RED & WHITE

LESIONS(PART III)

CONTENTS

• ORAL SUBMUCOUS FIBROSIS• CLASSIFICATION OF RED LESIONS• ERYTHROPLAKIA

ORAL SUBMUCOUS FIBROSIS

• Schwartz In 1952, First described OSMF as a fibrosing condition – ‘Atrophica Idiopathica Tropica Mucosae Oris’

• Joshi In 1953, coined term OSMF, implying to its histological nature

• Sui P In 1954, termed it ‘Idiopathic Scleroderma Of The Mouth’

• Paymaster In 1956 described it as a Precancerous Condition.

• The term derives from: oral (meaning mouth), submucosal (meaning below the mucosa of mouth), and fibrosis (meaning hardening and scarring) (Aziz, 1997)

DEFINITION BY PINDBORG J.J & SIRSAT S.M (1966) STATES-

“It is a slowly progressing chronic fibrotic disease of the oral cavity & oropharynx characterized by fibroelastic change and inflammation leading to a progressive inability to open the mouth, swallow or speak”.

CLINICAL FEATURES

AGE• Range wide & regional; even prevalent among

teenagers in India. Ranges from 11-60 years (Ahmed, 2006; Aziz, 1997)

SEX• From 0.2-2.3% in males to 1.2-4.57% in females in

Indian communities (Aziz, 1997). RACE• Indian subcontinent, in Indian immigrants to other

countries & among Asians & Pacific Islanders (Cox, 1997).

MORTALITY/MORBIDITY• high rate of morbidity- progressive inability to

open mouth, resulting in difficulty eating &consequent nutritional deficiencies.

• significant mortality rate -can transform into oral cancer, particularly SCC , at rate of 7.6% (Aziz, 1997).

PATHOGENESIS

• Areca alkaloids causing fibroblast proliferation and increased collagen synthesis

• Stabilization of collagen structure by tannins - by inhibiting collagenases - more resistant collagen molecules • Copper in nut and fibrosis• Upregulation of cyclo-oxygenase (COX-2)• Fibrogenic cytokines - endothelin & TGF, proinflammatory cytokines

& anti fibrotic IFN gamma.

• Inhibition of collagen phagocytosis• Stabilization of extracellular matrix -disruption of balance of MMP’s & TIMP• Nutritional deficiencies -Iron deficiency -Folic acid deficiency : increased premitotic

phase of cells & delayed cell turnover - Vitamin A & beta carotene -Proteins

• Ingestion of chilies • Genetic - HLA-A10, HLA-B7, HLA-DR3• Immunologic processes - PGE2 induced by areca nut -potent immunosupressor, induces CD4+ helper cells to synthesize immunosuppressive cytokines & inhibit CMI -Decreased CD4:CD8 ratio

OSF AS AN AUTOIMMUNE DISORDER

Reasons for investigating autoimmune basis:- 1) slight female predilection 2) occurrence in middle age 3) the presence of circulating immune complexes, 4) their immunoglobulin contents and 5) detection of various autoantibodies in pt’s sera

ORAL MUCOSA SUSCEPTIBILITY DUE TO DEFICENCY BETEL QUID

CONSTANT IRRITATION

CHRONIC INFLAMMATION

ACTIVATED T-CELL & MACROPHAGES

CYTOKINES – IL-6, TNF, IFN GROWTH FACTOR – TGF-ß

INITIAL EVENTS IN THE DISEASE PROCESS

COLLAGEN PRODUCTION PATHWAY

Three events: 1) Activation of procollagen genes

2) Elevation of procollagen proteinases levels

3) Upregulation of lysyl oxidase (LOX) activity

TGF-ß

PNP Procollagen gene PCP activation ProLOX LOX Increased procollagen

Increased collagen(soluble) LOX Increased collagen(insoluble) INCREASE IN COLLAGEN PRODUCTION

COLLAGEN DEGRADATION PATHWAY

Two main events:-

1) Activation of tissue inhibitor of MMP gene

(TIMP)

2) Activation of plasminogen activator inhibitor

(PAI) gene

TGF-ßActivation of TIMP gene Activation of PAI gene Increased TIMP’s Increase PAI

Inhibits activated Plasminogen Plasmin collagenase Procollagenase Collagenase

Decrease in collagenase activity DECREASE IN COLLAGEN DEGRADATION

OVERALL EFFECT OF ACTIVATED TGF-ß PATHWAY

Increase in collagen Decrease in collagen

production production Increased collagen (cross linking of insoluble collagen) Fibrosis

ORAL SUBMUCOUS FIBROSIS

MALIGNANT TRANSFORMATION

• Malignant transformation rate was found to be 7–13%.

Dense fibrosis & less vascularity of corium +altered cytokine activity unique environment for carcinogens from tobacco & areca nut to act on epithelium.

• PAYMASTER in 1957, first to consider OSF as precancerous condition.

• PINDBORG in 1972 suggested 5 criteria:1.high occurrence of OSF in cancer patients2.high incidence of cancer in OSF patients3.histological diagnosis of cancer without clinical

suspicion in OSF cases4.high frequency of epithelial dysplasia5.high prevalence of leukoplakia among OSF cases

SYMPTOMS OF OSF (Murti, 1992; Cox, 1996)

• Progressive inability to open the mouth (trismus) due to oral fibrosis and scarring

• Oral pain and a burning sensation upon consumption of spicy foodstuffs

• Increased salivation • Change of gustatory sensation • Hearing loss due to stenosis of eustachian tubes • Dryness of the mouth

• Nasal tonality to the voice • Dysphagia to solids (if the esophagus is

involved) • Impaired mouth movements (eg, eating,

whistling, blowing, sucking)

CHEEK FLEXIBILITY

MULTIPLE PIN POINT PETECHIAE & GENERALISED DEPAPILATION OF TONGUE IN OSMF

Oral submucousfibrosis involving the buccal mucosa with leukoplakia

Oral submucousfibrosis involving the entire anterior tongue with leukoplakia (thick arrows)

CLINICAL DIVISION OF OSF

Three stages (Pindborg, 1989) based on physical findings:

• Stage 1: Stomatitis includes erythematous mucosa, vesicles, mucosal ulcers, melanotic mucosal pigmentation & mucosal petechiae.

• Stage 2: Fibrosis occurs in ruptured vesicles & ulcers when they heal, hallmark of this stage. – Early lesions demonstrate blanching of the oral

mucosa.

– Older lesions - vertical & circular palpable fibrous bands in buccal mucosa & around mouth opening or lips, resulting in a mottled, marble like appearance of mucosa because of vertical, thick, fibrous bands running in a blanching mucosa.

– Specific findings include the following: • Reduction of the mouth opening (trismus) • Stiff and small tongue • Blanched and leathery floor of the mouth • Fibrotic and depigmented gingiva • Rubbery soft palate with decreased mobility

• Blanched and atrophic tonsils • Shrunken budlike uvula• Sinking of the cheeks, not commensurate with age or

nutritional status

• Stage 3: Sequelae of OSF are as follows: – Leukoplakia is precancerous and is found in more

than 25% of individuals with OSF. – Speech and hearing deficits may occur because of

involvement of the tongue and the eustachian tubes.

LAI D R (1995) : Divided population based on interincisal distance

Group A : Mouth opening greater than 35mm Group B : Mouth Opening Between 30-35 mm Group C : Mouth Opening Between 20-30 mm Group D: Mouth opening less than 20 mm

RANGANATHAN K (2001)

Group I : Only Symptoms, No Mouth Opening Group II : Mouth Opening > 20mm Group III: Mouth Opening < 20mm Group IV: Limited mouth opening, precancerous & cancerous changes throughout mucosa

DIFFERENTIAL DIAGNOSIS

• Amyloidosis• Generalized fibromatosis• Scleroderma• Oral lichen planus• Anemia

LABORATORY STUDIES

• No specific laboratory tests available. Some OSF studies report following findings: – Decreased hemoglobin levels – Decreased iron levels – Decreased protein levels – Increased erythrocyte sedimentation rate – Decreased vitamin B complex levels

HISTOPATHOLOGY [PINDBORG J J & SIRSAT S M (1996)]

VERY EARLY STAGE – - fine fibrillar collagen dispersed with marked oedema.- many plump, young fibroblast with abundant cytoplasm.- dilated & congested vessels- inflammatory cells- PMN’S, eosinophils EARLY STAGE – - juxta epithelial hyalinization- collagen – thick, separate bundles- moderate, plump young fibroblasts- dilated & congested vessel- inflammatory cells – lymphocytes, eosinophils, plasma cells.

MODERATELY ADVANCED STAGE – - collagen moderately hyalinized- thickened collagen bundles separated by residual edema-fibroblastic response- less- vessels- normal or compressed- inflammatory cells- lymphocytes & plasma cells

ADVANCED STAGE – -collagen completely hyalinized- smooth sheets, no edema- no fibroblasts- vessels- obliterated or narrowed- inflammatory cells- lymphocytes & plasma cells.

MANAGEMENT

1. BEHAVIORAL THERAPY - Patient counseling, stoppage of habit

2. MEDICINAL THERAPY -Supportive treatment -Vitamin supplements -Steroids a) Local b) Systemic

-Placental extracts - Hyaluronidase - Antioxidants

3. SURGICAL THERAPY - Conventional - Laser - Cryosurgery - Diathermy - Physiotherapy

THERAPEUTIC INTERVENTION

CLASSIFICATION OF RED LESIONS

INFLAMMATORY• Red lesion due to

trauma• Red lesion due to

Infection Pharyngitis

Scarlet fever Chronic erythematous

candidiasis

Red lesion due to Immunological reaction Allergic Mucositis Lupus Erythematosus Sjogren Syndrome Erosive Lichen planus Desquamative gingivitis Erythema multiforme

NON INFLAMMATORY– Red lesion due to Vascular defect

1)Purpura due to thrombocytopenia 2)Echymosis due to clotting factor deficiency 3)Hereditary Haemorrhagic Telangiectasia 4)Haematoma

5)Port wine naevus– Red lesion due to Unknown cause

Erythroplakia Geographic tongue– Red lesion due to Nutritional disorder

Vitamin def. Glossitis/Mucositis Iron def. Glossitis/Mucositis

ERYTHROPLAKIA

CLASSIFICATIONA) Clinical variants -Homogenous erythroplakia -Erythroplakia interspersed with patches of leukoplakia -Granular or Speckled leukoplakiaB) Microscopic variations 1) Neoplastic -Squamous carcinoma -Carcinoma in situ

2) Inflammatory -Candida albicans infections -Tuberculosis -Histoplasmosis -Miscellaneous

DEFINITION

WHO DEFINITION: “Any lesion of the oral mucosa that

presents as bright red velvety plaques which cannot be characterized clinically or pathologically as any other recognizable condition”

• Etiology: same as oral SCC & leukoplakia• Age: mainly middle age, peak 65-74 years• Gender: Predilection for men• Location/size: -soft palate, floor of the mouth & buccal mucosa & tongue. -Typical lesion < 1.5 cm in diameter but >4cm also observed.

CLINICAL APPEARANCE

ERYTHROLEUKOPLAKIA

Malignant transformation

• Highest risk-14-50%• Based on the fact that on histology 80-90%

of cases present as- -CIS -Severe epithelial dysplasia -Microinvasive carcinoma

DIFFERENTIAL DIAGNOSIS

• Atrophic candidiasis• Atrophic lichen planus• Lupus erythematosus • Nutritional deficiency• Allergic mucosal reaction• Geographic tongue

MANAGEMENT

• Biopsy should be performed• Treatment guided by histopathologic

diagnosis• Recurrence , multifocality common• Careful long term follow up

REFERENCES

• BURKET’S ORAL MEDICINE DIAGNOSIS & TREATMENT – 9TH & 10TH EDITION

• TEXTBOOK OF ORAL PATHOLOGY –SHAFER 5TH EDITION• ORAL SUBMUCOUS FIBROSIS -Critical reviews in oral

medicine and biology, 6(2);147-160,1995.• A MODIFIED CLASSIFICATION & STAGING SYSTEM FOR

ORAL SUBMUCOUS FIBROSIS- Oral oncology Vol36; 264-266,2000.

• ORAL SUBMUCOUS FIBROSIS :A CLINICOPATHOLOGIC REVIEW. Oral oncology vol 33,no.5,291-301

THANK YOU

8. APOPTOSIS & OSMF - AS FIBROSIS INCREASES, MEAN APOPTOTIC BODIES ALSO INCREASE - GENETIC PREDISPOSITION RENDERS MUCOSA SUSCEPTIBLE TO CHRONIC INFLAMMATORY CHANGES

INFLAMMATORY CELLS

CYTOKINES / CHEMICAL MEDIATORS

INDIRECT EFFECTS DIRECT EFFECTS

FIBROBLAST CELL DEATH OF PROLIFERATION SURROUNDING TISSUE

FIBROSIS

ATROPHIC EPITHELIUM ATROPHIC EPITHELIUM

TREATMENT• 1.      Reduce / stop habit• 2.      i) Local treatment• a)      Vitamin A• b)     Local corticosteroid ointment• ii) Systemic Therapy• a)      Intra lesional injection • b)     Placentrix• Corticosteriods• a)      Hydrocortisone• b)     Dexamethasone• c)      Betamethasone1.      Collagenases • 7. Diathermy • 1.      Hyalorunic acid • Fibrinolytic agent

CLINICAL PRESENTATION

1. GEOGRAPHIC DISTRIBUTION:• ETHNIC BASIS – ASIAN – INDIANS – SOUTHERN STATES• CHINA, MALAYSIA, SRI LANKA, S. AFRICA, UK, CANADA

2. AGE PREDILICTION:• 2nd & 3rd DECADE OF LIFE• AVGERAGE - 53.6yrs IN MEN & 37.7yrs IN WOMEN

3. SEX PREDILICTION:• MALE PREDOMINANCE BUT WOMEN AFFECTED EQUALLY

4. CLINICAL SYMPTOMS:• PRODROMAL SYMPTOMS:

- ONSET INSIDIOUS, 2-5yrs DURATION

- NON SPECIFC SIGNS & SYMPTOMS

- COMMON FEATURES: BURNING SENSATION, BLISTER, ULCERATION, RECURRENT STOMATITIS, EXCESSIVE SALIVATION, DEFECTIVE

GUSTATORY SENSATION

- VESICLES : PAINFUL, RUPTURE – SUPERFICIAL ULCERATION

- FOCAL VASCULAR DILATATIONS MANIFEST CLINICALLY AS PETECHIAE ON TONGUE, LABIAL & BUCCAL MUCOSA

• LATE SYMPTOMS:

- STIFFENING OF CERTAIN AREAS OF THE MUCOSA

- DIFFICULTY IN MOUTH OPENING & SWALLOWING

- INABILITY TO WHISTLE OR BLOW

- REFERRED PAIN IN THE EAR WITH LOSS OF AUDITORY ACUITY - NASAL VOICE

- ADVANCED CASES: JAWS INSEPARABLE : Bu MUCOSA ULCERATED SECONDARY TO ISCHEMIA & CONSTANT IRRITATION VIA TEETH

5. CLINICAL SIGNS:

• ORAL MUCOSA:

- BLANCHED, OPAQUE, FIBROUS BANDS, EXTENT VARIES FROM SMALL FOCAL PALE STREAKED OR PUCKERED AREAS TO EXTENSIVE DIFFUSE

WHITE INDURATED AREAS

• PALATE & FAUCIAL PILLARS:

- OPAQUE, SCAR LIKE FORMATION IN LATERAL PART OF PALATE

- FIBROUS BANDS RADIATE FROM PTERYGOMANDIBULAR RAPHAE - SEAR LIKE APPEARANCE

- LATER, UVULA SHRINKS, APPEARS AS FIBROUS BUD

- ENTIRE ISTHMUS FAUCIUM & MOBILITY OF PALATE REDUCED

- FAUCIAL PILLARS - THICK, SHORT, HARD

- FIBROSIS SPREADS TO PHARYNX & PYRIFORM FOSSA

• BUCCAL MUCOSA & LIPS:

- MUCOSA: PALE & FIRMLY ATTACHED TO UNDERLYING STRUCTURES. VERTICAL FIBROUS BANDS SEEN

- LIPS: CIRCULAR BANDS AROUND RIMA ORIS- ATROPHY OF VERMILION BORDER- DARK BROWN BILATERAL HYPERPIGMENTATION AROUND COMISSURES

• TONGUE:

- IMPAIRED MOVEMENT & DIFFUSE PAPILLARY ATROPHY

• TGF – KEY REGULATOR OF ECM ASSEMBLY & REMODELLING.

• ITS ACTION ON GENES TAKES PLACE AT TRANSCRIPTIONAL LEVEL THROUGH ILL DEFINED INTRACELLULAR PATHWAYS

• MOLECULAR EVENTS THAT FOLLOW – COLLAGEN PRODUCTION PATHWAY & COLLAGEN DEGRADATION PATHWAY.

2. COLLAGEN PRODUCTION PATHWAY

• 3 EVENTS: ACTIVATION OF PROCOLLAGEN GENES

ELEVATION OF PROCOLLAGEN PROTEINASES LEVELS

UPREGULATION OF LYSYL OXIDASE (LOX) ACTIVITY

3. COLLAGEN DEGRADATION PATHWAY • TWO MAIN EVENTS - ACTIVATION OF TISSUE INHIBITOR OF MMP GENE - ACTIVATION OF PLASMINOGEN ACTIVATOR INHIBITOR GENE

ROLE OF OXIDATIVE STRESS

• CELLULAR OXIDATIVE STRESS - IRREVERSIBLE CELL DAMAGE - INFLAMMATION - FIBROSIS - CELL MODULATION

• BODY COUNTERACTS THESE STRESSES BY ANTIOXIDANTS LIKE ENZYMES AND VITAMINS

• THE ANTIOXIDANTS & FREE RADICAL SCAVENGERS DOWN REGULATE FIBROGENIC CYTOKINE GENE EXPRESSION

• IN OSF, SUPEROXIDE DISMUTASE & GLUTATHIONE PEROXIDASE LEVELS ARE REDUCED

• INFLAMMATION ---- CYTOKINES----OXYGEN REACTIVE SPECIES--- DAMAGE TISSUE ARCHITECTURE, MUTAGENIC CHANGES

In 1995 Khanna & Andrade - group classification system for surgical management of trismus:

Group I: This is earliest stage & is not associated with

mouth opening limitations. Interincisal distance >35 mm.

Group II: Patients with an interincisal distance of 26-35 mm

Group III: Moderately advanced cases. interincisal distance of 15-26 mm. Fibrotic bands are visible at soft palate & pterygomandibular raphe & anterior pillars of fauces are present.

Group IVA: Trismus is severe, with an interincisal distance < 15 mm & extensive fibrosis of all the oral mucosa.

Group IVB: Disease is most advanced, with premalignant and malignant changes throughout mucosa.