€ Cancer

being a genetic disorder involves multiple alterations of the genome progressively accumulated during a period. € The overall effects of which surpasses the inherent reparative ability of the cell. € In the course of its progression, visible physical changes are taking place at the cellular level (atypia). € And at the resultant tissue level (dysplasia). € These alterations include genetic changes, epigenetic changes, surface alterations and alterations in intercellular interactions.

€ The

sum total of these physical and morphological alterations are of diagnostic and prognostic relevance and are designated as ¶precancerous· changes. € In many situations, the relationship between these changes and the progression towards neoplasia is not understood. € These changes are ultimately involved in driving cells further along the path to neoplastic transformation.

€ Identification

of preneoplastic lesions of upper aerodigestive tract
- through clinical, morphological and -more recently, molecular means, -helps in the early detection and treatment of head and neck squamous cell carcinoma.

€ Understanding

and documenting the morphological and molecular abnormalities associated with this progression may shed light on the biology of these tumors.

Clinical term used to denote mucosal conditions that produce a whiter than normal coloration of the mucous membrane. € It is used as a clinical term only to describe a variety of white mucosal lesions. € Usually cannot be removed by gently rubbing the superficial mucosa. € Term leukoplakia means white patch. .

€ WHO . € Precancerous condition ´ a generalized state associated with a significantly increased risk of cancerµ. € Examples ² sederopenic dysphagia. submucous fibrosis and lichen planus.1978 definition ´a morphologically altered tissue in which cancer is more likely to occur than in its apparently normal counterpartµ.

morphologically altered tissue that has a greater than normal risk of malignant transformation. premalignancy). € Precancerous condition : A disease or patient habit that does not necessarily alter the clinical appearance of local tissue but is associated with a greater than normal risk of precancerous lesion or cancer development in that tissue.€ Precanceous lesion (pre cancer.A benign. .

The potential for mucosa without pre cancerous lesions or conditions is called ´normalµ. expressed as a ratio of the incidence or prevalence of a disease among those exposed and those not exposed to the factors. either at initial diagnosis or in the future (usually expressed in percentages).Malignant transformation potential: The risk of cancer being present in a pre cancerous lesion or condition. € . € Relative risk: A specific epidemiologic measure of the association between exposure to a particular factor and the risk of acquiring a disease.

€ Epithelial dysplasia to indicate microscopic features in a biopsy specimen that are associated with a risk of malignant change and then assign a grade of severity.of precancers is primarily based on morphology and its grading on histology (dysplasia). € Diagnosis . € There is good correlation between higher grades of dysplasia and increasing risk of cancer € But less so with the lower grades.

€ ´It comprises a loss in the uniformity of the individual cells. at the expense of cytoplasmic volume. as well as a loss in their architectural orientation.principally in the epithelia. € Encounterd . € Nuclear:cytoplasmic ratio increases from 1:4 to 1:1.µ € Dysplastic cells exhibits considerable € Pleomorphism (variation in size and shape) nuclei. which are abnormally large for the size of the cell.

figures more abundant than usual. € Usual proliferative organization of epithelium is lost is replaced by disorderly arranged scramble of cells. € Mitotic . € Cellular atrophy. € Hyperplasia.broadening the progenitor compartment. € Mitotic figures appear in abnormal or at all location.

is a reversible & therefore controlled. cellular alteration. € Dysplasia . the dysplastic alterations revert to normal. € When the underlying inciting/insulting stimulus is removed.

Enlarged nucleoli Reduction of cellular cohesion Keratinization of single cells or cell groups in the prickel cell layer. Irregular epithelial stratification. Increased number of mitotic figures (a few abnormal mitoses may be present) Presence of mitotic figures in the superficial half of the epithelium Cellular pleomorphism Nuclear hyperchromatism.1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) Loss of polarity of basal cells Presence of more than one layer of cells having a basaloid appearance Increased nuclear cytoplasmic ratio. Drop shaped rete processes. .

REACTIVE -Hyperkeratosis (ortho/para) -Acanthosis -Actinic cheilitis -Snuff dipper·s keratosis -Nicotine stomatitis -Heat/Chemical burns NEOPLASTIC -Epithelial dysplasia -Carcinoma in situ -Squamous cell carcinoma -Verrucous carcinoma INFECTIONS -Chronic hyperplatic candidiasis -Hairy leukoplakia -Syphilitic mucous patch IMMUNE MEDIATED -Lichen planus -Lupus erythematosus HEREDITARY -Leukoedema -White sponge nevus IDIOPATHIC -Hairy tongue -Geogrpahic tongue .

High risk 3 Pathological indices: Genetic patterns: .Severe dysplasia/ CIS G1.Moderate dysplasia & P3.No dysplasia P3 mild dysplasia or + G3 P2.Stage (Cancer risk) 1 2 Pathology (P) & Genetic (G) patterns P1 + G1 P1 + G1 P2 + G1 P2 + G1 P3 + G1 P3 + G2 P1 + G3 P2 + G3 P1.Intermediate risk & G3. G2.Low risk.

Histological & Clinical .Type 2 Type 1 Type 3 Genetic changes Type 4 Genetic changes Dysplasia & atrophy Genetic change Normal Genetic changes Dysplasia Leukoplakia Erythroplakia Dysplasia & Hyperplasia Molecular Molecular & Histological Molecular.

a more elaborate sub division may be used such as 1) Homogenous 2) Non homogenous nodulospeckled: well demarcated raised white areas. interspersed with reddened areas When recording leukoplakia. space has been allowed in the recording form for three different subdivisions.a) Homogeneous b) Non homogeneous Lesions that are uniformly white Lesions in which part of the lesion is white and rest appears reddened. 1) Homogeneous ² Smooth and fissured 2) Homogeneous ² Ulcerated 3) Non homogeneous ² Nodulospeckled. a) Smooth b) Furrowed (Fissured) c) Ulcerated Alternatively. .

€ The term leukoplakia describes a greyish white patch or plaque found in the mucous membrane of the oral cavity. alveolar mucosa. . € Leukoplakia occurs most often in middleaged and older men and arises most frequently on the buccal mucosa. and lower lip.

Ventral /floor of mouth Lower lip/labial mucosa right side .

2. 3. 5. Tobacco chewing or smoking Alcohol Local irritations Vitamin deficiency : Vit A and Vit B Endocrine disturbances Candidiasis Syphilis . 4. 7.1. 6.

.

history € Prevention of the cause € Surgical excision of the small lesion € In females: supplementation of Oestrogen € Topical chemotherapy and radiation € Proper .

mandibular mucosa and sulcus y . soft palate. tongue.retromolar area. Smoking: Pipe smokers 2. Dental irritation Common Site: y Buccal muosa. Trauma 3.These are red patches found in the oral cavity y Erythroplakia not very common than Leukoplakia y There is no sex difference y Occurs in 6th and 7th decades of life Etiology: 1. floor of the mouth.

Area of Squamous Cell Carcinoma Surrounded by Erythroplakia

1.Homogenous form: y Which appears as a bright red, soft,velvety lesions and quite extensive in size y Site: Commonly found in buccal mucosa and soft palate 2. Speckled erythroplakia: y These are soft, red lesions, slightly elevated with an irregular outline y Surface being granular³These are often referred to as speckled leukoplakia/erythroplakia Common Site: Anywhere in the oral cavity

shows lack of keratin production and is often atrophic. € In some may be hyperplastic. € Lack of keratinization with epithelial thinness, allows underlying microvasculature to show red color. € Underlying connective tissue often demonstrates chronic inflammation.
€ Epithelium

1-2 weeks following elimination of suspected irritants. € Immediate biopsy if lesions persist. € Surgical excision gives excellent results. € Recurrence is less than 5%.
€ Observation

€ This is due to fibroelastic change of oral mucosa with epithelial atrophy leading to stiffness of oral mucosa and causing trismus and inability to eat. € WHO definition ´a generalized pathological state of the oral mucosa associated with a significantly increased risk of caner-accords well with characteristics of osmf. tobacco. Diffuse firm whitish areas of submucosal scarring usually caused by frequent and prolonged contact with betel nut quids. or hot chili peppers. lesions have a higher than normal risk of developing squamous cell carcinoma .

swallow. characterized by fibroelastic changes and inflammation of the mucosa.´Oral submucous fibrosis (OSF) is a slowly progressive chronicfibrotic disease of the oral cavity and oropharynx. or speak. leading to a progressive inability to open the mouth.µ .

Chewing betel nut with lime € Vitamin B deficiency € Protein deficiency € Genetic susceptibility ² raised HLA-A10. -B7 & -DR3.. € Panparag .

This is accompanied by the formation of the vesicles. ulceration or recurrent stomatitis with excessive salivation or xerostomia .y y y Most common between 20-40 years of age. but can occur in any decades of life The disease is characterized by burning sensation of mouth particularly when eating spicy foods.

y y Ultimately the patient develops stiffning of certain area of the oral mucosa with difficult in opening the mouth and swallowing. The fibroelastic band eventually appear on mucosa usually involving the buccal mucosa.soft palate.lips and tongue .

.

.

.

€ Lesions involving palate showed predominantly orthokeratosis and those of buccal mucosa parakeratosis. € Predominantly .hyperplasia (early stages) € Atrophy in (advanced stages) € Associated with increased tendency for keratinizing metaplasia.

.

Cellular elements and blood vessels are greatly reduced. . The underlying lamina propria exhibits severe hyalinization. Varying degrees of epithelial atypia may be present.€ € € € Reveals severely atrophic epithelium with complete loss of rete ridges. with homogenization of collagen.

more common in osmf & association with parakeratotic leukoplakia & atrophic epithelial changes predisposes osmf to malignancy.€ High mitotic count in parakeratotic epithelium. .

c) Moderately advanced & d) Advanced.SUBEPITHELIAL CHANGES Based on h/p appearance & H & E staining grouped into a) Very early b) Early. .

) d) State of blood vessels and e) Predominant cell type in inflammatory exudate. following criteria a) Presence or absence of odema b) Physical state of mucosal collagen c) Overall fibroblastic response (number of cells and age of individual cells. .Not only on the amount nature of subepithelial collagen.

€ Inflammatory response mainly in lymphocytes and plasma. . € Rise in mast cells also occurs in earlier stages of tissue reaction. € In advanced stages counts are fewer. € Atrophic changes in epithelium are secondary. Excessive fibrosis in mucosa seems to be the primary pathology of osmf.

€ Physiotherapy: .Measures such as forceful mouth opening and heat therapy. € Nutritional support: . for vitamin B complex and other vitamins and minerals. .€ The reduction or even elimination of habit of arecanut chewing.high protein and calories. € Immunomodulatory Drugs: .Local and systemic applications of glucocorticoids.

Measures such as forcing the mouth open and cutting the fibrotic bands have been used. but it can cause more fibrosis and disability. oral iron preparations. surgical intervention is the only treatment:. € In severe cases.€ Local Drug Delivery: . .Submucosal injected steroids and hyaluronidase. and topical vitamin A and steroids are some of the agents that are used.

€ Physiotherapy.includes forceful mouth opening & heat therapy.€ Investigations for all premalignant lesions:Biopsy € Treatment: € Treated with Local Hydrocortisone injection and Systemic corticosteroids € Nutritional support. . € Immunomodulatory drugs ² glucocorticoids & placental extracts commonly used.

€ Local drug devlivery. € Surgical management. collagenase to breakdown intercellular cement substances & also decrease collagen formation.Hyaluronidase. .

€ In a 17-year follow-up study in India. oral cancer developed in 7. € -The malignant transformation rate for submucousfibrosis was 4 to 13%.€ -The use of an oral stent as an adjunct to surgery to prevent relapse has also been studied. € -OSF is considered to be a premalignant condition. .6% of patients with submucous fibrosis.

€ Common mucocutaneous disease.5-1% of world·s population. . € First described by British physician Erasmus Wilson in 1869. € Effect 0. € This condition can affect either skin or mucosa or both.

.7) among those who smoked and chewed tobacco.€ The relative risk for oral lichen planus was highest (13.

or erosive lesions with a prominent T-lymphocyte response in the immediate underlying connective tissue € Clinical sub type a) Reticular b) Atrophic c) Hypertrophic & d) Erosive More than one clinical subtype may be seen at a time. plaque.Lichen planus : a skin disease common within the oral cavity. where it appears as either white reticular. .

And Angiotensin Converting Enzyme (Ace Inhibitors) Gold. Sulphathiazides . Beta Blockers.Precise cause of OLP is unknown. Penicillamine. € T-cell mediated auto-immune disease in which cytotoxic CD8+ T cells trigger the apoptosis of oral epithelial cells € Oral lichen planus like lesions can be induced by drugs known as ¶lichenoid drug reaction· € Commonly known drugs € NSAIDS Anti-malarials.

€ In many patients a cause for the oral lichenoid lesions cannot be identified. the disease is called idiopathic OLP Stress Smoke /tobacco Trauma Infection and Allergy Malnutrition . in these patients.

g. Langer ans cells. and dendroc tes) L mp oc tes (T-cells) recruited in sub mucosa (Through receptors to endothelial adhesion molecules) Basal keratinoc tes neoexpress ICAM and l mphoc tes attach (Through l mphoc te receptors to ICAM) Basal keratinoc tes undergo apoptosis (Mediated b l mphoc te derived c tokines) Hyperkeratosis (Reduced keratiocyte desquamation due to enhanced membrane adhesion) ¤ ¡ ¤ ¡ £   ¡ £ £ ¤ ¡   ¢ ¡ ¡ ¤ ¤ ¤ £   ¤ ¤ ¤ £ . ICAM & ELAM) (Induced b resident macrop ages.HYPOTHETICAL MOLECULAR EVENTS Antigenic stimulation (Exogenous/Endogenous) Langer ans cells and factor XIIIa dendroc tes increase (Associated it antigenic c allenge) Endot elium upregulates ad esion molecules (E.

€ An interesting association of lichen planus. diabetes mellitus. and vascular hypertension a traid called Grinspan·s syndrome .

with a female to male ratio of 1.€ € € € € It affects all racial groups. Its surface is covered by characteristic. glistening scale. called Wickham·s striae. but they soon take on a reddish. each of which is covered by a fine. The papules are sharply demarcated from the surrounding skin. € € € € € . purple or violaceous hue. Later. a dirty brownish color develops.4 :1 Occurs in adults older than 40 years Skin lesions Small. angular flat topped papules only a few mm in diameter These may be discrete or gradually coalesce into larger plaques. The center of the papule may be slightly umbilicated. Early in the course of the disease the lesions appear red. very fine grayish white lines.

and the trunk.€ The lesions may occur anywhere on the skin surface € Distributed in a bilaterally symmetrical pattern € Most often on the flexor surfaces of the wrist and forearms. the inner aspect of the knees and thighs. especially the sacral area € Primary symptom is the severe pruritis .

Disease assumes a somewhat different clinical appearance than on the skin. known here also as the striae of Wickham. rings and streaks over the buccal mucosa and to a lesser extent on the lips. thread like papules in a linear. € Reticular pattern is the most common type € . € And classically is characterized by lesions consisting of radiating white or gray. annular or retiform arrangement forming typical lacy. tongue and palate. velvety. € A tiny white elevated dot is frequently present at the intersection of the white lines. reticular patches.

smooth. red.well circumscribed elevated white lesion resembling leukoplakia. Biopsy is usually necessary to establish the diagnosis . poorly defined areas. often but not always with peripheral striae evident chronic desqumative gingivitisEspecially on tongue shows atrophic glossitis with atrophy of filiform and fungiform papillae 2) Hypertrophic.1) Atrophic.

raised or not has shiny upper surface known as mother of pearl 6) Verrucous ² hyperplastic mass of tissue having a verrucous or hyperplastic appearance .3) Bullous ² vesicle formed few mm-cm large vesicles are fluctuant. fluid clear and thick may become purulent in secondary infection 4) Erosive or ulcerative. Erosive form.most dangerous rupture of vesicles or from beginning irregular in size and shape appear as raw painful areas Complain of burning sensitivity n discomfort. 5) Plaque.central area is ulcerated. Fibrinous plaque or pseudomembrane covers ulcer.

.

.

pruritic papules on flexor surfaces. flat-topped. leave painful ulcer. polygonal. € Bullae range from few mm to cm in diameter. violaceous. . € Short lived and on rupturing. € Skin features: € Presence of small.€ Rare form is bullous variant.

Hyperkeratosispara/ortho with thickening of granular layer. € Acanthosis with intercellular edema of spinous cells in some cases. € Band line subepithelial mononuclear infiltrate consisting of T-cells and histiocytes: € .

hyaline. and € .Increased number of intraepithelial T-cells. cytoid )bodies which appear as homogenous eosinophilic globules € Basal layer vacuolization with apoptotic keratinocytes. € Degenerating basal keratinocytes form colloid (Civette .

Lymphophagocytic infiltrate at epthelium-connective tissue interface. resulting in reduced thickness and a saw tooth rete ridge pattern. € Within epithelium increased numbers of Langerhans cells € . € With time epithelium undergoes gradual remodeling.

€ Degeneration .Max-Joseph spaces. € Results histologic clefts.of hemidesmosomes. fibrils weakens the epithelialconnective tissue interface. € Blisters on oral mucosa (bullous li pl) may be seen. filaments.

.

€ Lupus erythematosus € White sponge nevus € Cheek biting € Hairy leukoplakia € candidiasis € Sq cell ca .€ Lichenoid drug reaction.

€ . € Topical application and local infection successfully used. € Topical Vit A ²because of their antikeratinizing and immunomodulating effects. € Severe cases systemic steroids given. € Addition of antifungal therapy enhances results.Since autoimmune disease € Corticosteriods € Rationale for their use is their ability to modulate inflammation and immune response.

€ Periodic recall and observation.€ Reversal of white striae can be achieved by topical retinoids. Prognosis : € Malignant transformation-0. .3-3% in erosive and atrophic forms.

€ Commonly seen among smokers. € Consists of greyishwhite palate with small nodular excrescences having small central red spots. . € Corresponding to inflamed orifices of minor salivary glands.

palatal mucosa becomes diffusely gray or white. € Such papules represent inflamed minor salivary glands & their ductal orifices. € With long term exposure to heat. usually with punctate red centers.commonly found in men older than 45 years of age. € Mucosa that covers papules frequently appears whiter than surrounding epithelium. € Most . € Numerous slightly elevated papules are seen.

Based on different habits lesions can be grouped ² a) Predominantly associated with smoking i) Leukodema ii) Leukokeratotis nicotina palati iii) Palatal erythema iv) Central papillary atrophy of tongue b) Predominantly assoicated with chewing i) Paan chewer·s lesions ii) Oral lichen planus like lesion iii) Oral submucous fibrosis c) Associated with smoking & chewing (mixed habit) i) Leukoplakia & Preleukoplakia ii) Oral Lichen Planus iii) Oral Squamous carcinomas .

€ A heavy brown or black tobacco stain my be present on teeth. and leukoplakia of buccal mucosa is occasionally seen. € Whiteness usually involves marginal gingiva and interdental papillae.keratin become so thickened that fissured or ´dried mudµ appearance . € Palatal .

€ Keratosis ²diffuse whitening of entire palatal mucosa € Excrescences-1-3 mm elevated nodules. and € Non-pigmented areas-areas of palatal mucosa that are devoid of pigmentation. € Ulcerated areas-crater-like areas covered by fibrin. € Patches-well defined. often with central red spots. elevated white plaques € Red areas-well defined reddening of the palatal mucosa. .

€ Squamous metaplasia of excretory ducts is usually seen. € Inflammatory exudate may be noted within duct lumina. € Hyperkeratosis . € Epithelial dysplasia and inflammatory cells in connective tissue. € Melanin deposits in lamina propria.& acanthosis € Epithelium atrophic in 60% red areas.

€ Degree of epithelial hyperplasia & hyperkeratosis ²correlate positively with duration and level of heat of exposure. hyperplastic ductal epithelium may be seen near orifice. .€ In case of papular elevation.

cessation. € Any white lesion of palatal mucosa that persists after 1 month of habit cessation should be considered a true leukoplakia & managed accordingly. € Palate usually returns to normal usually within 1-2 weeks of smoking. .€ Completely reversible.

DEFINI I N: A i si i s hr i is s ff ti y part f the oral avity and sometimes pharyn and is associated with ju taepithelial inflammatory reaction followed by fibroelastic changes in lamina propria. . with the epithelial atrophy leading to stiffness of oral mucosa and causing trismus and inability to eat.

ORAL SUBMUCOUS FIBROSIS INTRODUCTION: It is a chronic and high-risk precancerous condition. The condition was prevalent in the days of Sushruta (600 BC). He described this condition as ¶Atrophia idiopathic mucosa oris· . After the lapse of many years. a great practitioner of ancient medicine labeled this condition as ¶Vidhari·. Schwatz (1952) was the first person to bring this condition to limelight.

.ETIOLOGY:  Betel-nut chewing  Excessive use of chillies  Lime used in betel nut chewing  Tobacco usage  Nutritional deficiency  Defective iron metabolism  Bacterial or viral infections  Psychological stress  Immunological factors  Genetic factors STAGES OF ORAL SUBMUCOUS FIBROSIS:  Stage of stomatitis and vesiculation  Stage of fibrosis  Stage of sequelae and complication.

LABORATORY INVESTIGATIONS:  Routine blood examination.  Marked irregular epithelial stratification. nuclear pleomorphism and intercellular edema.  Underlying connective tissue shows hyalinization.  The stromal blood vessels are dilated and congested.  Scanning and transmission electron microscopy.  Biopsy.HISTOPATHOLOGY:  Variable degree of cellular atypia.  Hyperkeratinized. atropic epithelium. .

 B complex preparation  Corticosteroids  Placental extract  Hyaluronidase  Vitamin E Surgical treatment.  Excision of fibrous bands followed by use of tongue flap  CO2 laser surgery  Cryosurgery  Oral physiotherapy  Diathermy . Medicinal therapy.MANAGEMENT: Restriction of habit / behavioural therapy.

.

BUCCAL MUCOSA ² LEFT .

RIGHT .BUCCAL MUCOSA .

DEPAPILATED TONGUE .

SHRUNKEN UVULA .