• Further, it is evident that both ROS and HIF-α were necessary for
hypoxia-induced TGF-β1 upregulation.
• In OSF a possible relationship between Hif-1 α, ROS and EMT has
been revealed as an upregulation of Hif-1 α in OSF and also
production of ROS by arecoline treatment have been shown.
• In summary the above events show possible EMT in OSF leading
to fibrosis.
Molecules in cell cycle control and OSF
• ROS generated by arecoline may cause cell cycle arrest at the

G1/G0 phase in human keratinocyte cells.
• Further, oxidative stress may induce epithelial cell death without
eliciting apoptosis at higher arecoline concentration.
• However, sub-lethal concentrations of arecoline upregulated the
expression of several stress responsive genes namely; heme
oxygenase-1, ferritin light chain, glucose-6-phosphate
dehydrogenase, glutamate-cysteine ligase catalytic subunit and
glutathione reductase.
• It is also revealed that inhibition of KB epithelial cell growth in a
dose and time dependant manner and a reduction in cell number
with higher arecoline concentration.
• Further increase in arecoline concentration has induced both cell
necrosis and apoptosis.
Genetic polymorphisms predisposing to OSF
• There are estimated to be over 600 million areca nut chewers

worldwide .
• However, only 1-2% of areca nut chewers may develop the
disease.
• This suggests a possible genetic predisposition in the affected
people.
• Rapid development of OSF in young adults or even children
reported in clinical case reports further adds weight to this
hypothesis.
• HLA typing has shown certain HLA antigens with a high
significantly raised frequency in OSF patients..
• Although the exact mechanisms are not clear, various
chromosomal, genetic and molecular alterations are associated with
the pathogenesis of OSF.
• A study using Oligonucleotide microarray has shown 716 genes

upregulated and 149 genes were downregulated in OSF.
• It is identified that genes are involved in immune response,
inflammatory response and EMT induced by TGF β signaling
pathway namely SFRP4. THBS1, MMP2, ZO-1.
• In another study, differentially expressed genes in OSF had been
analyzed using bio informatic tools and the genes were located on
chromosome 1,2,5,6,7,11 and 12.
• Gene ontology (GO) classification identified these genes to be
related to cellular component sub groups associated with extra
cellular matrix, cytoskeleton and cell membrane and also biological
process subgroups associated with protein binding, signal
transducer activity, immune and defense responses.
• Polymorphisms of various genes may also contribute to an
increased susceptibility to OSF.
• Polymorphism of Cytochrome P450 3A gene family is considered
as a major determinant of inter-individual variability in chemical
pharmacokinetics.
• Cytochrome P450 had been identified as a genetic biomarker for
susceptibility to develop OSF.
• A few genes related to the pathway of CYP metabolism such as
CYP2B6, CYP2C18, CYP2F1, CYP3A5,microsomal glutathione
S-transferase 2 (MGST2), alcohol dehydrogenase (ADH), UDP
glucuronosyl transferase 2B15 (UGT2B15), and ADH1C were
found to be down regulated in all stages of OSF, thereby reducing
the ability of CYP to metabolize and clear betel nut substances and
contributing to the pathogenesis.
• Recently, genetic polymorphism of lysyl oxidase, was identified
and LOX Arg158G
• In appeared to be associated more in elderly OSF patients.
• Polymorphisms of collagen-related genes on OSF risk had been
investigated.
• A study focused on the single nucleotide polymorphisms (SNPs)
of TGFβ -1 gene reported that polymorphism in 5¢UTR C-T in
TGF beta 1 gene associated with pro-angiogenic pathway has a
significant association with OSF.
• Relationship between OSF and TNF-α genetic polymorphism, was
not confirmed as the genotype distribution of TNF-α genetic
polymorphism show similar distribution among areca chewers and
nonareca chewers.
CLINICAL FEATURES
• The onset is insidious, over a two to five years.

• The disease first presents with a burning sensation of the mouth,
particularly during consumption of spicy foods.
• The first sign is erythematous lesions sometimes in conjunction
with petechiae, pigmentations.
• It is often accompanied by the formation of vesicles or ulcerations
and by excessive salivation or xerostomia and altered taste
sensations.
• These initial lesions are followed by a paler mucosa, which may
comprise white marbling
• Gradually, patients develop a stiffening of the mucosa, with a

dramatic reduction in mouth opening and with difficulty in
swallowing and speaking.
• The mucosa appears blanched and opaque with the appearance of
fibrotic bands that can easily be palpated.
• The bands usually involve the buccal mucosa, soft palate, posterior
pharynx, lips, and tongue.
• The atrophic epithelium may cause a smarting sensation and
inability to eat hot and spicy food.
• More than 25% of the patients exhibit also oral leukoplakias
• OSF usually affects young individuals in the second and third
decades of life but may occur at any age.
Early OSF
• This includes a burning sensation in the mouth when consuming

spicy food, appearance of blisters especially on the palate,
ulcerations or recurrent generalized inflammation of the oral
mucosa, excessive salivation, defective gustatory sensation and
dryness of the mouth.
• There are periods of exacerbation manifested by the appearance of
small vesicles in the cheek and palate.
• The intervals between such exacerbation vary from three months to
one year.
• Focal vascular dilatations manifest clinically as petechiae in the
early stages of the disease.
• This may be part of a vascular response due to hypersensitivity of
the oral mucosa towards some external irritant like arecanut
products.
• Petechiae are observed in about 22% of OSF cases (Rajendran,
1994), mostly on the tongue followed by the labial and buccal
mucosa with no sign of blood dyscrasias or systemic disorders.
• Pain in areas where submucosal fibrotic bands are developing

when palpated is a useful clinical test.
Reticular blanching: Reticular (lace like )blanching consists of
blanched areas with intervening,clinically normal mucosa,giving it
a lace-like appearance . Over a period of time ,one blanching may
change to another . ( Fali S . Mehta)
Advanced OSF
• As the disease progresses, the oral mucosa becomes blanched and

slightly opaque, and white fibrous bands appear.
• The buccal mucosa and lips may be affected at an early stage,
although it was thought that the palate and the faucial pillars are
the areas involved first.
• The oral mucosa is involved symmetrically (with possible
exception) and the fibrous bands in the buccal mucosa run in a
vertical direction.
• The density of the fibrous deposit varies from a slight whitish area
on the soft palate, causing no symptoms, to a dense fibrosis,
causing fixation and shortening or even deviation of the uvula and
soft palate.
• The fibrous tissue in the faucial pillars ranges from a slight
submucosal accumulation in both pillars to a dense fibrosis
extending deep into the pillars with strangulation of the tonsils.
• It is this dense fibrosis, involving the tissues around the
pterygomandibular raphae, that causes varying degrees of difficulty
in mouth opening.
• A factor which seems to be overlooked by many investigators
while recording the extent of mouth opening is the acuteness of
oral symptoms (persistent/recurrent glossitis and stomatitis) at the
time of recording.
• Sometimes the fibrosis spreads to the pharynx and down to the
piriform fossae.
• Upon palpation, a circular band can be felt around the entire rima
oris (mouth orifice), and these changes are quite marked in the
lower lip.
• All observers have noted impairment of tongue movement in
patients with advanced OSF with significant atrophy of the tongue
papillae.
• With progressing fibrosis, the stiffening of certain areas of the
mucosa occurs leading to difficulty in opening the mouth, inability
to whistle or blow out a candle and difficulty in swallowing.
• When the fibrosis involves the nasopharynx, the patient may

experience referred pain to the ear and a nasal voice as one of the
later signs in some patients.
• Rao AB etal 1962 finds deafness due to occlusion of the
Eustachian tubes in one third of the patients.
• DeSa and Millard mention a, nasal voice as one of the later
symptoms in some patients.
• Leukoplaki is found in about 26 % OSF cases
Association of Candida with clinical manifestations of OSF
• Burning sensation is the most common initial symptom of OSF

patients.
• Factors associated with burning sensation are- hyposalivation,
altered composition and rheological properties, systemic conditions
(e.g.-diabetes), altered epithelium and Candidal colonization.
• Mouth Opening, Salivary Flow Rate, xerostomia and burning
sensation are important to study as these manifestations could have
an effect and cause relationship.
• Various studies have reported the relationship between the
Candidal colonization and above-mentioned oral manifestations of
stomatopyrosis,reduced mouth opening and altered salivary flow.
(Siddabasappa S 2014 and Gupta B 2015)
ASSOCIATION OF CANDIDA AND OSF-
• It has been recently suggested that the mucosal alterations

(especially of the epithelium) like tough and leathery mucosal
texture, blanching of oral mucosa, palpable fibrous bands, and
restricted MO in OSF, act as a platform for increased Candidal
colonization, thus affecting the biological behavior of the disease
process.
• Studies regarding asoociation of Candida and OSF were initiated
almost a decade back.
Histological features
• Early OSF: Histologically, they revealed a slightly hyperplastic

epithelium, sometimes atrophic with numerous dilated and blood-
filled capillaries juxtaepithelially .
• The inflammatory cells seen are mainly lymphocytes, plasma cells
and occasional eosinophils.
• The presence together of large numbers of lymphocytes and

fibroblasts as well as plasma cells in moderate numbers, suggests
the importance of a sustained lymphocytic infiltration in the
maintenance of the tissue reaction in OSF.
• This picture is followed by a down-regulation of fibroblasts,
epithelial atrophy, and loss of rete pegs, and early signs of
hyalinization occur in concert with an infiltration of inflammatory
cells.
• Cellular elements and blood vessels are greatly reduced.
• Epithelial dysplasia in submucous fibrosis tissues appeared to vary
from 7 to 26% depending on the study population
Classifications of OSF
1. JV Desa (1957) divided OSF into three stages as follows:

• Stage I: Stomatitis and vesiculation
• Stage II: Fibrosis
• Stage III: As its sequelae
2. Wahi P.N. and Kapur V.L. et al (1996) classified OSF based

on the clinical features, severity and extent of involvement into 3
groups.
• Group I: Usually there are no symptoms referable to mucosal
involvement.
• The lesion affects one or other commonly involved anatomical
site, shows pallor or whitish coloration, wrinkling of mucosa
and minimal induration.
• Group II: Cases present with symptoms like soreness of mucosa
or increased sensitivity to chillies.
• The lesion is diffuse, white, extensive and indurated, involving
one or more anatomical sites.
• Group III: symptoms are mostly due to restricted mobility like
trismus, stretching at the angles of the mouth altered
pronunciation and inability to protrude the tongue.
• Firm submucosal bands are palpable. Surface may be fissured
or ulcerated.
3. Bhatt A. P. and Dholakia H.M. clinically grouped the patients

into three grades as:
• Grade I: Comprised of mild and early cases with a very slight
fibrous bands and little closure of the mouth.
• Grade II: Moderately pronounced symptoms with fibrous bands
extending from the cheek to the palate.
• Grade III: Excessive amount of fibrosis involving the cheek, palate,
uvula, tongue and the lips with narrow opening of the mouth.
4. Gupta D.S. and Golhar B.L. classified into four stages based on
the increasing intensity of trismus as:
• Very early stage: The patients complain of burning sensation in
the mouth or ulceration without difficulty in MO.
• Early stage: Along with burning sensation, the patients complain
of slight difficulty in opening the mouth.
• Moderately advanced stage: The trismus is marked to such an
extent that the patient cannot open his/her mouth more than two
fingers width therefore experiencing difficulty in mastication.
• Advanced stage: Patient is undernourished, anemic and has a
marked degree of trismus.
5. Jain P et al (1988) co-relate the severity of OSF with the degree of

mouth opening as
• · Grade I- 40-42 mm
• · Grade II- 31- 39 mm
• · Grade III- 21- 30 mm
• · Grade IV- 10- 20 mm
6. Pindborg JJ in 1989 divided OSF into three stages as follows

• Stage I: Stomatitis includes erythematous mucosa, vesicles,
mucosal ulcers, melanotic mucosal pigmentation and mucosal
petechiae.
• Stage II: Fibrosis occurs in healing vesicles and ulcers, which is
the hallmark of this stage.
· Early lesions show blanching of the oral mucosa.
· Older lesions include vertical and circular palpable fibrous
bands in the buccal mucosa and around the MO or lips.
· This results in a mottled marble like appearance of the
mucosa because of the vertical thick, fibrous bands in
association with a blanched mucosa.
· Specific findings include reduction of MO, stiff and small
tongue, blanched and leathery floor of the mouth, fibrotic
and de-pigmented gingiva, rubbery soft palate with
decreased mobility, blanched and atrophic tonsils, shrunken

bud like uvula and sunken cheeks, not commensurate with
age or nutritional status.
• Stage III: Sequelae of OSF are as follows:
· Leukoplakia is found in more than 25% of individuals with
OSF.
·Speech and hearing deficit may occur because of
involvement of tongue and the Eustachian tube.
7. Katharia S.K. et al described a scoring system based on the MO

present between upper and lower central incisors as:
• Score 0: MO is greater than 41 mm
• Score 1: MO between 37 to 40 mm
8. Racher S.K classified into 3 stages based on habits as:
• Stage I: Stage of Stomatitis and Vesiculation

• Characterized by recurrent stomatitis and vesiculation.
• Patient complains of burning sensation in the mouth and inability
to eat pungent food.
• The examination reveals vesicles on the palate that may rupture
and a superficial ulceration may be seen.
• Some amount of fibrosis can be seen.
• Stage II: Stage of fibrosis

• Inability to open the mouth completely and stiffness in mastication.
• As disease advances, there is difficulty in blowing the cheeks and
protruding the tongue.
• On examination, there is increased fibrosis in the submucosa.
Mucosa is blanched and white. Lips and cheeks are stiff. Dorsum
of the tongue may show atrophy of papillae. Blanching and
stiffness of the mucosa of the floor of the mouth is less marked
than that seen in the lips, cheeks and palate. Larynx is free from
disease and respiration is not affected
• Stage III: Stage of sequelae and complications

• Leukoplakia changes in the mucosa.
• An ulcerating malignant lesion may be seen involving the cheeks,
oropharynx or the tongue.
9. Lai D.R. grouped OSF on the basis of interincisal distance as:

• Group A: Interincisal distance greater than 35 mm.
• Group B: Interincisal distance 30 to 35 mm.
• Group C: Interincisal distance 20 to 30 mm.
• Group D: Interincisal distance less than 20 mm.
10. Haider S.M. classified on the basis of severity of disease taking

objective parameters like MO into consideration.
I: Clinical staging
1. Faucial bands only.
2. Faucial and buccal bands.
3. Faucial, buccal and labial bands.
II: Functional staging

1. MO greater than 20 mm.
2. MO between 11 to 19 mm.
3. MO less than 10 mm.
11. Ranganathan K. et al divided OSF based on MO as follows:

• Group I: Only symptoms with no demonstrable restriction of
MO.
• Group II: Limited MO 20 mm and above.
• Group III: MO less than 20 mm.
• Group IV: OSF advanced with limited MO. Precancerous or
cancerous changes are seen throughout the mucosa.
12. Rajendran R. reported the clinical features of OSF as follows:

• Early OSF: Comprises of burning sensation in the mouth,
blisters especially on the palate, ulceration or recurrent
generalized inflammation of oral mucosa, excessive salivation,
defective gustatory sensation and dryness of mouth.
• Advanced OSF: Comprises of blanched and slightly opaque
mucosa, fibrous bands in the buccal mucosa running in vertical
direction. Palate and faucial pillars are the areas first involved
with gradual impairment of tongue movement and difficulty in
MO.
13. Bose T. and Balan A. classified based on clinical features as:

• Group A: Mild cases

• Only occasional symptoms, pallor, vesicle formation, presence
of one or two solitary palpable bands, loss of elasticity of
mucosa, variable tongue involvement with protrusion beyond
vermillion border. MO is greater than 3 cm.
• Group B: Moderate cases

• Symptoms of soreness of mucosa or increased sensitivity to
chillies, diffuse involvement of the mucosa, blanched
appearance, buccal mucosa tough and inelastic fibrous bands
palpable, considerable restriction of MO(1.5 to 3 cm) and
variable tongue movement.
• Group C: Severe cases

• Symptoms are more severe, broad fibrous bands palpable,
blanched opaque mucosa, rigidity of mucosa, very little opening
of mouth (less than 1.5 cm), depapillated tongue and protrusion
of tongue very much restricted.
14. Kumar K. et al categorised OSF based on MO as follows:

• Stage I: MO greater than 45 mm.
• Stage II: MO between 20 to 44 mm.
• Stage III: MO less than 20 mm.
15. Mehrotra D. et al suggested a clinical grading of the disease as:

• Grade I: Stomatitis, burning sensation in the buccal mucosa
and with no detection of fibres.
• Grade II: Symptoms of grade I, palpable fibrous bands,
involvement of soft palate and maximal MO of 26 to 35 mm.
• Grade III: Symptoms of grade II, blanched oral mucosa,
involvement of tongue and maximal MO of 6 to 25 mm.
• Grade IV: Symptoms of grade III, lip fibrosis and MO of 0 to 5
mm.
16. More C.B. et al gave the following classification based on

clinical and functional parameters as:
• I: Clinical staging:
• Stage 1 (S1): Stomatitis and/or blanching of oral mucosa.
• Stage 2 (S2): Presence of palpable fibrous bands in buccal
mucosa and/or oropharynx, with/without stomatitis.
• Stage 3 (S3): Presence of palpable fibrous bands in buccal
mucosa and/or oropharynx, and in any other parts of oral cavity,
with/without stomatitis.
• Stage 4 (S4): A: Any one of the above stage along with other
PMD e.g. oral leukoplakia, oral erythroplakia, etc.
• B: Any one of the above stage along with oral carcinoma.
• II: Functional staging:

• M1: Inter-incisal MO up to or greater than 35 mm.
• M2: Inter-incisal MO between 25 to 35 mm.
• M3: Inter-incisal MO between 15 to 25 mm.
• M4: Inter-incisal MO less than 15 mm.
17. Kerr A.R. et al gave the following grading system for OSF as:
• Grade 1: Mild: Any features of the disease triad for OSF
(burning, depapillation, blanching or leathery mucosa) may be
reported and inter-incisal opening >35 mm.
• Grade 2: Moderate: Above features of OSF and inter-incisal
limitation of opening between 20 to 35 mm.
• Grade 3: Severe: Above features of OSF and inter-incisal
opening < 20 mm.
• Grade 4A: Above features of OSF with other PMD on clinical
examination.
• Grade 4B: Above features of OSF with any grade of oral
epithelial dysplasia on biopsy.
• Grade 5: Above features of OSF with oral SCC.
CLASSIFICATIONS BASED ON HISTOPATHOLOGICAL

FEATURES OF OSMF:
1. Pindborg JJ and Sirsat SM (1966) were the first to divide OSMF

depending only on histopathological features alone are as follows:
• Very early stage: Finely fibrillar collagen dispersed with marked
edema. Plump young fibroblast containing abundant cytoplasm.
• Blood vessels are dilated and congested. Inflammatory cells,
mainly polymorphonuclear leukocytes with occasional eosinophils
are found.
• Early stage: Juxta-epithelial area shows early hyalinization.
Collagen still in separate thick bundles.
• Moderate number of plump young fibroblasts is present. Dilated
and congested blood vessels. Inflammatory cells are primarily
lymphocytes, eosinophils and occasional plasma cells.
• Moderately advanced stage: Collagen is moderately hyalinized.
Thickened collagen bundles are separated by slight residual edema.
Fibroblastic response is less marked. Blood vessels are either

normal or compressed. Inflammatory exudate consists of
lymphocytes and plasma cells.
• Advanced stage: Collagen is completely hyalinized. Smooth
sheets with no separate bundles of collagen is seen. Edema is
absent. Hyalinized area is devoid of fibroblasts. Blood vessels are
completely obliterated or narrowed. Inflammatory cells are
lymphocytes and plasma cells.
2. Utsunomiya H, Tilakratne WM, Oshiro K et al (2005) histologically

divided OSMF based on the concept of Pindborg and Sirsat and modified
it as follows:–
• Early stage: Large number of lymphocytes in subepithelial,
connective tissue, zone along with myxedematous changes.
• Intermediate stage: Granulation changes close to the muscle layer
and hyalinization appears in subepithelial zone where blood vessels
are compressed by fibrous bundles. Reduced inflammatory cells in
subepithelial layer.
• Advanced stage: Inflammatory cell infiltrate hardly seen. Number
of blood vessels dramatically small in subepithelial zone. Marked
fibrous areas with hyaline changes extending from subepithelial to
superficial muscle layers. Atrophic, degenerative changes start in
muscle fibers.
3. Kiran Kumar et al (2007) proposed histological grading as follows:

• Grade I: Loose, thick and thin fibers
• Grade II: Loose or thick fibers with partial hyalinization
• Grade III: Complete hyalinization
CLASSIFICATION BASED ON CLINICAL AND

HISTOPATHOLOGICAL FEATURES:
• Khanna JN and Andrade NN (1995) developed a group

classification system for the surgical management of OSMF.
• Group I:- Very early cases: Common symptom is burning

sensation in the mouth, acute ulceration and recurrent stomatitis
and not associated with mouth opening limitation.
• Histology: Fine fibrillar collagen network interspersed with marked
edema, blood vessels dilated and congested, large aggregate of
plump young fibroblasts present with abundant cytoplasm,
inflammatory cells mainly consist of polymorphonuclear

leukocytes with few eosinophils. The epithelium is normal.
• Group II: Early cases—Buccal mucosa appears mottled and

marble like, widespread sheets of fibrosis palpable, interincisal
distance of 26 to 35 mm.
• Histology: Juxta -epithelial hyalinization present, collagen present
as thickened but separate bundles, blood vessels dilated and
congested, young fibroblasts seen in moderate number,
inflammatory cells mainly consist of polymorphonuclear
leukocytes with few eosinophils and occasional plasma cells,
flattening or shortening of epithelial rete-pegs evident with varying
degree of keratinization.
• Group III: Moderately advanced cases— Trismus, interincisal

distance of 15 to 25 mm, buccal mucosa appears pale firmly
attached to underlying tissues, atrophy of vermilion border, vertical
fibrous bands palpable at the soft palate, pterygomandibular raphe
and anterior faucial pillars.
• Histology: Juxta -epithelial hyalinization present, thickened
collagen bundles, residual edema, constricted blood vessels, mature
fibroblasts with scanty cytoplasm and spindle-shaped nuclei,
inflammatory exudate which consists of lymphocytes and plasma
cells, epithelium markedly atrophic with loss of rete pegs, muscle
fibers seen with thickened and dense collagen fibers.
• Group IVA: Advanced cases—severe trismus, interincisal
distance of less than 15 mm, thickened faucial pillars, shrunken
uvula, restricted tongue movement, presence of circular band
around entire lip and mouth.
• Group IVB: Advanced cases—presence of hyperkeratotic

leukoplakia and/or squamous cell carcinoma.
• Histology: Collagen hyalinized smooth sheet, extensive fibrosis,

obliterated the mucosal blood vessels, eliminated melanocytes,
absent fibroblasts within the hyalinized zones, total loss of
epithelial rete pegs, presence of mild to moderate atypia and
extensive degeneration of muscle fibers.
Diagnosis
 The diagnosis of submucous fibrosis is based on the clinical

characteristics and on the patient‘s report of a habit of betel quid
chewing.
 An international consensus has been reached where at least one of
the following characteristics should be present:
• Palpable fibrous bands
• Mucosal texture feels tough and leathery
• Blanching of mucosa together with histopathologic features
consistent with oral submucous fibrosis (atrophic epithelium with
loss of rete ridges and juxtaepithelial hyalinization of lamina
propria)
Biological Studies on Individuals and Tissues from OSF
• Blood chemistry and hematological variations

• Deficiency of vitamin B12, folate and iron can affect the integrity
of the oral mucosa.
• Significant hematological abnormalities have been reported in
OSF, including an increased erythrocyte sedimentation rate (ESR),
anemia and eosinophilia, increased gammaglobulin, a decrease in
serum iron and an increase in total iron binding capacity (TIBC).
• The percentage saturation of transferrin also decreased and a
significant reduction in total serum iron and albumin was found.
• The role of iron deficiency anemia as the cause or the effect of the
disorder is doubtful.
• A rise in serum mucoproteins, mucopolysaccharides and
antistreptolysin titer ‗O‘ (measured in Todd‘s unit) has also been
reported.
• A significant depression of the lactate dehydrogenase isoenzyme
ratio (LDH IV/LDH II) is reported at the tissue level in OSF.
• A significant alteration in the serum copper and zinc ratio is also
reported with a reduction in zinc content.
• Chromosomal instability has long been associated with the
neoplastic process and the quantitative assay of sister chromatid
exchange (SCE) provides an easy, rapid and sensitive method for
studying chromosome/DNA instability and its subsequent repair
processes.
• This increase may be attributed to the genotoxic effect of the
constituents of betel quid.
• The role of areca nut alkaloids in this regard may be significant.
• Silver-binding nucleolar organizer region proteins (AgNORs)
• comprise a simple and reproducible cytological test indicative of

the proliferative status of cells, particularly of epithelial and
hematopoetic origin.
• It was found that the pooled mean AgNOR count in clinically
advanced OSF was higher than in moderately advanced cases.
• Counting of AgNORs may be useful as a predictor of the biological
behavior of OSF.
Immunological studies
• Because of a possible immunological connection, the fact that the
disease has been reported in subjects who do not practice the betel
habit and the inability to prove a dose and effect relationship in all
cases, the question arose whether there is a predisposition for the
disease.
• In this respect, the finding by Canniff et al (1981) that the human
leukocyte antigens (HLA) A10, B7 and DR3 occurred significantly
more frequently in OSF, is important.
• In addition, studies on the relationship between systemic disease
and OSF proved negative.
Cell kinetic studies

• Investigations carried out in the UK and South Africa found that
the growth of OSF fibroblasts is normal.
• However, when fibroblasts are exposed to the alkaloids of areca
nut their proliferation rate, according to certain workers, increases;
a finding in contrast to others‘ results.
• The second group found a dose-dependent inhibition of growth by
alkaloids (van Wyk et al, 1995).
• These studies prompt one to propose that the connective tissue
changes in OSF are probably not due to increased fibroblast
proliferation.
• On the other hand, OSF fibroblasts can play a role in
overproduction of collagen.
• The UK group (Scutt A et al, 1987) found that collagen formation
by fibroblasts increases when exposed to nut extracts and alkaloids,
a finding which has been questioned recently by Jeng et al (1996),
whose findings were contradictory.
• Thus it would seem that OSF fibroblasts have the capability to
produce collagen in excess, but what triggers it, is controversial.
• Ma et al (1995) discovered increased lysyl oxidase activity in
fibroblasts cultured from OSF patients.
• Lysyl oxidase, an extracellular metalloenzyme of copper, is
secreted by fibroblasts and initiates cross-linking of collagen which
makes it relatively resistant to digestion by mammalian

collagenase.
• Therefore, increased lysyl oxidase activity can result in collagen
accumulation.
DIFFERENTIAL DIAGNOSIS
• Anemia: Pale oral mucosa can mimic atrophy and fibrosis

• Oral lichen planus : Wickham striae can mimic atrophy and
fibrosis esp in case of reticular blanching in early OSF.
• Oral manifestations of scleroderma : Scleroderma can be
distinguished by other cutaneous, systemic, and characteristic
laboratory findings.
• Generalized fibromatosis : Although soft tissue masses are not
produced in the usual sense, the fibrosis of oral submucous fibrosis
may be confused with generalized fibromatosis.
• Amyloidosis: Hyalinized stroma can be distinguished from
amyloid infiltration by using Congo red and thioflavine T staining
under polarized and immunofluorescent light, respectively.
• Recently Trivedy et al (1997) demonstrated that the copper
content in areca nut is relatively high and that it is released in the
mouth with chewing.
• Other reasons proposed for an excessive accumulation of collagen
are decreased collagenase activity in OSF mucosa and reduced
phagocytosis by OSF fibroblasts, recently shown by Taiwanese
researchers.
• In both instances, accumulation of collagen is enhanced.
• Unfortunately, none of these findings give an answer for the
persistence of the disease, or for the continuing deposition of
excessive collagen after stoppage of the habit.
• To conclude, the effect of the areca nut on cells is the trigger
resulting, initially among others, in excessive accumulation of
collagen which is followed by a permanent change possibly in the
fibroblast population, characterized by a continued abnormal
accumulation of collagen.
• The mechanism of this permanent change is not known at present.
TREATMENT AND PROGNOSIS
• OSF is very resistant to treatment.

• Products derived from areca nuts are carcinogenic, regardless of

tobacco use as an adjunct.
• Thus, treatment of submucous fibrosis should be focused on
cessation of the chewing habits.
• If this is successfully implemented, early lesions have a good
prognosis as they may regress.
• Many treatment regimens have been proposed to alleviate the signs
and symptoms, without much success.
• To improve current treatment regimens of OSF, the following

strategies have been proposed:
1. Nutritional support , Micronutrients and Antioxidants : Mainly for
high proteins and calories and for vitamin B complex and other
vitamins and minerals ( Zn,Cu,I,Mn,Mg,Se,) and
Antioxidants :
Lycopene (16 mg of lycopene daily in 2 divided doses for 2
months ) ,
Beta carotene : 6 weeks of treatment with tablets containing
mostly beta-carotene and vitamin E thrice daily, showed an
effective increase in MO and tongue protrusion in OSF patients ,
Curcumin, Spirulina (capsules 0.5gm twice daily for a period of 4

months), Papain (cysteine protease) with keratolytic action of urea:
(Gupta et al., 1992)
2. Immunomodulatory drugs: Local and systemic applications of
glucocorticoids and collagenase placental extracts (Lin and Lin
2007) are commonly used.
These also prevent or suppress inflammatory reaction, thereby
preventing fibrosis by decreasing fibroblastic proliferation and
deposition of collagen.
• Levimazole, Immune milk from cows immunised with multiple
human intestinal bacteria(Tai et al., 2001)
3. Physiotherapy: This includes measures such as forceful mouth

opening (splints and device) , physical excersise and heat therapy.
• Kneading is an effective form of massage therapy in improving the
elasticity of fibrous tissues and mobilizing scar tissues.
• The gentle soft tissue manipulation is extensively used in
physiotherapy for improving their extensibility
• Heat (Microwave Diathermy) has been commonly used and the
results have been described as satisfactory. Heat in the form of
lukewarm water, hot rinses or selective deep heating therapies like
short wave or micro wave diathermy. It acts by physio fibrinolysis

of bands.
4. Local drug delivery: Local injections of corticosteroids and

placental extract have been tried, in addition to hyaluronidase,
collagenase and similar substances which break down intercellular
cement substances and also decrease collagen formation.
• Glucocorticoids were the first group of drugs to be used in the
treatment of OSF patients
• Due to its anti-inflammatory action, it inhibits the production of
inflammatory factors and increases the apoptosis of inflammatory
cells, thus, inhibiting the proliferation of fibroblasts, up-regulation
of collagen synthesis and down-regulation of collagenase
production.
• Hydrocortisone intralesional injection 1.5cc given once a week for
a duration of 12 weeks have proven to be beneficial.
• Topical triamcinolone acetonide 0.1% and local injection of
triamcinolone acetonide can be used in very early and early cases.
• Dexamethasone 4mg intralesional injections, is given biweekly.
dexamethasone bio-adhesive mucosal patch Sumanth et al (2010 )
• DeSa and Rao recommended the combined use of systemically
administered corticosteroids and locally injected hydrocortisone.
• Improvement does not seem to be permanent, however.
Placental Extracts (Placentrax)

• 2cc of placentrix injection intralesionally at weekly intervals for 10
weeks was found to be superior to cortisone.
Recombinant Human Interferon Gamma (γ-IFN)

• γ-IFN is a known anti-fibrotic cytokine.
• The antifibrosis factor caused down regulation of fibroblast
proliferation and collagen synthesis, upregulation of antifibrotic
cytokine and collagen synthesis in the basal layer of epithelium and
lamina propria.
Enzymes
• Chymotrypsin an endopeptidase, acts as a proteolytic and anti-
inflammatory agent.
• Local injection of chymotrypsin has proved to be successful in
treating OSF.
• Chymotrypsin (5000 IU), twice weekly submucosal injections for

10 weeks.
• Hyaluronidase by breaking down hyaluronic acid, lowers the
viscosity of intracellular substances and decreases collagen
formation.
• The combination of steroids and hyaluronidase shows better long-
term results than either agent used alone.
• Intralesional injections of 1500 IU of hyaluronidase mixed with
2% lignocaine twice daily for 10 weeks have been tried and
satisfactory results have been obtained in OSF patients who have
severe limitation in MO.
• Collagenase: is a lysosomal enzyme, capable of degrading
phosphate esters, proteins, polysaccharides, glycosides and
sulphate esters.
• Collagenase treatment is approximately five fold more effective
than triamcinolone acetate. 2mg of collagenase materials dissolved
in 1ml of distilled water for injection purposes
5. Combined therapy: With peripheral vasodilators (nylidrin

hydrochloride, Pentoxifylline 400mg twice daily), vitamins D, E
and ‗B‘ complex, iodine, placental extract, local and systemic
corticosteroids and physiotherapy claim a high success rate in OSF
management.
The evaluation of the merits and disadvantages of individual items
in treatment is not possible due to the use of combined treatment
protocols; unavoidable at present because of the empirical nature of
each approach.
6. Ultrasound as treatment modality-

• During ultrasound therapy, cell membrane permeability is
increased by altering sodium and potassium ion gradients.
• This increased permeability improves gas exchange and promotes
healing.
• It increases vasodilatation, accelerates lymph flow, decreases
inflammation and stimulates metabolism.
• Ultrasound used for therapeutic purpose has a frequency of about
0.8-1 MHz and an intensity of 0.5-3 w/cm2.
• Ultrasound treatment accelerate healing, increase the extensibility
of collagen fibers, provide pain relief and selectively raises the
temperature in some well circumscribed areas
7. Surgical management: Measures such as forcing the mouth open

and cutting the fibrotic bands have resulted in more fibrosis and
disability.
• Submucosal resection of fibrotic bands and replacement with a
partial thickness skin or mucosal graft have also been attempted
along with procedures such as bilateral temporalis myotomy.
• At a retrospective glance, surgery seems to be a poor option in the
overall management of the disease.
• Controlled studies of different regimens in the management of OSF
are needed.
• They will not be easy to organize becauseof the number of items in
current management protocols, but they should greatly increase our
understanding of OSF.
• Systematic review with objectives
1. To develop a systematic map on the current medical (ie
non-surgical) interventions available for the management of
OSF.
2. To update the evidence on the medical interventions for
the management of OSF
In this systematic review a low grade of evidence was found to support
recommendations for the management of OSF.
• However, using the information from the review, this working
group developed a framework to propose multi-center research in
countries where OSF remains a serious public health issue.
Malignant transformation
• Malignant transformation of OSF has been a topic of much

discussion and uncertainty since it was first described in 1956.
• In a 17- year-follow-up study Murti et al., 19 recorded a malignant
transformation rate of 7.6%.
• A study from Kolkata, India reported 2.6% transformation rate
whereas a report from Nagpur, India found a transformation rate of
3.3%.
• The often cited metric of a 7-13% malignant transformation rate of
OSF stems from a Taiwanese study which aimed to estimate the
rate and the time to transformation in a group of patients from
southern Taiwan with potentially malignant oral epithelial lesions.
• This study reported a transformation rate for epithelial dysplasia
with OSF as 5.4% with the mean duration of 40 months (the rate
for OSF only was 1.9%).
• A similar study from Taiwan found malignant transformation in

epithelial dysplasia with OSF to be 4.84% whereas the
transformation with OSF alone was 3.72%.
• The highest transformation rate we found was reported in the
IARC monograph in OSF being 7.6% from India.
• Other studies have reported transformation rate of 1.9% with a
median duration of 52.3 months.
• Use of alcohol contributed significantly to malignant
transformation of OSF.
PALATAL LESIONS IN REVERSE SMOKERS
• Reverse smoking is smoking with the lightened end inside the

mouth is a peculiar habit mostly prevalent among adult fishermen
of coastal rural Andhra Pradesh, India.
• Reverse smoking was also reported in various other populations
like rural barangays in Cabanatuan City, Philippines and also from
few communities in South America, The Caribbean, The
Netherlands, Columbia, Sardinia etc.
• The smoking device is a homemade cigar made by crudely rolling
few semi dried tobacco twigs, called as ―chutta‖.
• practice of this habit in the local language is called as ―Adda
Poga‖.
• The word chutta is derived from the Tamil word ―churutu‖ which
means ―to roll or fold‖.
• The characteristic feature of this habit is that the lit extreme of the
chutta is kept inside the mouth and then closed, lips seal the mouth
thereby allowing slow inhalation of smoke from chutta and the
smoke is let out from the unlit end.
• This habit of reverse smoking is frequently observed in females
than males.
• According to Gavarasana and Susarla, the frequency of reverse
smoking was 6.23 times higher in females than males.
• The prevalence of this habit among females has been attributed to
various reasons like:
1. Females started reverse smoking because they wanted to keep their

smoking habit a secret from their husbands and parents.
2. Because of strong winds and splashing water during household
work and fishing, the lit end of the chutta would get extinguished if
used in the conventional method.
3. Also, fisherwomen during weaving wanted to prevent the hot ashes

from falling on to the fishing net to prevent its damage.
There are few taboos involved such as: The habit was practiced to
reduce the tooth ache, mask halitosis and children were forcefully
made to smoke chutta in reverse to get rid of various diseases.
4. Reverse smoking was also reported in various other populations
like rural barangays in Cabanatuan City, Philippines and also from
few communities in South America, The Caribbean, The
Netherlands, Columbia, Sardinia etc.
5. In India, this habit of reverse smoking is predominantly seen in
regions of Andhra Pradesh like Srikakulam District, East Godavari
District and in states of Orissa and Goa.
6. The female predominance has been consistently reported among all
the above communities except in Sardinia.
7. According to Van Der EB et al., 33% of total north rural coastal
areas of Andhra population practised reverse smoking out of that
the prevalence rate of palatal lesions was 55% of the population.
Clinical features
• The clinical manifestations of the oral mucosa in patients with

reverse smoking habit are reported to vary from conventional
smokers and nonsmoking individuals.
• The commonly affected areas in reverse smokers are palate and
tongue.
• This form of smoking evokes diverse alterations which can be
categorized into several interrelated components such as: palatal
keratosis, excrescences,patches,red areas, leukoplakia, ulcerations
and pigmentation changes.
• According to Ortiz 96.7% of Fillipino women with reverse
smoking habit exhibited palatal mucosal changes including
leukoplakia, mucosal thickening, fissuring, pigmentation,
nodularity, erythema and ulceration whereas 26.7% of
conventional smokers exhibited mucosal changes predominantly
focal pigmentation and mild erythema.
• Earlier, these changes induced by reverse smoking were called as
nicotinic stomatitis.
• This led to a controversy as it is well-known that nicotine alone is
not the etiological factor.
• There is no report about the actual terminology yet, the term
―palatal changes associated with reverse smoking‖ or ―palatal
keratosis associated with reverse smoking‖ is well-accepted.
• Gupta et al. in 1984 performed a 10-year followup study of

tobacco usage and oral disease in a random sample of 10,169
individuals of Srikakulam district between 1967 and 1976, they
reported that both in men, as well as in women the age-adjusted
mortality rates were nearly twice for reverse smokers than those of
other tobacco users.
PALATAL CHANGES INDUCED BY REVERSE

SMOKING/CLASSIFICATION
Palatal keratosis :
• Palatal keratosis denotes the diffuse whitening of the palatalal
mucosa .
• It may be mild, moderate or severe in intensity.
• Palatal keratosis may occur independently or coexist with other
components.
• Overall ,it forms upto 55% of the palatal components.
Excrescences:
• It comprise 1-3mm elevated areas ,often with central red dots
marking the orifices of the palatal mucous glands.
• Some 46% of the palatal changes consists of it
• It represents the initial palatal reaction and they are generally
transient.
• The milder form of excrescences resemblethe smoker‘s palate seen
in conventional smokers.
Reverse dhumti smokers lesion :

• Dhumti is akind of cigar used in Goa .
• It is smoked in reverse by a small section of people
• This form of smoking produces a palatal reaction akin to, but less
severe than the palatal changes by reverse chutta smoking.
Patches :
• Are welldefined ,elevated plaques which could qualify for the
clinical term Leukoplakia.
• Palatal patches show characteristic histological features that differ
from the features of leukoplakia.
• Patches can be small or large.
• These account upto 12% of the palatal components.
Red areas:
• Red areas are well difined reddening of the palatal mucosa .
• Clinically ,they are indistinguishable from erythroplakias.
• Red areas form only 2% of the palatal components.
• Nevertheless, they are the most serious ,showing epithelial
dysplasia in 52% of the cases.
• Long term studies demonstrate a high rate of malignant
transformation.
Ulcerated areas:
• Ulcerated areas are charcterized by crater-like ulcerations with
deposits of fibrin often surrounded by keratinization
• Ulcerations form only 2% of the palatal components.
• They represent a ‗burn‘ type reaction of the palatal mucosa from
the intense heat of the lighted end of chutta.
• A similar lesion was observed in an individual from Ernakulam
district who ate ‗ piping –hot‖ rice ,but never smoked in reverse
fashion.
Hyperpigmentation:
• Pigmentation changes that include hyperpigmentation and loss of
pigmentation ,occur almost in all cases of chutta smokers
• Hyperpigmentation manifests in various forms,such as the spotted
,linear,patchy,diffuse and reticular types.
• Palatal pigmentation is perhaps a protective reaction to the heat and
smoke ; it is not known to redispose to a melanoma or any other
pathology.
• Microscopically ,hyperpigmentation areas show increased melanin
deposits in the basal cell layer and the lamina propria.
Nonpigmented areas
• Nonpigmented areas indicate areas of platal mucosa which are
clinically devoid of melanin pigmentation.
• Nonpigmentated areas result following the regression of red areas.
• Loss of pigmentation may render the palatal mucosa more
vulnerable to the action of carcinogens in tobacco.
• Microscopically ,nonpigmented areas are marked by minimal or no
melanin deposits in the basal cell layer.
• Epithelial dysplasia was observed in 19% of nonpigmented areas.
Multimorphic lesion:
• Various palatal components may coexist and they also occur in
association with non palatal lesions.
• Keratosis and excrescences coexist more frequently followed by a
combination of excrescences and patches; and red areas and
patches.
• Furthermore , palatal changes may occur with non-palatal lesions
as well.
Natural history
• Palatal changes remain stationary ,regress,recur,or progress to

cancer.
• Some 75% of the palatal changes remain stationary ,14% regress
spontaneously ,about 11% show variable characteristics,i.e they
regress,recur and regress again.
• The most imposrtant consequence from a clinical point of view is
that small proportion (0.3%) progress to cancer.
Malignant transformation
• Malignant transformation of palatal changes was responsible for

91% of oral cancers that developed in Srikakulam District of
Andhra prades during a 6-year observation period.
• Palatal cancer developed from patches (figures) and most often
from red areas.
• Palatal patches exhibited a malignant transformation rate of 12 per
1000 and red areas ,118 per 1000.
• This finding shows that the palatal red area is the most dangerous
component of palatal changes
• The dorsum of the tongue is an uncommon location for leukoplakia

and it is also rare to see malignant transformation in that site in
convetional smokers.
• Among reverse smokers ,however leukoplakias do occur
commonly and some of them even progress to oral cancer in this
location.
• This indicates that the deleterious effects of reverse smoking
extends to other location that are in close proximity to the lighted
end of the chutta.
Management
• All palatal patches and red areas must be biopsied.

• If they show moderate or severe epithelial dysplasia ,they mus tbe
treated accordingly.
• All atients must be educated to discontinue their tobacco use as it is
known that discontinuation will lead to higher regression rates of
the palatal changes.
ACTINIC CHEILITIS (KERATOSIS )
• Actinic (or solar) keratosis is a premalignant epithelial lesion that

is directly related to long-term sun exposure.
• These lesions are classically found on the vermilion border of the
lower lip as well as on other sun-exposed areas of the skin.
• Actinic keratosis and actinic cheilitis occur more frequently in pale
people, particularly in those with fair complexions, persons with
albinism, males, the elderly, those who live at high altitudes or
close to the equator, and of course, those who by reason of their
occupations or their leisure activities have excessive exposure to
the sun
• A small percentage of these lesions will transform into squamous
cell carcinoma.
Etiopathogenesis
• These lesions are commonly found in individuals with extensive

sun exposure, such as those with outdoor occupations and/or fair
complexions.
• Ultraviolet (UV) light lies within the range of 100-400 nm (1 nm =
10-9 m) of the electromagnetic spectrum.
• UV light is classified as UV-A, -B and -C.
• UVC is in the range of 100- 290 nm; UVB, 290-320 nm; and UVA,
about 320-400 nm.
• Sunlight UVC is almost completely filtered out by the atmosphere.
• Both UVA and UVB can contribute to ageing of the skin by
damaging collagen, breaking down vitamin A, by causing local
immunosuppression and by ionisation, which releases hydroxyl
and oxygen radicals and thus contributes indirectly to DNA
damage.
• UVB from the sun, which is only partly filtered out by the
atmosphere, cancause mutagenic changes; a common event of this
kind is the formation of aberrant covalent bonds between adjacent
cytosine bases in epithelial DNA.
• Cells with these dimers of cytosine in their DNA then propagate,
giving rise to clones of mutated cells.
• Actinic keratosis of the skin is thus a primarily UVB-induced intra-
epithelial neoplasm: the analogous lesion of the vermilion border
of the lip is called actinic cheilitis.
• In the initiation stage of actinic-induced carcinogenesis following
significant exposure to the sun, UVB causes mutations in the
epithelial p53 tumour-suppressor gene that result in the

dysregulation of its functions.
• If there is only limited exposure to UVB, p53 can retain sufficient
functionality to arrest the cell cycle, permitting activation of repair
processes of cellular DNA before the cell enters the phase of DNA
synthesis.
• A cell with repaired DNA can then proceed through the rest of the
cell cycle to cell division.
• Very severe UVB exposure, in contrast, can damage the DNA
sufficiently to render it beyond repair, and p53 then activates
cellular pathways leading to programmed cell death (apoptosis).
• UVB-induced dysregulation of the function of the tumour-
suppressor gene p53 results in genomic instability, making the cells
susceptible to further critical UVB-induced genetic alterations with
ultimate malignant transformation of the affected cells .
• It is evident that UVB is a complete carcinogen since it not only
initiates the genetic alteration of epithelial cells but also
subsequently promotes the expansion of clones of transformed
cells, which then display all the characteristics of malignancy.
• In the past, actinic cheilitis was regarded as being potentially
malignant, with not infrequent transformation intoinvasive,
metastasizing squamous cell carcinoma.
• An alternative view states that the keratinocytes in actinic cheilitis
have already undergone ultraviolet light-induced molecular and
genetic transformation into neoplastic keratinocytes, that actinic
cheilitis is in fact the result of clonal expansion of the transformed
keratinocytes, and that it should be considered from its initiation to
be an in-situ squamous cell carcinoma.
• The vermilion border of the lower lip may also be more vulnerable
to sunlight-induced lesions because its epithelium is thin, has a thin
keratin layer and has a lower melanin content.
• Smoking and infection of the lip by the human papillomavirus may
cause additional cytogenetic alterations and further increase the
risk of actinic cheilitis becoming carcinomatous.
• As melanin protects the basal (progenitor) layer of keratinocytes
from solar energy, persons with relatively few granules of melanin
in their keratinocytes, especially those with Oculocutaneous
albinism (OCA) , are more likely to develop non-malignant and
malignant actinic skin lesions, including sunburns, blisters, solar
elastosis and lentigenes, and squamous and basal cell carcinomas
TYPICAL FEATURES
• Actinic keratosis may be seen on the skin of the forehead, cheeks,

ears, and forearms.
• On the lip, it appears as a white plaque, oval to linear in shape,
usually measuring < 1 cm in size .
• The surface may be crusted and rough to the touch.
• The affected person complains of an inelastic or tight sensation in
the lip.
• On examination one finds mottling of the lip with atrophic areas or
shallow erosions and rough, scaly, flaky keratotic patches on some
parts, or on the entire exposed portion of the lip and sometimes
with small wrinkles in the vermilion border.
• When the surface of the lesion is palpated, there is a fine
sandpaperlike feeling.
• The keratotic patches progress to palpable thickening and
induration, and eventually one or more of them may become
clearly demarcated or may ulcerate.
• Such changes are suggestive of invasive squamous cell carcinoma.
Diagnosis
• A clinical diagnosis of actinic cheilitis must always be supported

by histopathological evidence, but a single biopsy result may not
be conclusive, and the prudent clinician would be well advised to
take a biopsy from more than one site.
• Histopathologically, the surface epithelium appears atrophic, with
a basophilic homogenous amorphous alteration of the collagen
(solar elastosis) in the lamina propria.Varying degrees of atypical
features such as increased nucleocytoplasmic ratios, loss of cellular
polarity and orientation, and nuclear and cellular atypia are found
within the epithelium.
• A mild lymphocytic infiltrate may also be noted in the lamina

propria
TREATMENT AND PROGNOSIS
• The mainstay of treatment of actinic keratosis is surgery.

• surgical excision of the entire vermilion border (vermilionectomy)
with histological examination of serial sections is the preferred
treatment
• Chemotherapeutic agents such as topical 5-fluorouracil have been
used with some success.
• However, follow-up biopsies in individuals who were treated with
5-fluorouracil showed that the dysplastic changes persist in
clinically healthy-appearing epithelium.
• Other possible treatment modalities include electrodessication,
cryosurgery, laser treatment, photodynamic therapy ,however, with
these modalities, the tissue is not available for histological
examination.
• It has recently been reported that photodynamic therapy using the
methyl-ester of aminolevulinic acid as a photosensitising agent is a
very effective treatment modality for actinic cheilitis.
• It is well tolerated by patients and provides excellent cosmetic
outcomes.
• Patients treated with nonsurgical methods therefore require long-
term follow-up
• About 10% of these lesions will undergo malignant transformation.
• Protection against the potentially damaging effects of sunlight
exposure depends upon taking a few straightforward precautions
that must be introduced in childhood and continued throughout life.
• The basic precautions are: avoidance of outdoor activities during
peak sunlight hours; wearing of protective clothing that covers as
much of the skin as the outdoor activity will allow and of a wide-
brimmed hat for the face and lips; and the liberal and frequent use
of an effective sunscreen preparation
ORAL LICHEN PLANUS
• Lichen planus is an autoimmune chronic, inflammatory,

mucocutaneous disease mediated by T lymphocytes that involve
the stratified squamous epithelial tissues which frequently involves
the oral mucosa.
• Lichen planus were presented by the English physician Erasmus
Wilson in 1866.
• In the majority of patients with oral lichen planus (OLP) there is no
associated cutaneous lichen planus or lichen planus at other
mucosal sites. ( ―isolated‖ OLP ).
• OLP should be considered as potentially malignant condition,
emphasizing the importance of periodic follow up in all the
patients
• This normally affects the oral mucosa, but it may involve the skin
nails & genital mucosa.
• Oral lichen Planus can develop on any mucosal surface including
larynx & oesophagus but lesions have predilection for posterior
buccal mucosa.
• Lesions most commonly occur on both oral and cutaneous surfaces
(40%), followed by cutaneous alone (35%) and mucosa alone
(25%).
• Oral form tend to be more persistent and more resistant to
treatment.
• Oral Lichenoid reactions include the following disorders: Lichen
planus, Lichenoid contact reactions, Lichenoid drug eruptions,
Lichenoid reactions of graft-versus-host disease (GVHD)
Prevalence/Incidence
• In the literature, different prevalence figures for OLP have been

reported and vary from 0.5% to 2.2%.1–6
• These figures may represent an underestimation, because minor
lesions may easily be overlooked.
• The proportion of women is higher than men among referred
patients, but this may not be accurate in the general population.
• The mean age of the time of diagnosis is 55 years.
• The etiology of the disease remains unclear, but many causal

factors have been associated, among which: anxiety, diabetes,
autoimmune diseases, intestinal diseases, drugs, stress,
hypertension, infections, dental materials, neoplasms, and genetic
predisposition.
Systemic associations
• Patients infected with the hepatitis C virus (HCV) often have

extrahepatic manifestations, which significantly contribute to
HCV-related morbidity.
• Many studies have demonstrated an association of OLP and HCV
in southern Europe and in Asia (Bagan et al, 1994; Nagaoet al,
1995; Carrozzo et al, 1996; Chuang et al, 1999; Roy and Bagg,
1999; Klanrit et al, 2003).
• HCV infection is more frequently found in patients with erosive
OLP than in patients with non-erosive OLP (Carrozzo et al, 1996).
• The HCV related OLP association is supported by the fact that
HCV viral sequences have been found in the serum of patients with
OLP, and HCV was shown to occasionally replicate in oral lichen
planus tissue, possibly contributing to the pathogenesis of mucosal
damage (Jubert et al, 1994; Carrozzo et al, 1996, 2002; Arrieta et
al, 2000; ).
• Moreover, recent data has shown that HCV-specific T cells can be
found in the oral mucosa of patients with chronic hepatitis C and
OLP (Pilli et al, 2002).
• The association of OLP with both HCV infection and liver disease
appears to be partially dependent on geographic factors.
• Some, but not all studies of American patients (Eisen, 2002a), as
well as British (Ingafou et al, 1998), Irish (Roy et al, 2000), Dutch
(van der Meij and van der Waal, 2000), and German (Grote et al,
1999; Friedrich et al, 2003) patients failed to demonstrate an
association between LP and liver abnormalities.
• However, in studies from countries with a high HCV prevalence
(Egypt and Nigeria), there were negative or insignificant
associations with OLP, suggesting that a LP-HCV association
cannot always be explained on the basis of high prevalence in the
general population (Carrozzo and Gandolfo, 2003).
• The HCV-related OLP appears to be associated with the HLA
class II allele HLA-DR6, which would partially explain the
peculiar geographical heterogeneity of the association between

HCV and OLP (Carrozzo et al, 2001; Petruzzi et al, 2004).
• Even in countries where HCV infection appears to play an
etiologic role in the pathogenesis of OLP, the majority of patients
suffering from OLP are not infected by HCV (del Olmo et al,
2000).
• Although OLP patients do not appear to have an increased risk of
diabetes, diabetics who develop OLP have an increased frequency
of atrophic-erosive lesions and a greater proportion of lesions on
the tongue (Bagan et al, 1993).
Psychological factors
• Patients with OLP exhibit higher levels of anxiety, greater

depression and increased vulnerability to psychic disorders (Soto
Araya et al, 2004).
• OLP patients with erosive LP exhibit higher depression scores than
patients with non-erosive lichen planus (Rojo-Moreno et al, 1998).
• In addition to the chronic discomfort that can result in stress,
patients with OLP are concerned about the possibility of
malignancy, the contagious nature of the disease, and the lack of
available patient educational materials (Burkhart et al, 1997).
• Psychological intervention may be warranted given the fact that the
level of anxiety and salivary cortisol of OLP patients are high,
supporting the relationship of OLP with stress (Koray et al, 2003).
• Research exploring the pathogenesis of LP has yielded many data
suggesting that immunologic mechanisms are fundamental to the
initiation and perpetuation of LP
• Lichen planus result from an abnormal T-cell-mediated immune
response in which basal epithelial cells are recognized because of
changes in the antigenicity of their cell surface.
• Immune T cell are accumulated on the epithelium of the oral
mucosa due to increasing rate of differentiation in stratified
epithelium.
• T lymphocyte induce apoptosis & cell degeneration and perpetuate
the process by releasing chemokines in inflammatory site
Pathogenesis of Oral lichen planus
• The chronicity of OLP is significantly greater than its cutaneous

counterpart.
• Although the precise nature of this discrepancy has not been
elucidated, some evidence supports the role of T-cell RANTES
(regulated upon activation, normal T-cell expressed and secreted)
and mast cell degranulation, leading to the release of tumor
necrosis factor a and a cyclical process, where interleukin 4 and
interferon g may predict the chronicity of the disease process in
some cases.
Precipitating factors
• The Koebner phenomenon characteristic of cutaneous LP, whereby

lesions develop in response to trauma, is also observed in the oral
cavity.
• Mechanical trauma from dental procedures, heat and irritation from
tobacco products, friction from sharp cusps, rough dental
restorations and poorly fitting dental prostheses, and oral habits
including lip and cheek chewing are exacerbating factors (Conklin
and Blasberg, 1987).
• The Koebner phenomenon may explain why erosive lesions
develop most commonly in areas subjected to trauma, such as the
buccal mucosa and lateral surfaces of the tongue.
• When such factors are minimized or eliminated, oral lesions either
revert to the less severe forms of the disease or, rarely, resolve
completely (Eisen, 2002b).
• When atrophic or erosive lesions are present, especially where
there is desquamative gingivitis, there are particular problems
because toothbrushing may be complicated by gingival tenderness
and bleeding.
• This situation frequently results in the accumulation of dental
plaque, which may adversely influence the course of OLP.
• Dental plaque and calculus can also result in worsening gingival
lichen planus and are associated with a significantly higher
incidence of erythematous and erosive gingival lesions (Ramon-
Fluixa et al, 1999).
• Gingival OLP can ultimately result in gingival recession, advanced
periodontal disease and, rarely, in tooth loss. Periodontal surgical
procedures, which are required to correct these defects, may
themselves exacerbate OLP (Katz et al, 1988).
• Therefore, oral hygiene procedures in OLP patients must be gentle

but effective – when there can be subjective and objective
improvement of the lesions (Holmstrup et al, 1990).
Clinical Features
• Oral lichen planus lesions usually have recognizable and

distinctive clinical features and a characteristic distribution.
• OLP may manifest in one of three clinical forms: reticular,
erythematous (atrophic) and erosive (ulcerated, bullous).
• Whereas reticular lesions occur as isolated lesions and are often the
only clinical manifestation of the disease, erythematous lesions are
accompanied by reticular lesions, and erosive lesions are
accompanied by reticular and erythematous lesions in almost all
cases (Eisen, 1993; Scully et al, 2000).
• This feature helps clinically differentiate OLP from other vesiculo-
erosive diseases such as pemphigus and pemphigoid, which are
characterized by isolated areas of erythema and/or erosions.
• The reticular lesions, the most recognized form of OLP,
encompass white lesions, which appear as a network of connecting
and overlapping lines, papules or plaques.
• Annular and linear forms: consists of striae that occur in a

circular and linear forms (figure)
• Although some patients may display an impressive array of diffuse

and widespread reticulated lesions, they rarely complain of
symptoms and often, are unaware of their presence.
• Erythematous and erosive OLP lesions result in varying degrees
of discomfort.
• Erythematous OLP lesions, when present, are almost always
accompanied by reticulated lesions
• The most severe and painful lesions of OLP develop in the erosive
form of the disease
• Plaque form: The plaque form of lichen planus consists of either a

pearly white or grayish white plaque.
• At times it is diffucuilt to distinguish it from leukoplakia on
clinical basis
• The presence of whickham‘s striae ,papules or other morphological
forms may often help in distinguishing it from leukoplakia
• The number of ulcerations is variable as are their size and location;

rarely, bulla that rupture easily may be observed in the erosive
form of OLP (Thorn et al, 1988).
• The erosive lesions hardly ever remit spontaneously and may lead
to confusion with other autoimmune mucosal, vesiculo-erosive
diseases, which share similar clinical features.
• The posterior buccal mucosa is the most frequent site of
involvement followed by the tongue, gingiva, labial mucosa, and
vermilion of the lower lip (Silverman et al, 1985; Bagan-Sebastian
et al, 1992; Eisen, 2002a).
• Lesions on the palate, floor of the mouth, and upper lip are
uncommonly noted.
• Approximately 10% of patients with OLP have the disease
confined to the gingiva (Scully and el Kom, 1985).
• Gingival LP presenting as small, raised white, lacy papules or
plaques, may resemble keratotic diseases such as leukoplakia.
• Erythematous lesions affecting the gingiva result in desquamative
gingivitis , the most common type of gingival LP (Scully and
Porter, 1997).
• Erosive lesions resembling those observed in other vesiculo-

erosive diseases including pemphigoid, pemphigus, linear IgA
disease, and foreign body gingivitis(Gordon and Daley, 1997) also
produce desquamative gingivitis not easily identified as lichen
planus unless there are coexistent reticular lesions on the gingiva or
elsewhere in the oral cavity.
• Lichen planus isolated to a single oral site other than the gingiva is
uncommon.
• Patients with isolated lip lesions (Allan and Buxton, 1996) and
tongue lesions (Andreasen, 1968) have been described although
many patients who present with isolated lesions eventually develop
more widespread disease.
Oral lichen planus associated with pigmentation:
• In about 11% of cases ,OLP may be associated with pigmentation

(figures).
• It may begin either with pigmentation or the pigmentation may
appear susequently.
• While the appearance of pigmentation in cutaneous lichen planus
indicates the resolution of the condition ,no such conclusions can
be made in regard to its oral counter part.
Multiforms:
• Ocassionally several forms of OLP may coexist and one form may
change to another over time.
Extraoral manifestations
• Patients with OLP frequently have concomitant disease in one or

more extraoral sites.
• Therefore, a thoroughevaluation and multidisciplinary approach is
required to uncover potential sites of extraoral involvement.
• Approximately 15% of patients with OLP develop cutaneous
lesions (Eisen, 1999).
• The classic appearance of skin lesions consists of erythematous to
violaceous papules that are flat topped and occasionally polygonal
in form .
• A network of fine lines (Wickham‘s striae) often overlies many of

the papules.
• Cutaneous LP may also appear in several atypical forms that are
not easily recognizable.
• Typically, 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 (Eisen, 1999).
• Undoubtedly, the most frequent extraoral site of involvement in
female patients with OLP is the genital mucosa with lesions
developing in 20% of women with OLP (Rogers and Eisen, 2003).
• The association of LP of the vulva, vagina and gingiva is
recognized as the vulvovaginal-gingival syndrome (Pelisse, 1989).
• When LP affects the genital mucosa, the erosive form of the
disease is the predominant type although asymptomatic reticular
lesions can be identified in a quarter of all patients (Eisen, 1994).
• Various symptomsincluding burning, pain, vaginal discharge are
frequent and are noted in patients with erythematous and erosive
disease.
• Not uncommonly, patients with mild oral involvement display
severe erosive vulvovaginal disease, and patients afflicted with
severe oral involvement develop only mild asymptomatic genital
disease.
• Reports of malignant transformation of genital lichen planus in
women (Dwyer et al, 1995; Franck and Young, 1995) underscore
the need for an early diagnosis and the institution of prompt
treatment for these patients.
• The penogingival syndrome represents the male equivalent of the
vulvovaginal-gingival syndrome of LP (Cribier et al, 1993).
• Although the concomitant involvement of oral and genital LP is
much less common in males than females, recognition and
treatment of the disease are important as malignant transformation
of penile LP has been reported (Bain and Geronemus,1989).
• Lichen planopilaris represents LP involvement of the scalp and hair

follicles causing a scarring alopecia.
• Lichen planus may also involve the nails producing thinning and
ridging of the nail plate and splitting of the distal free edge of the
nail.
• Healing with a scar produces a ptyergium, an uncommon but
characteristic LP nail manifestation.
• Lichen planus of the nails and scalp are uncommon in patients
with OLP (Eisen, 1999).
• The clinical features of esophageal LP have been well documented
(Harewood et al, 1999; Abraham et al, 2000; Evans et al, 2000),
and the disease appears to develop most commonly in patients with
OLP.
• The overwhelming majority of patients with esophageal LP are
diagnosed as a result of painful symptoms, with dysphagia being
the predominant complaint.
• Although malignant transformation has not been reported,
untreated esophageal LP may result in chronic pain and strictures
(Souto et al, 1997).
• Patients with OLP may also develop the disease in one or more
sites including the ocular, bladder, nasal, laryngeal, otic, gastric,
and anal structures although these sites of involvement are
uncommon.
Malignant potential
• The most important complication of OLP is the development of

oral squamous cell carcinoma.
• The reported frequency of malignant transformation varies greatly,
between 0.4% to over 5%, over periods of observation from 0.5 to
over 20 years (van der Meij et al, 1999b).
• The significantly increased risk of oral cancer appears to be
independent of the clinical type of OLP and therapy administered
(Gandolfo et al, 2004).
• There is considerable controversy regarding the malignant
transformation of OLP.
• Despite the fact that more than 25 follow-up studies have focused
on this topic, as recently reviewed by Barnard et al (Barnard et al,
1993), many investigators have questioned the criteria utilized for
diagnosing OLP in published reports (Krutchkoff et al, 1978;
Eisenberg, 2000).
• For example, while some studies included patients diagnosed with
OLP based on clinical and histological criteria, others included
patients that were based solely on clinical features (Murti et al,

1986).
• Consequently, some published cases of OLP associated with
malignant transformation, diagnosed clinically as OLP, may
actually have been lichenoid dysplasia, a premalignant condition
with lichenoid features.
• It is known that patients with lichenoid dysplasia often display
erythematous and erosive lesions clinically identical to OLP
lesions (Eisenberg and Krutchkoff, 1992).
• However, the results of three studies (Holmstrup et al, 1988;
Gandolfo et al, 2004; Rodstrom et al, 2004) with strict diagnostic
criteria for the disease demonstrated a statistically significant risk
for OLP patients to develop squamous cell carcinoma.
• Unfortunately, these studies failed to identify factors that would
modify the risk of developing oral cancer among OLP patients.
• 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.
Fali S. Mehta etal :

• Oral lichen planus may remain stationary (in 87% to 93% cases,
regress spontaneously (in 7 -13% cases) and recur in 3% of the
cases.
• In a sample of 722 cases of oral lichen planus that were followed

up for 10 years(mean ,5.1 years) in Ernakulam district ,about 0.4 %
showed malignant transformation.
• This was not statistically significant to confirm its precancerous
nature.
• As compared to other forms of lichen planus,erosive form is more

prone to the develovment of cancer.
• In nonerosive forms,cancer development was observed to be
preceded by the appearance of erosive areas.
Diagnosis:
• The characteristic clinical aspects of OLP may be sufficient to

make a correct diagnosis if there are classic skin lesions present.
• An oral biopsy with histopathologic study is recommended to
confirm the clinical diagnosis and mainly to exclude dysplasia and
malignancy.
• However, the histopathologic assessment of OLP is a rather
subjective and insufficiently reproducible process (van der Meij et
al, 1999a) and in about 50% of OLP cases, there is a lack of
clinicopathologic correlation in the diagnostic assessment of OLP
(van der Meij and van der Waal, 2003).
• Gingival LP may be more difficult to diagnose, and direct
immunofluorescence of perilesional mucosa may facilitate the
diagnosis and exclude other causes such as bullous diseases (Firth
et al, 1990).
• The value of direct immunofluorescence for confirmation of the
disease is well accepted, especially with non-diagnostic
histopathologic features and for the desquamative gingivitis form
of LP.
Histology (Eisenberg, 2000)
Essential features
• Superficial band-like infiltrate of T lymphocytes
• Basal cell liquefaction degeneration
• Normal epithelial maturation pattern
Additional features
• Jagged, spindly rete ridges
• Civatte bodies
• Separation of epithelium from lamina propria
Immunofluorescence of perilesional mucosa (Helander and Rogers,

1994)
• Fibrin and shaggy fibrinogen in a linear pattern at the basement
membrane zone
• Cytoids in the absence of deposition of fibrinogen
Differential diagnosis
• OLP can often be separated from Lichenoid Contact Reactions to

dental materials,which are most often detected on the buccal
mucosa and the lateral borders of the tongue.
• OLP, on the other hand, usually displays a more general
involvement.
• Oral lichenoid drug eruptions have the same clinical and
histopathologic characteristics as OLP.
• The patient‘s disease history may give some indication as to which
drug may be involved, but OLP may not start when the drug was
first introduced.
• Withdrawal of the drug and rechallenge are the most reliable way
to diagnose lichenoid drug eruptions but may not be possible.
• Testing for contact allergy with patch testing may be required in
some cases.
• Oral GVHD has the same clinical appearance as OLP, but the
lesion is usually more generalized.
• The lichenoid reactions are frequently seen simultaneously with

other characteristics, such as xerostomia and the presence of
localized skin involvement and liver dysfunction, even if an oral
lichenoid reaction may emerge as the only clinical sign of GVHD.
• Discoid lupus erythematosus (DLE) shows white radiating striae
sometimes resembling those of OLP.
• The striae present in DLE are typically more prominent, with a
more marked hyperkeratinization, and the striae may abruptly
terminate against a sharp demarcation .
• Differntiated histologically and on DIF
Treatment
• Treatment should be directed at achieving specific goals after

considering the degree of clinical involvement, the predominant
clinical type of lesions, the patient‘s symptoms, and age.
• Reticular lesions that are asymptomatic generally require no
therapy but only observation for change.
• In general, all treatment should be aimed at eliminating atrophic
and ulcerative lesions, alleviating symptoms, and potentially
decreasing the risk of malignant transformation.
• Mechanical trauma or irritants such as sharp filling margins or
rough surfaces or badly fitting dentures should receive attention.
• A drug history should be obtained to identify reversible causes of
lichenoid eruptions as discontinuation of the offending agent is
often curative.
• Hypersensitivity reactions should be suspected when the lichenoid
lesions are confined to oral mucosal sites in close proximity to
dental restorations.
• An optimal oral hygiene program should be instituted in patients
with gingival disease.
• Patients with OLP who are elderly and have poor nutrition could
have folate deficiency, even when they are not found to be anemic
when screened (Thongprasom et al, 2001).
Drug therapy
• Patients with oral LP are managed with medications that were

neither developed nor intended for oral diseases and, consequently,
most lack adequate efficacy studies.
• Thus, such factors as optimal dose, duration of treatment, safety,
and true efficacy remain unknown (Scully et al, 2000).
Corticosteroids
• The most commonly employed and useful agents for the treatment
of LP are topical corticosteroids.
• A response to treatment with midpotency corticosteroids such as
triamcinolone, potent fluorinated corticosteroids such as
fluocinolone acetonide and fluocinonide and superpotent
halogenated corticosteroids such as clobetasol has been reported in
30–100% of treated patients (Lozada- Nur et al, 1994; Aleinikov et
al, 1996; Carbone et al,1999; Buajeeb et al, 2000; Thongprasom et
al, 2003).
• The greatest obstacle in using topical corticosteroids in the mouth
is the lack of adherence to the mucosa for a sufficient length of
time.
• For this reason, some investigators prefer using topical
corticosteroids in adhesive pastes although there is no data that
topical steroids in adhesive bases are more effective than as base
preparations (Buajeeb et al, 2000; Lo Muzio et al, 2001).
• Elixir forms of corticosteroids, such as dexamethasone,
triamcinolone and clobetasol have been used as an oral rinse for
patients with diffuse oral involvement or for elderly patients who
may find it technically difficult to apply medication to various
active locations of the oral cavity.
• Careful consideration should be given to the vehicle as unlike skin
compounds, which have been well-studied,clinical trials that have
compared the strength of corticosteroids in various bases in the oral
cavity are generally lacking.
• Few serious side-effects arise with topical corticosteroids.
• Unlike the skin, atrophy in the oral mucosa is rarely observed.
• As many as one third of OLP patients treated with topical
corticosteroids develop secondary candidiasis which necessitates
treatment (Vincent et al, 1990) or instituting antifungal therapy
before the patient begins using topical steroids (Lozada-Nur et al,
1994; Carbone et al, 1999).
• Prolonged use of these drugs may occasionally result in diminished
biological effectiveness (tachyphylaxis), which can be avoided by
using alternate day therapy or by using a very potent steroid (e.g.
clobetasol) initially and then a moderately potent corticosteroid
(e.g. triamcinolone) for maintenance therapy.
• Although a number of studies have demonstrated the safety of

topical corticosteroids when applied to mucous membranes for
short intervals (Lehner and Lyne, 1969; Plemons et al, 1990) and
even up to 6 months (Carbone et al, 2003), the potential for adrenal
suppression with prolonged use, especially for a disease that is
chronic, necessitates careful and frequent follow-up examinations.
• When using superpotent steroids such as clobetasol, one should be
aware that the drug is indicated for no longer than a 2 week period,
occlusive dressing are contraindicated with its use (Abma et al,
2002), adrenal insufficiency following prolonged use in moderate
dosages (at doses as low as 2 g day)1) may be more common than
previously recognized (Ohman et al, 1987), and the total amount of
drug used per week and the duration of treatment should be
carefully monitored by those familiar with its adverse effects.
• In general, therapy should be initiated with a potent preparation to
achieve a rapid response particularly in erosive OLP lesions
(Thongprasom et al, 1992).
• Patients should be instructed to apply the agent several times daily,
maintain prolonged contact of the medication with the mucosa, and
refrain from eating and drinking for 1 h afterwards.
• It is advisable to lower the strength of the preparation as soon as
erosions heal and erythematous lesions become asymptomatic.
• Once the disease becomes inactive and there is either an absence of
lesions or the presence of only white reticular lesions, therapy may
be temporarily discontinued.
• For intractable erosive OLP lesions, intralesional steroids such as
triamcinolone acetonide (10–20 mg ml)1) injections can be
effective and repeated every 2–4 weeks.
• Other steroids such as hydrocortisone may also be used but there
are no studies to suggest which steroid is preferable.
• Frequent injections of steroids, however, are painful, not
invariably effective, and may result in an unwanted systemic dose.
• Although some consider systemic corticosteroids to be the most
effective treatment modality to control OLP, the literature on their
use is limited, and a recent comparative study did not find
differences in treatment response between prednisone (1 mg kg)1
day)1) plus clobetasol in an adhesive base and clobetasol alone
(Carbone et al, 2003).
• Systemic corticosteroids should be reserved for recalcitrant
erosive or erythematous LP, where topical approaches have failed,
or for widespread oral LP with concomitant skin, genital,
esophageal, or scalp involvement.
• Daily doses of prednisone in the range of 40–80 mg is usually

sufficient to achieve a response without the need for higher doses
as in other mucocutaneous diseases such as pemphigus or
pemphigoid.
• The toxicity of prednisone requires that it be used only when
necessary, at the lowest dose possible and for the shortest duration
of time.
• Therefore, prednisone should either be administered for brief
periods of time, i.e. 5–7 days and then abruptly withdrawn, or the
dose should be reduced by 5–10 mg day)1 gradually over a 2–4
week period.
• If patients are able to tolerate alternate day administration of the
same total dose, adverse effects may be minimized.
Other topical agents
• Patients who exhibit desquamative gingivitis, widespread oral

disease, or diffuse ulcerations, may not respond adequately to
topical corticosteroids alone.
• The addition of potent immunosuppressants or immunomodulatory
agents such as cyclosporine, tacrolimus, pimecrolimus or tretinoin,
in topical formulations, may be beneficial in this group of patients.
• The standard solution of cyclosporine (100 mg /ml) intended for
systemic use in organ transplant recipients may be used as a
mouthrinse in oral LP (Eisen et al, 1990a).
• However, the solution is prohibitively expensive for routine use
and should be reserved for patients recalcitrant to other treatments.
• Utilizing a smaller quantity of drug (500 mg day)1 vs 1500 mg
day)1) may reduce the cost of the drug (Harpenau et al, 1995);
even finger rub application using very low doses of cyclosporine
(48 mg day)1 or less) in an adhesive base preparation is beneficial
(Carrozzo and Gandolfo,1999).
• Systemic absorption is generally low with topical cyclosporine and
the efficacy of the drug does not correlate with cyclosporine blood
levels (Eisen et al, 1990b).
• Tacrolimus, a steroid free topical immunosuppressive agent
approved for the treatment of atopic dermatitis, is 10–100 times as
potent as cyclosporine and has greater percutaneous absorption
than cyclosporine.
• Several uncontrolled studies have documented the efficacy and
safety of this agent in recalcitrant erosive OLP (Kaliakatsou et al,
2002; Olivier et al, 2002; Rozycki et al, 2002; Hodgson et al,
2003), although in one study, only 14% of patients had complete
resolution of ulcers and erosions when the drug was applied over a
19 month period (Hodgson et al, 2003).
• Burning is the commonest side-effect with tacrolimus and is
observed in <20% of patients (Hodgson et al, 2003).
• Therapeutic levels of tacrolimus can be demonstrated in OLP
patients using the drug but are unrelated to the extent of oral
mucosal involvement (Kaliakatsou et al, 2002).
• Relapses of OLP after cessation of tacrolimus therapy are common
(Olivier et al, 2002).
• Notably, in a mouse model, topically applied tacrolimus has been
shown to accelerate skin carcinogenesis (Niwa et al, 2003).
• The US Food and Drug Administration recently issued a health
advisory to inform healthcare providers and patients about a
potential cancer risk from use of tacrolimus.
• They recommended the drug be used in minimum amounts, only
for short periods of time, not continuously, and only as labelled –
for atopic dermatitis.
• Topical retinoids such as tretinoin have been reported to be
effective for oral LP (Sloberg et al, 1979).
• However, topical corticosteroids (0.1% fluocinolone acetonide) are
more effective than topical 0.05% tretinoin in the treatment of
atrophic-erosive OLP (Buajeeb et al, 1997).
• Therefore, as a monotherapy, tretinoin has limited value in OLP
but in combination with topical corticosteroids, especially for
reticular lesions, modest benefits may be achieved with high doses
and frequent applications (Eisen, 2002b).
• Retinoids applied to the skin often cause considerable irritation
and inflammation, and the same is to be expected when applied to
oral mucous membranes.
Systemic therapy
• A number of systemic immunosuppressive agents have been

reported to be beneficial in the treatment of OLP although rigorous
evaluation of their efficacy is lacking.
• None of the agents used for OLP results in long-term remission,
and when they are withdrawn, the disease usually recurs.
• Nevertheless, despite these shortcomings, systemic agents could
produce significantly better results than topical agents alone
although direct comparative studies are lacking.
• As with other diseases treated with these agents, such as cutaneous
LP and psoriasis, topical therapy should be maintained while
undergoing treatment with systemic agents.
Drug Dose Comments
Acitretin (Laurberg et 30 mg Highly effective and acceptable therapy for

al, 1991) /day severe cases of cutaneous LP; less effective
and less tolerated for OLP
Azathioprine 75–150 Highly effective, requires frequent laboratory

(Lear and English, mg /day evaluation; useful as a corticosteroid sparing
1996) agent Basiliximab
Cyclosporine (Levell et 1–3 Severe adverse effects; should be reserved for

al,1992) mg/kg/ severe and refractory cases
day
Dapsone (Beck and 100–150 Few case reports; no improvement with

Brandrup, 1986) mg /day gingival disease
Eiconol (Barer and 6 g /day Positive changes in 69% of patients with

Polovets, 1995) atrophic OLP
Enoxaparin (Hodak et 3 mg Improvement of 25% of cases, no side-effects

al, 1998) /week
Griseofulvin (Bagan et 1 g day Mixed results; very safe but several studies
al, 1985; Naylor, 1990) show no improvement
Glycyrrhizin (Da 40 ml 66.7% OLP patients improved clinically

Nagao et al, 1996) /day significant
Drug Dose Comments
Hydroxychloroquine (Eisen, 200– Small open label study; response

1993) 400 mg may take several months
day
Levamisole (Lu et al, 1995) 150 mg When administered with

day prednisolone, excellent response and
1·3 long-term remission
days
week
Mycophenolate mofetil (Nousari 2–4 g New immunosuppressive; expensive;

et al, 1999) /day well tolerated; highly effective with
long-term use
Thalidomide (Camisa and 100– Serious side-effects should restrict its

Popovsky, 2000; Macario-Barrel 150 mg use to the most severe forms of the
et al, 2003) /day disease
Treatment Comments
Psoralens and long wave ultraviolet A Excellent results in several studies; PUVA
(PUVA) (Jansen et al, 1987; Lundquist has oncogenic potential limiting its use
et al, 1995)
Extracorporeal photochemotherapy Limited by complexity and potential

(Becherel et al, 1998) serious adverse events 308-nm UVB
Excimer laser (Kollner et al, 2003;
Passeron et al, 2004) Preliminary benefits
warrant further studies
Surgery (excision, CO2 laser, Effective for persistent or dysplastic

cryosurgery) (Emslie and Hardman, lesions; surgery may lead to worsening
1970; Tal and Rifkin, 1986; Loh, 1992; OLP presumably via a Koebner
Huerta et al, 1999) phenomenon; high rate of recurrence
• A cochrane review on ―Interventions for treating oral lichen

planus‖ to assess the effectiveness and safety of interventions to
treat symptomatic, biopsy-proven oral lichen planus was conducted
in 2011.
Conclusion : Implications for practice

• There are no trials comparing topical steroids with placebo and
these may now be considered unethical.
• There are many trials comparing different steroids with different
alternative treatments, with little duplication.
• There is no evidence that one steroid treatment is better or worse
than another.
• There is weak evidence to suggest that aloe vera may reduce pain
and clinical signs of oral lichen planus (OLP), compared to
placebo.
• There is weak and unreliable evidence that cyclosporin may
reduce pain and clinical signs of OLP.
• There is no evidence that pimecrolimus is more effective than
placebo.
• Although there are 28 trials included in this systematic review the

wide range of interventions compared means there is insufficient
evidence to support any specific treatment as being superior.
DISCOID LUPUS ERYTHEMATOSUS
• An immunologically mediated inflammatory condition

• Discoid lupus erythematosus(DLE) comprises 85% cases of
cutaneous lupus erythematosus.
• The classical clinical presentation is a plaque with central
depigmentation, surrounding hyperpigmentation with adherent
scales, (which on removal show ―carpet tack‖ appearance) with
telangiectasia and scarring alopecia.
• Discoid lupus erythematosus (DLE) is a relatively common disease
and occurs predominantly in females in the third or fourth decade
of life.
• DLE can present in both localized and disseminated forms and is
also called chronic cutaneous lupus (CCL).
Clinical features
• DLE is confined to the skin and oral mucous membranes .

• Typical cutaneous lesions appear as red and somewhat scaly
patches that favor sun-exposed areas such as the face, chest, back,
and extremities.
• These lesions characteristically expand by peripheral extension and
are usually disk-shaped.
• Discoid oral lesions are similar to those occurring on the skin and
appear as whitish striae frequently radiating from the central
erythematous area, giving a so-called ―brush border.‖
• Atrophy and telangiectases are also frequently present.
• As the lesions expand peripherally, there is central atrophy, scar

formation, and occasional loss of surface pigmentation.
• Lesions often heal in one area only to occur in a different area later
• Buccal mucosa, gingiva, and labial mucosa are the most
commonly affected intraoral sites.
• Isolated erythematous areas are also common, especially on the
palate.
• The oral lesions can occur in the absence of skin lesions, but there
is a strong association between the two.
Diagnosis and Differential diagnosis
• The oral mucosal lesions of DLE frequently resemble reticular or

erosive lichen planus.
• The primary locations for these lesions include the buccal mucosa,
palate, tongue, and vermilion border of the lips.
• Unlike lichen planus, the distribution of DLE lesions is usually
asymmetric, and the peripheral striae are much more subtle .
• The lesions may be atrophic, erythematous, and/or ulcerated and
are often painful.
• The oral lesions of DLE are markedly variable and can also
simulate leukoplakia.
• Therefore, the diagnosis must be based not only on the clinical
appearance of the lesions but also on the coexistence of skin
lesions and on the results of both histologic examination and
direct immunofluorescence testing.
• Despite their similar clinical features, lichen planus and lupus
erythematosus yield markedly different immunofluorescent
findings.
• Some authors believe that the histology of oral lupus
erythematosus is characteristic enough to provide a definitive
diagnosis at the level of light microscopy, but most feel that the
diagnostic standard must involve direct immunofluorescence.
• Importantly, lesions with clinical and immunofluorescent features
of both lichen planus and lupus erythematosus have also been
described (overlap syndrome)
Histopathologic Features
• The histopathologic changes of oral lupus consist of

hyperorthokeratosis with keratotic plugs, atrophy of the rete ridges,
and (most especially) liquefactive degeneration of the basal cell
layer.
• Edema of the superficial lamina propria is also quite
prominent.Most of the time, lupus patients lack the bandlike
leukocytic inflammatory infiltrate seen in patients with lichen
planus.
• Immediately subjacent to the surface epithelium is a band of PAS-
positive material, and frequently there is a pronounced vasculitis in
both superficial and deep connective tissue.
• Another important finding in lupus is that direct
immunofluorescence testing of lesional tissue shows the deposition
of various immunoglobulins and C3 in a granular band involving
the basement membrane zone.
• Importantly, direct immunofluorescent testing of uninvolved skin
in a case of SLE will show a similar deposition of
immunoglobulins and/or complement.
• This is called the positive lupus band test, and discoid lesions will
not show this result.
Management
• The dental management of the lupus patient should take into

account the complex pathologic manifestations of the disease,
including oral aspects and complications of immunosuppressive
treatment.
• There is no reported control studies specifically addressing
management of oral mucosal involvement .
• Hydroxychloroquine is commonly used for discoid lesions on
skin and mucosa.
• Topical steroids with antifungal agents are recommended for
discoid lesions as well as topical tacrolimus ointment and
intralesional injection of steroids for refractory lesions.
Malignant Potential, Importance, and Scope of Oral Lesions
• The precancerous potential of intraoral discoid lupus is

controversial.
• Basal cell and (more commonly) squamous cell carcinomas have
been reported to develop in healing scars of discoid lupus.
• However, this malignant change may have been caused by the
radiation and ultraviolet light used in the treatment of lupus in the
early twentieth century.
• The development of squamous cell carcinoma has been described
in lesions of discoid lupus involving the vermilion border of the
lip, and actinic radiation may play an important adjunct role in this.
• Malignant transformation is a rare complication of this
condition.
( S Grover - 2007 , MR Bhat - 2012 and HJ Dadapeer - 2017)
• Incidence of SCC over DLE in the Indian population is found to
be 0.98% ( MS Fernandes - 2015 )
• Oral ulcers are one of the defining features of lupus erythematosus.
• The frequency of oral lesions in all forms of lupus combined varies
from 5 to > 50%.
• Importantly, oral ulcers are found in patients who have a higher
level of disease activity as measured by the system lupus activity
measure.
• In a recent survey of international centers devoted to the treatment
of lupus, there was an extremely low level of agreement on the
incidence of oral manifestations of this disease.
• An increase in the frequency of generalized periodontal disease has
been reported with SLE.
• However, most studies have found that there is either a decrease in
periodontal probing depth in lupus or no change in periodontal
status.
• In fact, recent evidence suggests that the tendency of periodontitis
to be more severe or progressive in some patients with collagen
vascular diseases is a consequence of xerostomia and not a result of
the primary disease.
XERODERMA PIGMENTOSUM (XP)
• Xeroderma pigmentosum (literally dry pigmented skin), is defined

by extreme sensitivity to sunlight, resulting in sunburn, pigment
changes in the skin and a greatly elevated incidence of skin
cancers.
• About 60% of affected individuals show an exaggerated and
prolonged sunburn response.
• In a minority of cases there are neurological abnormalities of
varying severity.
• Historically, the disorder was classified originally as ―classical XP‖
(skin abnormalities only) and the De-Sanctis-Cacchione
syndrome with skin abnormalities and extreme neurological
degeneration.
• The latter term is currently rarely used as it is evident that there is a
wide range of neurological abnormalities of varying severity and
varying age of onset.
Epidemiology
• XP has been found in all continents and across all racial groups.
• Consistent with autosomal recessive inheritance, males and
females are similarly affected.
• Estimates made in the 1970‘s suggested an incidence in the USA
of 1 in 250, 000 and in Japan of 1 in 20, 000 .
• A more recent survey in Western Europe suggests approximately
2.3 per million live births .
• Anecdotally, the incidence in North Africa and the Middle East,
where there is a high level of consanguinity, is substantially higher.
• The incidence in India is not known.
• A literature search identified several case reports from India but
mutation analysis had not been performed in any of the cases.
[5],[6],[7],[8],[9],[10]
• Till 2015 , 37 unrelated families with patients having XP have been
reported from India.
• Many families have been reported from South India especially
Karnataka, where significant consanguinity is observed.
Etiopathogenesis
• Exposure to UV radiation
• Ultraviolet (UV) irradiation is composed of UVA spectrum and
UVB spectrum, where UVB plays an important role in the etiology
of XP.
• UV irradiation causes photoproducts in DNA, chiefly cyclobutane
pyrimidine dimers (CPDs) and 6-pyrimidine-4-pyrimidone,
which further brings about cell death, mutagenesis, carcinogenesis
and cellular ageing .
• XP is an autosomal recessive disorder which results from
mutations in any of the eight genes.
• These genes restore the DNA damage induced by UV radiation by
a process known as nucleotide excision repair (NER) .
• XP patients have mutations in one or more NER genes, and cause
molecular defects in cellular DNA repair mechanisms and
hypersensitivity to UV radiation.
• As a result, the accumulation of unrepaired UV induced DNA
damage occurs which either facilitate cell death, contributing to
accelerated skin ageing, or cellular transformation resulting in the
development of malignancies.
• Many XP patients with tumors show mutations in the p53 gene,
indicating that p53 mutations are characteristic of UV exposure.
• Consanguinity
• Consanguinity has been implicated as an etiological factor.
• This has been reported to varying degrees of up to 92.8% in XP
patients in Libya.
• Other studies reported from Egypt, Pakistan, and Nigeria etc. have
a high incidence of XP .
• Drugs and Chemicals
• A number of DNA-damaging agents apart from UV radiation have
been implicated to cause a hypersensitive response to XP cell.
Aetiology
• XP is an autosomal recessive disorder with 100% penetrance and

can result from mutations in any one of eight genes.
• The products of seven of these genes (XP-Athrough G) are
involved in the repair of ultraviolet induced photoproducts in DNA
by the process of nucleotide excision repair (NER) [5].
• The XPC and XPE proteins are needed to recognise the photo
products in DNA.
• XPB and XPD are part of a protein complex TFIIH, which opens
up the structure of the DNA around the site of the photoproduct.
• XPA protein verifies that proteins are in the correct position and
then the nucleases XPG and XPF cut the DNA on either side of the
damage, so that the damaged section can be removed and replaced
with intact DNA.
• There are two branches of NER, designated transcription- coupled
repair, which rapidly repairs areas of DNA that are ―active‖ and
being transcribed into RNA, and global genome repair, which
repairs damage in the rest of the genome more slowly. XPC and
XPE proteins are only required for the latter branch, whereas all
the other XP proteins are required for both branches. Probably as
• a consequence of this, patients defective in the XPC or XPE genes
do not, in general, have the extreme sunburn reactions or
neurological abnormalities described above.
• Defects in the eighth XP gene do not affect NER.
• Instead these so-called XP variants (XP-V) have problems
replicating DNA containing ultraviolet-induced damage. DNA
replication is carried out by DNA polymerases.
• The DNA polymerases that normally replicate DNA cannot deal
with damage in the DNA template and specialised polymerases
have to be employed to get past the damage (translesion synthesis).
• For UV damage, the cell uses DNA polymerase h, encoded by the
gene POLH and it is this gene that is mutated in XP-V patients.
Like XP-C and XP-E patients, XP-V patients rarely have extreme
sunburn reactions or neurological problems.
• The molecular defects in XP cells result in a greatly elevated
induction of mutations in sun-exposed skin of affected individuals.
• This increased mutation frequency probably accounts for the
pigmentation changes and the skin cancers. Indeed examination of
mutations in the p53 gene in tumours from XP patients reveal p53
mutations characteristic of UV exposure in the majority of
tumours.
• The molecular defect also results in increased UV-induced

lethality, which varies substantially between individuals. The level
of cell killing is less in individuals mutated in the XPC and XPE
genes and with some hypomorphic mutations in other XP genes,
because of the residual functional DNA repair.
• These individuals also do not show the sunburn reaction found in
other groups. This has led to the suggestion that the extreme
sunburn reaction is likely to be a consequence of cell death.
Clinical features
• In about 60% of cases, the first signs are extreme sensitivity to

sunlight , which takes many days or weeks to resolve.
• In these individuals, this sunburn reaction can happen in the first
weeks of life and is often blamed on neglect or labelled wrongly as
cellulitis or impetigo.
• The other 40% of cases do not show any sunburn reaction.
• In these cases, the first manifestation, often by two years of age, is
an unusually increased number of lentigines (freckle-like
pigmentation) in sunexposed areas.
• They are present on the nose, zygoma and forehead and then
appear on the sides of the neck, sparing the area under the chin.
• Photophobia is often present.
• In the absence of sun protection, the skin ages, becoming dry,
rough and atrophic.
• Lentigines increase in number and darken and are difficult to
distinguish clinically from the many, flat, pigmented seborrhoeic
warts, which also proliferate and become warty.
• Small, hypopigmented macules are commonly seen amongst the
lentigines and may even be the first presentation.
• Telangiectasia can be a late feature.
• As all the skin changes are the result of exposure to UV radiation,

the severity of these changes is absolutely dependent on the
amount of sun-exposure.
• The effects vary a great deal between individuals.
• In the absence of rigorous protection from the sun, areas of hyper-
and hypo-pigmentation will result, followed by accelerated photo-
ageing, warty lesions, in-situ melanocyte and keratinocyte
malignancy, and eventually multiple basal cell carcinomas and
invasive squamous cell carcinomas and melanomas.
• It has been estimated that XP patients have a 10, 000-fold
increased risk of non-melanoma skin cancer and a 2, 000-fold
increased risk of melanoma under the age of 20.
• The early age of onset and the frequency of skin cancers in an
otherwise normal individual should trigger further assessment for
XP.
• In addition to the very large increase in skin cancer there is an
approximately 50-fold increase in internal neoplasms, especially of
the central nervous system.
• Ocular abnormalities are almost as common as the cutaneous
abnormalities, but they are strikingly limited to the anterior, UV-
exposed structures of the eye (lids,cornea, and conjunctiva).
• Photophobia is often present .
• Continued sunlight exposure may result in severe keratitis, leading
to corneal opacification and vascularization, and in neoplasms
(epithelioma, squamous cell carcinoma, and melanoma)
Oral manifestations
• Oral manifestations are rarely seen and only about 4% patients

exhibit these symptoms .
• Some common oral manifestations associated with XP are
leukoplakia, erythroplakia, Actinic cheilitis and SCC of the tip of
the tongue and lips .
• The precancerous and cancerous lesions of the tip of the tongue are
sites that are seldom affected in the normal population and are
likely to be induced by UV radiation .
• SCC of the tip of the tongue in XP patients usually occurs in
individuals younger than 20 years of age and progresses slowly .
• Actinic cheilitis is a potentially malignant lesion that affects the
lower lip of white patients who are frequently exposed to the sun.
• Multiple labial plasty result in areas of fibrosis.
• Stretching of these fibrosed areas causes pain when the patients
opens the mouth for eating, speaking, breathing, and oral hygiene
procedures.
• These patients usually have poor oral hygiene habits and a high
rate of dental plaque, caries, and periodontal disease .
• Cases of chronic desquamative gingivitis, fissured tongue,
geographic tongue and keratoacanthoma have also been reported.
• 20-30% of patients have neurological problems and intellectual

deficiency .
• The time of onset can vary from the age of two to middle age.
• The neurological abnormalities are the result of progressive
neuronal degeneration resulting in sensorineural deafness, ataxia,
areflexia, microcephaly and intellectual deficiency as well as
impaired eyesight.
Diagnosis
• In most cases, the initial clinical diagnosis can be made on the

basis of either the extreme sensitivity to UV in those individuals
who show this feature, or in the appearance of lentiginosis on the
face at an unusually early age.
• The diagnosis can be confirmed definitively by employing robust
cellular tests for defective DNA repair that are available in several
countries.
• The most commonly used test is the measurement of unscheduled
DNA synthesis in cultured skin fibroblasts.
• After DNA damage has been removed, a patch of newly-
synthesised DNA replaces the damaged section.
• Synthesis of this new DNA has some different features from
synthesis of DNA during normal replication and the former is
therefore referred to as unscheduled DNA synthesis or UDS.
• Skin fibroblast cultures are established from a 3-4 mm punch
biopsy taken from an unexposed area of the skin, such as the upper,
inner arm or the buttocks.
• Fibroblasts are UV-irradiated in a Petridish, and UDS can be
measured as incorporation of nucleotides into DNA of the
irradiated cells either by autoradiography or liquid scintillation
counting , or more recently using a fluorescence assay .
• A reduced level of UDS confirms the diagnosis of XP.
• Individuals with XP-V do not show this defect in UDS, as NER is
unaffected in these patients.
• Furthermore XP-V cells are not hypersensitive to killing by UV
light. However, it has been found empirically, that caffeine
specifically sensitises XP-V cells to killing by UV.
• To diagnose XP-V cells, cultures are exposed to UV, incubated in
caffeine for a few days and their viability compared to that of
normal cells. Specific sensitivity to UV in the presence of caffeine
together with normal UDS confirms the diagnosis of XP-V.
• Further tests can identify the gene defective in patients
(complementation analysis) and the causative mutation.
• This can give further insight into the clinical features but at present
is not offered routinely as part of the diagnosis.
Differential diagnosis
• In severe cases, the diagnosis should be unequivocal.

• In milder cases, however, diagnosis can be much less clearcut,
with pigmentation changes not appearing until adolescence or even
later.
• Solar urticaria can be excluded by the fact that the rash resolves
within an hour of going indoors.
• Erythropoietic protoporphyria is easily screened through the
finding of normal porphyrins and not every exposed skin site is
affected in polymorphic light eruption.
• Likewise the sun-sensitive rash of Rothmund-Thompson Syndrome
is not associated with the pigmentation changes associated with
XP.
• The pigmented lesions of Carney complex and Leopard
syndrome are not related to sun exposure and in Peutz-Jeghers
syndrome the lentigines are perioral and acral.
• A family history should also exclude these autosomal dominant
lentiginoses.
Management
Genetic counselling
• As with all genetic disorders, genetic counselling and
psychological support is appropriate for the families, to discuss
aetiology, probability of occurrence in future pregnancies,
increased likelihood of occurrence in communities in which
consanguineous marriages are common.
Antenatal diagnosis
• The DNA repair tests described above can be carried out on
chorionic villus-derived cells or on amniocytes in affected families,
as can molecular analysis if the mutation in the proband has been
identified.
• Although no cure is available for XP, the skin problems can be
dramatically ameliorated by appropriate protection.
• However, some effects of sun exposure before diagnosis may
appear years later despite adequate sun protection after diagnosis.
• As the skin changes are all caused by UV light, complete
protection from exposure to UV can prevent further skin changes
completely.
Protective measures include the following:

• All windows in the home, car and school should be covered with
UV-resistant film, which iscommercially available. Hospital
theatre lights, halogen lights, metal halide lamps and some
fluorescent lights need to be avoided or covered.
• When outside during daylight hours, exposed skin should be
covered with sunscreen and lip balm.
• Long trousers, long sleeves and gloves should be worn together
with a UV-resistant face mask.
• If the patient finds this unacceptable, a broad-rimmed hat or
―hoodie‖ and wrap-around sunglasses should be worn.
• Regular visits should be paid to the dermatologist, so that any pre-
cancerous lesions can be removed as early as possible.
• Frequent eye examinations by an ophthalmologist are
recommended.
• Rigorous sun-protection is likely to result in vitamin D deficiency,
so vitamin D supplements should be prescribed.
• Patients should avoid cigarette smoke and other environmental
carcinogens.
• Psychosocial issues need to be addressed: social isolation from
peers at school and at home is common; career prospects are
thwarted and the meticulous photoprotection measures can lead to
denial.
SIDEROPENIC DYSPHAGIA
• Plummer-Vinson Syndrome or Paterson-Kelly Syndrome or

Paterson-Brown-Kelly syndrome
• The Plummer-Vinson syndrome is one manifestations of iron-
deficiency anemia and was first described by Plummer in 1914 and
by Vinson in 1922 under the term ‗hysterical dysphagia‘.
• Not until 1936; however, was the full clinical significance of the
condition recognized.
• Ahlbom then defined it as a predisposition for the development of
carcinoma in the upper alimentary tract.
• It is, in fact, one of the few known predisposing factors in oral
cancer.
Etiopathogenesis
• Etiopathogenesis of Plummer-Vinson syndrome is unknown;

however, the most important possible etiologic factor is iron
deficiency.
• It is thought that the depletion of iron-dependent oxidative
enzymes may produce myasthenic changes in muscles involved in
the swallowing mechanism, atrophy of the esophageal mucosa, and
formation of webs as mucosal complications.
• It is also thought to be an autoimmune phenomenon as the
syndrome is seen in association with autoimmune conditions such
as rheumatoid arthritis, pernicious anemia, celiac disease, and
thyroiditis.
• Other factors such as nutritional deficiencies, genetic
predisposition are thought to play roles in the causation of this
disease.
Clinical features
• Age: It usually affects middle-aged white women in the fourth to

seventh decade of life but has also been described in children and
adolescents.
• is a rare syndrome with the classic triad of dysphagia, iron
deficiency anemia, and upper esophageal webs or strictures.
• The dysphagia may be intermittent or progressive over years, is
usually painless and limited to solids, and sometimes is associated
with weight loss.
• Symptoms resulting from anemia (weakness, pallor, fatigue,

tachycardia) predominate the clinical picture, although
splenomegaly and enlargement of the thyroid and upper alimentary
tract cancers may also be found.
• Presenting symptoms of the anemia and the syndrome are cracks or
fissures at the corners of the mouth (angular cheilitis), a lemon-
tinted pallor of the skin, a smooth, red, painful tongue (glossitis)
with atrophy of the filiform and later the fungiform papillae, and
dysphagia limited to solid food resulting from an esophageal
stricture or web.
• The mucous membranes of the oral cavity and esophagus are
atrophic and show loss of normal keratinization.
• Koilonychia (spoon-shaped fingernails) or nails that are brittle and
break easily have been reported in many patients; splenomegaly
has also been reported in 20–30% of the cases.
• Radiologic examination of the pharynx shows the presence of
webs.
• The depletion of iron stores in the body, manifested as iron-
deficiency anemia, may be the direct cause of the mucous
membrane atrophy, since the integrity of epithelium is dependent
upon adequate serum iron levels.
• The atrophy of the mucous membranes of the upper alimentary
tract predisposes to the development of carcinoma in these tissues.
• This relationship was first noted by Ahlbom, who reported that half
of all women with carcinoma of the hypopharynx and upper part of
the esophagus seen at Radiumhemmet in Stockholm suffered from
Plummer-Vinson syndrome.
• Subsequently the predisposition to the development of oral
carcinoma was also established.
Laboratory Findings
• Blood examination reveals a hypochromic microcytic anemic of

varying degree, while sternal marrow examination shows no
megaloblasts typical of pernicious anemia.
• The red blood cell count is generally between 3,000,000 and
4,000,000 cells per cubic millimeter, and the hemoglobin is
invariably low.
• That the anemia is of an iron deficiency type can be confirmed by
lack of a reticulocyte response following administration of vitamin
B12.
• A low serum iron and ferritin with an elevated total iron binding
capacity (TIBC) are diagnostic of iron deficiency.
• There is an absence of free hydrochloric acid in the stomach.

• The achlorhydria is generally the cause of the faulty absorption of
iron, since the absence of hydrochloric acid prevents the
conversion of unabsorbable dietary ferric iron to the absorbable
ferrous state.
• The absence of stainable iron in a bone marrow aspirate is further
diagnostic of iron deficiency.
• Unusual alterations in exfoliated squamous epithelial cells of the
tongue in cases of severe iron-deficiency anemia have been
reported by Monto and his associates.
• These changes consisted of a deficiency of keratinized cells, a
reduced cytoplasmic diameter of cells with a paradoxical
enlargement of the nucleus, and abnormal cellular maturation
characterized by a disturbed nuclear pattern, an increase in
nucleoli, presence of double nuclei and karyorrhexis.
• Testing stool for the presence of hemoglobin is useful in
establishing gastrointestinal bleeding as the etiology of iron
deficiency anemia; however, they produce a high incidence of
false-positive results in people who eat meat.
Management
• Plummer-Vinson syndrome can often be treated effectively with

iron supplementation.
• Dysphagia may improve with iron replacement alone, particularly
in patients whose webs are not substantially obstructive.
• In cases of significant obstruction of the esophageal lumen by
esophageal webs/ strictures with persistent dysphagia despite iron
supplementation, rupture and mechanical dilation of the web may
be required.
• Since Plummer-Vinson syndrome is associated with an increased
risk of squamous cell carcinoma of the pharynx and the esophagus,
the patients should be followed closely.
DYSKERATOSIS CONGENITA
• Zinsser-Engman-Cole syndrome, Hoyeraal-Hreidarsson

syndrome
• The classic triad of reticulated skin hyperpigmentation, nail
dystrophy, and mucosal leukoplakia was first described in 1906 by
Zinsser et al.
• Dyskeratosis congenita (DKC) is a well recognized but rare
genodermatosis characterized by:
• Cutaneous reticulated hyperpigmentation,
• Nail dystrophy,
• Premalignant leukoplakia of the oral mucosa, and
• Progressive pancytopenia.
DC is classified as one of the Inherited Bone Marrow Failure
Syndromes (IBMFS).
• DC patients demonstrate signs of premature aging in addition to
having a 50-fold greater risk for certain malignancies over the
general population.
• This includes Acute Myelogenous Leukemia, head and neck
squamous cell carcinoma (HNSCC), squamous cell
carcinoma(SCC) of the cervix, non-Hodgkins lymphoma,
myelodysplastic syndrome, and basal cell carcinoma (BCC)
• It has been described in more than 400 families worldwide.
(Savage SA etal 2017)
Etiology
• Shortened telomeres are responsible for DC‘s clinical

manifestations.
• Mutations in DKC1 have been shown to cause the X-linked form
of DKC.
• The inheritance pattern of most cases of DKC is X-linked
recessive, but autosomal dominant and recessive patterns have
been reported.(Multiple modes of inheritance can occur )
Clinical Features
• Because this disorder is primarily X-linked recessive, the male-to-

female ratio is approximately 10 : 1.
• The nail changes are usually the first manifestation of the disease,
becoming dystrophic and shedding some time after the age of five
years.
• The grayish-brown skin pigmentation appears at the same time or a
few years later and is distributed over the trunk, neck, and thighs.
• The skin may become atrophic and telangiectatic and the face
appears red.
• Dermatologic manifestations typically occur between the ages of 5
and 12, however the presentation of DC can be heterogeneous.
• Some patients may have no mucocutaneous manifestations while
displaying the anemia associated with bone marrow failure alone.
• Occasional cases have also been reported with a wide spectrum of
other minor manifestations including a frail skeleton, mental
retardation, small sella turcica, dysphagia, transparent tympanic
membranes, deafness, epiphora and eyelid infections, urethral
anomalies, small testis, dental abnormalities and, commonly,
hyperhidrosis of the palm and soles.
Oral Manifestations
• The oral leukoplakia is the most common presentation, found in

65- 80% of DC patients.
• The oral leukoplakia associated with DC carries a significantly
increased risk of conversion to SCC- up to 1000 fold more than the
general population.
• Mucosal leukoplakia typically occurs on the buccal mucosa and
can affect the tongue and oropharynx.
• The leukoplakia may become verrucous, and ulceration may occur.
• Other mucosal sites may be involved (esophagus)
• Constriction and stenosis can occur, with the development of
dysphagia, dysuria.
• Patients also may have an increased incidence and severity of
dental caries , tooth loss , decreased root to crown ratio,
hypodontia, aggressive periodontitis, intraoral brown pigmentation,
and taurodontism
Histologic Findings
• Skin biopsy specimens from the areas of reticulated pigmentation

typically show mild hyperkeratosis, epidermal atrophy,
telangiectasia of the superficial blood vessels, and melanophages in
the papillary dermis.
• Interface changes have also been reported, with mild basal layer
vacuolization and a lymphocytic inflammatory infiltrate in the
upper dermis.
• Oral lesions have not been thoroughly studied but the leukoplakic
lesions appear to be nonspecific hyperparakeratosis or
hyperorthokeratosis and acanthosis.
• Depending on the stage of the disease, the epithelium may show
dysplasia.
• The exact nature of the preceding vesicles and ulcers has not been
described.
Laboratory Findings
• Many cases have been characterized also by hematologic changes

including anemia, leukopenia, thrombocytopenia and
pancytopenia.
• Some patients have developed Fanconi's anemia.
• In fact, the suggestion has been made that Fanconi's syndrome, or
Fanconi's familial pancytopenia, is simply a varied expression of
dyskeratosis congenita.
Treatment
• Short-term treatment options for bone marrow failure in patients

with DKC include erythropoietin and granulocyte colony-
stimulating factor;
• however, the only long-term, curative option is allogenic bone
marrow transfer.
• The high frequency of malignant transformation of oral lesions
would necessitate careful periodic examination of the patient for
such an occurrence.
• This patient population should receive biannual oral examinations
and should be closely monitored and biopsied early if there are any
changes to the oral leukoplakia.
• Potential carcinogens should be avoided in patients with DC

including: ultraviolet radiation, alcohol, tobacco, and exposure to
oncogenic viruses should be minimized as much as possible.
• There are no formal recommendations regarding the suitability of
human papillomavirus (HPV) vaccination in DC patients.
• It appears as though immunity can be obtained from HPV
vaccination in patients with other IBMFS, however HPV does not
appear to be associated with SCC in DC patients and the role of
vaccination to prevent SCC is unclear.
• HNSCC are the most frequent solid tumor malignancies seen in
DC patients, however, bone marrow failure and its sequelae
account for more than 70% of deaths in this patient population.
• A multidisciplinary approach to management of DC patients is
necessary and should, include early genetic testing and counseling.
• The composition of the multidisciplinary team can vary but will
typically include dermatology, otolaryngology, dentistry and
gynecology for female patients.
EPIDERMOLYSIS BULLOSA
• Epidermolysis bullosa is a general term that encompasses one

acquired and several genetic varieties (dystrophic, junctional,
simplex) of disease that are basically characterized by the
formation of blisters at sites of minor trauma.
• The several genetic types range from autosomal dominant to
autosomal recessive in origin and are further distinguished by
various clinical features, histopathology, and ultrastructure.
• A group of inherited bullous disorders characterized by blister
formation in response to mechanical trauma.
• Historically, epidermolysis bullosa subtypes have been classified
according to skin manifestations.
• Recent discoveries of the molecular basis of EB have resulted in
the development of new diagnostic tools, including prenatal
testing.
• Epidermolysis bullosa is classified into three major categories
including:
• Epidermolysis bullosa simplex (EBS) (intraepidermal skin
separation)
• Junctional epidermolysis bullosa (skin separation in lamina
lucida or central basement membrane zone)
• Dystrophic epidermolysis bullosa (sublamina densa basement
membrane zone separation).
Etiology
• In the hereditary forms of epidermolysis bullosa, circulating

antibodies are not evident.
• Rather, pathogenesis appears to be related to genetic defects in
basal cells, hemidesmosomes, or anchoring connective tissue
filaments, depending on the disease subtype
• Most cases of epidermolysis bullosa simplex (EBS) are
associated with mutations of the genes coding for keratins 5 and
14.
• The level of skin separation is at the mid-basal cell associated with
variable intermediate filament clumping.
• Junctional epidermolysis bullosa (JEB) has a highly variable
molecular etiology and represents a collection of different diseases.
• These diseases all cause blistering in the lamina lucida and variable
hemidesmosomal abnormalities.
• More than one half of JEB cases are caused by one of two
recurrent nonsense mutations in the LAMB3 gene, which is helpful
for mutation analysis and prenatal testing.
• Dystrophic epidermolysis bullosa (DEB) thus far has been
associated in all cases with mutations of the gene coding for type
VII collagen (COL7A1).
• Anchoring fibrils are affected in patients with DEB, and the degree
of involvement ranges from subtle changes to complete absence.
Epidermolysis Bullosa Simplex
• The generalized form of epidermolysis bullosa simplex is

inherited as an autosomal dominant characteristic, manifests itself
at birth or shortly thereafter and is characterized by the formation
of vesicles and bullae, chiefly on the hands and feet at sites of
friction or trauma.
• The knees, elbows and trunk are only rarely involved and the nails
are only occasionally affected.
• When the blisters heal, usually within 2–10 days, it is an important
feature that there is no resultant scarring or permanent
pigmentation.
• The disease appears to improve at puberty and prognosis is good
for a normal life span.
• The localized form of the disease (Weber-Cockayne syndrome),
which is also familial may occur early in childhood or later in life
and is commonly recurrent.
• The bullae only develop on the hands and feet, are related to
frictional trauma and tend to exacerbate in hot weather.
• There is no scarring upon healing.
Oral Manifestations
• Bullae of the oral cavity have been reported in occasional cases of

generalized epidermolysis bullosa simplex, but it is doubtful that
they actually occur.
• In addition, the teeth are not affected.
Histologic Features
• In the generalized form of epidermolysis bullosa simplex, the

vesicles and bullae develop as a result of destruction of basal and
suprabasal cells so that some nuclei may persist on the floor of the
blister, according to Lowe.
• The individual cells become edematous and show dissolution of
organelles and tonofibrils with displacement of the nucleus to the
upper end of the cell.
• The PAS (periodic acid-Schiff)-positive basement membrane
remains on the dermal side of the separation.
• The elastic, pre-elastic and oxytalan fibers in the connective tissue
are normal.
• In the localized form of the disease, the bullae are intraepidermal
and suprabasal in location.
Junctional Epidermolysis Bullosa
• It was earlier suggested by some workers that the junctional or

lethal type is simply an extremely severe from of the dystrophic
recessive form which is incompatible with prolonged survival.
• However, recent studies have proven that the two are distinctly
different disorders.
• The bullae are similar to those seen in the dystrophic recessive type
except that they commonly develop spontaneously, and sheets of
skin may actually be shed.
• Three criteria have been established for the diagnosis of this form
of the disease
These are:
• Onset at birth
• Absence of scarring, milia or pigmentation
• Death within three months of age.
Oral Manifestations
• Oral bullae are frequently very extensive, and because of their

extreme fragility, produce serious feeding problems.
• Similar lesions also occur in the upper respiratory tract, the
bronchioles, and the esophagus.
• Severe disturbances in enamel and dentin formation of the
deciduous teeth also occur but this is of only academic interest.
• These have been described by Arwill and his associates and by

Gardner and Hudson in significant detail.
Histologic Features
• The microscopic changes, including the location of the bullous

cleavage, appear similar and probably identical to those occurring
in the dystrophic recessive disease.
Epidermolysis Bullosa Dystrophic, Dominant
• This form of the disease may have its onset in infancy or it may be
delayed until puberty.
• The blisters commonly develop scarring which is sometimes
keloidal in type.
• In the majority of cases, the nails are thick and dystrophic, and
milia are commonly present.
• However, the eye is never involved.
• Palmar-plantar keratoderma with hyperhidrosis also may occur as
well as ichthyosis and sometimes hypertrichosis.
Oral Manifestations
• Bullae of the oral cavity have been described as occurring in about
20% of cases of this type, and Andreasen has described oral milia.
• The teeth are unaffected.
Histologic Features
• The bullae in this form of the disease develop as a result of

separation through the very thin, irregular PAS-positive basement
membrane which becomes divided.
• The basal layer appears normal although flattened on the roof of

the blister.
• The underlying connective tissue shows an absence of elastic and
oxytalan fibers.
Epidermolysis Bullosa Dystrophic, Recessive
• This type of epidermolysis bullosa (EB) is the best known and

classic form of the disease.
• It has its onset at birth or very shortly thereafter and is
characterized by the formation ofbullae spontaneously or at sites of
trauma, friction or pressure (Fig. 19-30A).
• The typical sites of involvement are the feet, buttocks, scapulae,
elbows, fingers and occiput.
• The bullae contain a clear, bacteriologically sterile or sometimes
blood-tinged fluid.
• When these bullae rupture or are peeled off under trauma or
pressure, they leave a raw, painful surface.
• These patients frequently have a positive Nikolsky's sign The
bullae heal by scar, milia and pigmentation.
• This scarring may result in afunctional club-like fists.
• The hair may be sparse while the nails are usually dystrophic or
absent.
Oral Manifestations
• Oral bullae are common in this form of the disease.

• They may be preceded by the appearance of white spots or patches
on the oral mucous membrane or the development of localized
areas of inflammation.
• The bullae may be initiated by nursing or by any simple dental
operative procedure in the oral cavity.
• Unless great caution is used, large areas of mucous membrane may
be inadvertently denuded.
• These bullae are painful, especially when they rupture or when the
epithelium desquamates.
• Scar formation often results in obliteration of sulci and restriction
of the tongue.
• Hoarseness and dysphagia may occur as a result of bullae of the
larynx and pharynx.
• Esophageal involvement may produce serious stricture.
• Dental defects have also been described, consisting of rudimentary

teeth, congenitally absent teeth, hypoplastic teeth and crowns
denuded of enamel.
• These have been discussed in detail by Arwill and his associates.
Histologic Features
• The separation and bulla formation here occur immediately

beneath the poorly defined PAS positive basement membrane
which remains attached to the roof of the blister.
• Fragments of the basement membrane may adhere to the dermis,
however.
• The basal layer of cells is normal.
• The pre-elastic and oxytalan fibers in the connective tissue are
increased in number.
• Elastic fibers are also increased but appear fragmented, according
to Lowe.
Treatment
• This group of diseases cannot be cured so that therapy is chiefly

symptomatic.
• The simplex form of the disease requires little treatment; the lethal
form will terminate fatally in most cases regardless of
management.
• In the dystrophic forms, prevention of trauma may reduce the
incidence of bulla formation, but this is almost impossible to
achieve.
• Antibiotics are useful in controlling secondary infection and
corticosteroids have sometimes been found effective.
• EB is a lifelong disease.
• Some subtypes, especially the milder EB forms, improve with age.
Epidermolysis Bullosa Aquisita (EBA )
• Epidermolysis bullosa acquisita (EBA) is an acquired, autoimmune

subepidermal blistering disease with an approximate prevalence of
0,2/million people.
• No racial or gender predilection.
• EBA often presents in the fourth to fifth decades of life.
• The acquired nonhereditary autoimmune form, known as

epidermatysis acquisita, is unrelated to the other types and is often
precipitated by exposure to specific drugs.
• In this type, IgG deposits are commonly found in sub-basement
membrane tissue and type VII collagen antibodies located below
the lamina densa of the basement membrane.
Clinical features
• There are two forms of EBA:

• the classic form, which results in a lesion of the basement
membrane with little inflammation, or
• the inflammatory form, which includes a significant infiltration of
neutrophils.
• The clinical course of EBA can resemble BP or MMP with
widespread skin lesions or primary involvement of the oral
mucosa, genital mucosa, conjunctiva, and larynx.
Lab investigation
• Patients with EBA have IgG autoantibodies directed against type

VII collagen, a component of the anchoring fibrils of the basement
membrane.
• In EBA, DIF from perilesional skin demonstrates linear basement
membrane zone (BMZ) deposition of IgG.
• Several findings on DIF may be helpful to either raise the suspicion
for, or confirm the diagnosis of, EBA.
• Linear BMZ deposition of IgG in the absence of C3 is seen more
commonly in EBA than in BP,
• whereas linear IgG and C3 deposition or C3 deposition alone is
more characteristic of BP.
• Deposits of multiple conjugates, including IgG, IgM, C3, C4, or

properdin, at the BMZ is also more frequently seen in the setting of
EBA compared to BP.
• IIF is either negative or positive in low titer in classic form of the
disease. This is in contrast to the inflammatory form which may
show higher titer of antibodies in the serum.
• Using salt-split skin, antibodies binding to the dermal side (―floor
pattern‖) of the split can be demonstrated in 40%–60% of cases.
Management
• The treatment is similar as described for MMP and LAD, with the
therapy depending upon the extent and severity of the clinical
lesions.
• The classic form of the disease tends to be resistant to treatment,
whereas the inflammatory form often responds well to dapsone.
• Some patients with an inadequate response to dapsone (50 to
150mg /day) have obtained remission with colchicine (0.5-
2mg/day).
• Systemic corticosteroids and immunosuppressive drugs are often
required to control the lesions in severe widespread EBA.
REFERENCES:
1. Sarode SC, Sarode GS, Tupkari JV. Oral potentially malignant

disorders: A proposal for terminology and definition with review of
literature. Journal of oral and maxillofacial pathology: JOMFP.
2014 Sep;18(Suppl 1):S77.
2. Warnakulasuriya S, Johnson N, Van der Waal I. Nomenclature and
classification of potentially malignant disorders of the oral mucosa.
Journal of oral pathology & medicine. 2007 Nov 1;36(10):575-80.
3. World Health Organization Collaborating Centre for Oral
Precancerous lesions. Definition of leukoplakia and related lesions:
an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol
1978; 46: 518–39.
4. George A, Sreenivasan BS, Sunil S, Varghese SS, Thomas J,
Gopakumar D, Mani V. POTENTIALLY MALIGNANT
DISORDERS OF ORAL CAVITY. Oral & Maxillofacial
Pathology Journal. 2011 Jan 1;2(1).
5. Burket 8th edition
6. Burket 11th edition
7. Damm DD, Curran A, White DK, Drummond JF. Leu-koplakia of
the maxillary vestibule--an association with Via-dent? Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 1999;87:61-6.
8. Kumar A, Cascarini L, McCaul JA, Kerawala CJ, Coombes D,
Godden D, Brennan PA. How should we manage oral
leukoplakia?. British Journal of Oral and Maxillofacial Surgery.
2013 Jul 1;51(5):377-83.
9. Singh SK, Gupta A, Sahu R. Non-Surgical Management of Oral
Leukoplakia. J Dentofacial Sci 2013;2:39-47.
10.Basnet P, Skalko-Basnet N. Curcumin: an anti-inflammatory

molecule from a curry spice on the path to cancer treatment.
Molecules. 2011 Jun 3;16(6):4567-98.
11.Behura SS, Singh DK, Masthan KM, Babu NA, Sah S.
Chemoprevention of oral cancer: a promising venture. (2015): 80-
87.
12.Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Interventions
for treating oral leukoplakia. Cochrane Database of Systematic
Reviews 2006;4: Art. No.: CD001829. DOI:
10.1002/14651858.CD001829.pub3
13.Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment
outcome of oral premalignant lesions. Oral Oncol 2006;42:461–74.
14.van der Waal I, Axéll T. Oral leukoplakia: a proposal for uniform
reporting.Oral Oncol 2002;38:521–6.
15.Nielsen H, Norrild B, Vedtofte P, Praetorius F, Reibel J, Holmstrup
P. Human papillomavirus in oral premalignant lesions. Oral Oncol
Eur J Cancer B 1996;32:264–70.
16.Shear M. Erythroplakia of the mouth. Int Dent J 1972;22(4): 460–
73
17.Rhodus NL, Kerr AR, Patel K. Oral cancer: leukoplakia,
premalignancy, and squamous cell carcinoma. Dental Clinics. 2014
Apr 1;58(2):315-40.
18.Waldron CA, Shafer WG. Leukoplakia revisited. A
clinicopathologic study of 3256 oral leukoplakias. Cancer
1975;36(4): 1386–92.
19.Reichart PA, Philipsen HP. Oral erythroplakia – a review. Oral
Oncol 2005; 41: 551–61.
20.Zain RB, Ikeda N, Gupta PC, et al. Oral mucosal lesions associated
with betel quid, areca nut and tobacco chewing habits: consensus
from a workshop held in Kuala Lumpur,Malaysia, November 25–
27, 1996. J Oral Pathol Med 1999;28:1–4.
21.Rajendran R. Oral submucous fibrosis: etiology, pathogenesis,and
future research. Bull World Health Organ 1994;72(6):985–96.
22.Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Surgery,
Oral Medicine, Oral Pathology. 1966 Dec 1;22(6):764-79.
23.Sirsat SM, Khanolkar VR. Submucous fibrosis of the palate and
pillars of the fauces. Indian journal of medical sciences. 1962
Mar;16:189-97.
24.Phatak AG. Serum proteins and immunoglobulins in oral
submucous fibrosis. Indian Journal of Otolaryngology and Head &
Neck Surgery. 1978 Mar 1;30(1):1-4.
25.Binnie WH, Cawson RA. A new ultrastructural finding in oral
submucous fibrosis. British Journal of Dermatology. 1972 Mar
1;86(3):286-90.
26.Ratheesh AV, Kumar B, Mehta H, Sujatha GP, Shankarmurthy SP.
Etiopathogenesis of oral submucous fibrosis. Journal of Medicine,
Radiology, Pathology and Surgery. 2015;1:16-21
27.Tilakaratne WM, Ekanayaka RP, Warnakulasuriya S. Oral
submucous fibrosis: a historical perspective and a review on
etiology and pathogenesis. Oral surgery, oral medicine, oral
pathology and oral radiology. 2016 Aug 31;122(2):178-91.
28.Rao AB. Idiopathic palatal fibrosis. British journal of surgery.
1962 Jul;50(219):23-5.
29.Kamat MS, Vanaki SS, Puranik RS, Puranik SR, Kaur R. Oral
Candida carriage, quantification, and species characterization in
oral submucous fibrosis patients and healthy individuals. Journal

of investigative and clinical dentistry. 2011 Nov 1;2(4):275-9.
30.Tupkari JV, Bhavthankar JD, Mandate MS. Oral submucous
fibrosis (OSMF): A study of 101 cases. Journal of Indian Academy
of Oral Medicine and Radiology. 2007 Apr 1;19(2):311.
31.Wahi PN, Kapur VL, Luthra UK, Srivastava MC. Submucous
fibrosis of the oral cavity. 2. Studies on epidemiology. Bulletin of
the World Health Organization. 1966;35(5):793.
32.Berwal V. et al. Classification systems for oral submucous fibrosis-
from past to present: A review. Int J Dent Health Sci 2014;
1(6):900-913
33.Gupta D, Gupta M, Golhar B. Oral submucous fibrosis; clinical
study and management by physiofibrolysis. J Indian Dent
Assoc1980. 1980;52:375-8.
34.More CB, Gupta S, Joshi J, Varma SN. Classification system for
oral submucous fibrosis. J Indian Acad Oral Med Radiol. 2012 Jan
1;24(1):24-9.
35.Katharia SK, Singh SP, Kulshreshtha VK. The effects of placental
extract in management of oral sub-mucous fibrosis. Indian journal
of Pharmacology. 1992 Jul 1;24(3):181.
36.Haider SM, Merchant AT, Fikree FF, Rahbar MH. Clinical and
functional staging of oral submucous fibrosis. British Journal of
Oral and Maxillofacial Surgery. 2000 Feb 1;38(1):12-5.
37.Rajendran R. Oral submucous fibrosis. Journal of Oral and
Maxillofacial Pathology. 2003 Jan 1;7(1):1.
38.Kumar KK, Saraswathi TR, Ranganathan K, Devi MU, Elizabeth J.
Oral submucous fibrosis: A clinico-histopathological study in
Chennai. Indian journal of dental research. 2007 Jul 1;18(3):106.
39.Mehrotra D, Pradhan R, Gupta S. Retrospective comparison of

surgical treatment modalities in 100 patients with oral submucous
fibrosis. Oral Surgery, Oral Medicine, Oral Pathology, Oral
Radiology, and Endodontology. 2009 Mar 31;107(3):e1-0.
40.Dayanarayana U. Non surgical approaches in treatment of OSF.
Journal of Dental and Medical Sciences. 2014Nov;13(11):63-9.
41.Vijayakumar M, Priya D. Physiotherapy for improving mouth
opening & tongue protrution in patients with Oral Submucous
Fibrosis (OSMF)—case series. International journal of
pharmaceutical science and health care. 2013;3(2):52-8.
42.Madalli VI, Basavaraddi SH, Burde KR, Horatti PR. Oral
submucous fibrosis-an overview. International Journal of Dental
Research & Development. 2014;4(2):1-6.
43.Ray JG, Ranganathan K, Chattopadhyay A. Malignant
transformation of oral submucous fibrosis: overview of
histopathological aspects. Oral surgery, oral medicine, oral
pathology and oral radiology. 2016 Aug 1;122(2):200-9.
44.Rossi R, Mor M, Lott T. Actinic keratosis. Int J Dermatol
2007;46:895-904.
45.Torma H, Berne B, Vahlquist A. UV irradiation and topical
vitamin A modulate retinol esterification in hairless mouse
epidermis. Acta Derm Venereol 1988;68:291-299.
46.Matsumura Y, Ananthaswamy HN. Toxic effects of ultraviolet
radiation on the skin. Toxicology and Applied Pharmacology
2004;195:298-308.
47.Chiller KG, Washington C, Sober AJ, Koh HK. Cancer of the skin.
In: Kasper DL et al., eds. Harrisons Principles of Internal
Medicine. 16thed. New York: McGraw-Hill; 2005:497- 503.
Bickers DR. Photosensitivity and other reactants to light. In:
Kasper DL et al., eds. Harrison’s Principles of Internal Medicine.

16thed. New York: McGraw-Hill; 2005:324-329.
48.Horta MCR, de Assis LAP, de Souza AF, de Araujo VC, Gomez
RS, Aguiar MCF. p53 and p21 WAF1/CIP1 overexpression at the
invasive front of lower lip squamous cell carcinoma. J Oral Pathol
Med 2007;36:88-92.
49.Markopoulos A, Albanidou-Farmaki E, Kayavis I. Actinic chelitis:
clinical and pathologic characteristics in 65 cases. Oral Dis
2004;10:212-216.
50.Hong ES, Zeeb H, Repacholi MH. Albinism in Africa as a public
health issue. BMC Public Health 2006;6:212-222.
51.Alan Motta do Canto, Helena Muller, Ronaldo Rodrigues de Freita,
Paulo Sergio da Silva Santos. Oral lichen planus (OLP): clinical
and complementary diagnosis. An Bras Dermatol.2010;85(5):669-
75.
52.Marzieh Boorghani, Ali Taghavi Zenouz, Mehdi Vatankhah,
Masoumeh Mehdipour. Oral Lichen Planus: Clinical features,
Etiology, Treatment and Management; A review of
Literature.JODDD, Vol. 4, No. 1 Winter 2010.
53.Oral Lichen Planus: Clinical presentation and Management. J Can
Dent Assoc 2002; 68(8):494-9.
54.Oral Lichen Planus: Clinical presentation and Management. J Can
Dent Assoc 2002; 68(8):494-9.
55.Thongprasom K, Carrozzo M, Furness S, Lodi G. Interventions for
treating oral lichen planus. The Cochrane Library. 2011 Jan 1.
56.Robbins JH, Kraemer KH, Lutzner MA, Festoff BW, Coon HG:
Xeroderma pigmentosum: an inherited disease with sun-sensitivity,
multiple cutaneous neoplasms, and abnormal DNA repair. Annals
Internal Med 1974, 80:221-248.
57.Hirai Y, Kodama Y, Moriwaki S, Noda A, Cullings HM, Macphee

DG, Kodama K, Mabuchi K, Kraemer KH, Land CE, Nakamura N:
Heterozygous individuals bearing a founder mutation in the XPA
DNA repair gene comprise nearly 1% of the Japanese population.
Mutat Res 2006, 601:171-178.
58.Tamhankar PM, Iyer SV, Ravindran S, Gupta N, Kabra M, Nayak
C, Kura M, Sanghavi S, Joshi R, Chennuri VS, Khopkar U.
Clinical profile and mutation analysis of xeroderma pigmentosum
in Indian patients. Indian Journal of Dermatology, Venereology,
and Leprology. 2015 Jan 1;81(1):16.
59.Bunick CG, Miller MR, Fuller BE, Fanning E, Chazin, et al. (2006)
Biochemical and structural domain analysis of xeroderma
pigmentosum complementation group C protein. Biochemistry 45:
14965-14979.
60.Grosjean D, Sarasin S (2005) ―The role of UV induced lesions in
skin carcinogenesis: an overview of oncogene and tumor
suppressor gene modifications in xeroderma pigmentosum skin
tumors‖. Mutation Research 571: 43-56.
61.Khatri ML, Bemghazil M, Shafi M, Machina A (1999) Xeroderma
pigmentosum in Libya. Int J Dermatol 38: 520-524.
62.Ahmed H, Hassan RY, Pindiga UH (2001) ―Xeroderma
pigmentosumin three consecutive siblings of a nigerian family:
observations on oculocutaneous manifestations in black African
children‖. British Journal of Ophthalmology 85: 110-111.Hasan S,
Khan MA (2011)
63.J. E. Cleaver and K. H. Kraemer, ―Xeroderma Pigmento-sum and
Cockayne Syndrome in the Metabolic and Mo-lecular Basis of
Inherited Diseases,‖ 7th Edition, Mc- Graw-Hill, New York, 1995,
p. 4393.
64.Stefanini M, Kraemer KHK: Xeroderma pigmentosum. In

Neurocutaneous Diseases Edited by: Ruggieri M, Pascual-
Castroviejo I, Di Rocco C 2008,Chapter 51:771-792.
65.Lehmann AR, Kirk-Bell S, Arlett CF, Paterson MC, Lohman
PHM, de Weerd-Kastelein EA, Bootsma D: Xeroderma
pigmentosum cells with normal levels of excision repair have a
defect in DNA synthesis after UVirradiation. Proceedings of the
National Academy of Sciences of the United States of America
1975, 72:219-223.
66.Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa
M, Araki M,Iwai S, Takio K, Hanaoka F: The XPV (xeroderma
pigmentosum variant) gene encodes human DNA polymerase eta.
Nature 1999, 399:700-704.
67.Daya-Grosjean L, Sarasin A: The role of UV induced lesions in
skin carcinogenesis: an overview of oncogene and tumor
suppressor gene modifications in xeroderma pigmentosum skin
tumors. Mutat Res 2005, 571:43-56.
68.Bradford PT, Goldstein AM, Tamura D, Khan SG, Ueda T, Boyle
J, Oh KS, Imoto K, Inui H, Moriwaki SI, Emmert S, Pike KM,
Raziuddin A, Plona TM,Digiovanna JJ, Tucker MA, Kraemer KH:
Cancer and neurologic degeneration in xeroderma pigmentosum:
long term follow-up characterises the role of DNA repair. J Med
Genet 2011, 48:168-176.
69.Ramkumar HL, Brooks BP, Cao X, Tamura D, Digiovanna JJ,
Kraemer KH, Chan CC: Ophthalmic manifestations and
histopathology of xeroderma pigmentosum: two
clinicopathological cases and a review of the literature. Surv
Ophthalmol 2011, 56:348-361.
70.Hasan, S., and S. Saeed. "Xeroderma Pigmentosum-A Rare

Genodermatosis: Overview of Literature. Pigmentary Disorders 2:
230. Page 2 of 5 8 (2015).
71.Kraemer KH (2003) Heritable diseases with increased sensitivity to
cellular injury. Fitzpatrick‘s Dermatology in General Medicine.
McGraw-Hill, New York, USA.
72.Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in
dyskeratosis congenita. Blood. 2009 Jun 25; 113(26):6549-57.
73.Kirwan M, Vulliamy T, Marrone A, Walne AJ, Beswick R,
Hillmen P, Kelly R, Stewart A, Bowen D, Schonland SO, Whittle
AM, McVerry A, Gilleece M, Dokal I. Defining the pathogenic
role of telomerase mutations in myelodysplastic syndrome and
acute myeloid leukemia. Hum Mutat. 2009 Nov; 30(11):1567-73
74.Savage SA, Dokal I, Armanios M, Aubert G, Cowen EW,
Domingo Dl, et al. Dyskeratosis congenita: the first NIH clinical
research workshop. Pediatr Blood Cancer. 2009 Sep; 53(3):520- 3.
75.Alter BP1, Giri N2, Pan Y3, Savage SA2, Pinto LA3. Antibody
response to human papillomavirus vaccine in subjects with
inherited bone marrow failure syndromes. Vaccine. 2014 Feb
26;32(10):1169-73.
76.Alter BP1, Giri N, Savage SA, Quint WG, de Koning MN,
Schiffman M. Squamous cell carcinomas in patients with Fanconi
anemia and dyskeratosis congenita: a search for human
papillomavirus. Int J Cancer. 2013 Sep 15;133(6):1513-5.
77.Jindal A, Rao R, Bhogal BS. Advanced diagnostic techniques in
autoimmune bullous diseases. Indian journal of dermatology. 2017
May;62(3):268.

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Oral Potentially Malignant Disorders

• Several attempts to produce internationally accepted terminologies

World Health Organization proposed in 1978-

a) A precancerous lesion is a morphologically altered tissue in which

Oral Potentially malignant disorders

• The terminologies and concepts discussed till date in the literature

1. In longitudinal studies, areas of tissue with certain alterations in

Classification of precancerous lesions and conditions (WHO 1978)

RED AND WHITE LESIONS WITH DEFINED OR UNCERTAIN

• Leukoplakia and erythroplakia

 Leukoplakia (white patch) is the most common potentially

Definable White Lesions

Hyperplastic candidiasis (candidal leukoplakia).

Hairy leukoplakia (Greenspan lesion).

Tobacco-induced white lesions.

Viadent Leukoplakia (Sanguinaria-associated Keratosis)

• The prevalence of oral leukoplakia varies among scientific studies.

• Sixteen to 62% of oral carcinomas have been reported to be

Etiology and Pathogenesis

• The development of oral leukoplakia and erythroplakia as

• It could be scraped off with a piece of gauze (leukoplakia); it

• Preleukoplakia is defined as a low-grade or very mild reaction of

Various forms of leukoplakia and subdivisions recommended

• The typical homogeneous leukoplakia is clinically characterized

• The nonhomogeneous type of oral leukoplakia may have white

• Oral leukoplakia may be found at all sites of the oral mucosa.

Proliferative Verrucous Leukoplakia and its Related Lesions:

• Proliferative verrucous leukoplakia (PVL) and verrucous

 The histologic spectrum that is seen in PVL are:

Verrucous hyperplasia (VH)

• It should be emphasized that leukoplakia is a clinical term, and its

Histopathological features of epithelial dysplasia (Krammer et al.,

1. Loss of polarity of the basal cells

Grading of Epithelial Dysplasia

• Epithelial dysplasia is usually assessed subjectively and

Modified Classification and Staging System for Oral

 A proposal for a modified classification and staging system for oral

 Altogether four stages are recognized:

• L1 — Size of leukoplakia <2 cm

OLEP Staging System

Disorders that need exclusion to diagnose leukoplakia Disorder

• In homogeneous leukoplakia, the value of histological examination

exfoliative cytology are of limited value when dealing with

spectroscopy (fluorescence spectroscopy, elastic scattering

• Oral leukoplakia is a lesion with an increased risk of malignant

Fenretinide (200mg/day for 3 months) : vitamin A analogue , inhibit

• Photodynamic therapy (Aminolevulenic acid 10-20 %) : Twice a

Polyphenols as chemo-preventive agents

According to Cochrane review–

 None of the treatments are effective in preventing malignant

• Although clinical appearance such as non-homogeneous oral

epithelial dysplasia (44%) with a malignant transformation rate of

• Erythroplakia has been defined as a ―bright red velvety plaque or

• Fournier and Darier first described erythroplasia as a malignant

• The development of oral erythroplakia as premalignant lesions

• This notion is supported by the fact that markers of genetic defects

• Several clinical variants of erythroplakia have been described, but

• A special form of erythroplakia has been reported that is related to

ERYTHROPLAKIA WITH ULCERATION

• Another rare but high-risk premalignant lesion is the chronic