Diagnosis and treatment of Red and White Lesions of the Oral Mucosa

  • Non keratotic lesions are those lesions that can be removed easily and often leave a slightly reddened or raw patch of mucosa, are either simply debris or a pseudomembranous inflammation and are referred to as non keratotic.
  • Keratotic lesions are those lesions that resist rubbing and scrapping, are considered to involve thickening of mucosal epithelium possibly as a result of increased thickness of the keratinized layer (hyperkeratosis) and are referred to as keratotic.

A. Non keratotic lesions
• Pseudomemberanous candidiasis
• Morsicato buccarum.
• Thermal burns.
• Sloughing traumatic lesions (Cotton roll stomatitis).
• Reaction to toothpaste and mouthwash.
• Chemical burns.
• Secondary syphilis.
• Diptheria.
B. Keratotic lesions
• Leukoplakia
• Leukoedema
• Lichen planus
• Linea alba
• Hairy leukoplakia
• Hyperplastic candidiasis.
• White sponge nevus.

The white colour of the lesions may be due to:

  • Increase in the distance from the vascular bed (due to thickness of the epithelium).
  • Thickening of the keratin layer, or hyperkeratosis.
  • Acanthosis (thickening of the spinous cell layer).
  • Increase in the amount of edematous fluid in the epithelium (i.e., leukoedema).
  • Reduced vascularity in the underlying lamina propria.
  1. A. Local causes
    • Materia alba (debris from poor oral hygiene).
    • Keratosis.
    a. Frictional keratosis (and cheek/lip biting).
    b. Smoker’s keratosis.
    c. Snuff-dipper’s keratosis.
    • Burns.
    • Grafts.
    • Scars.
    • Furred or hairy tongue.
    B. Neoplastic and possibly pre-neoplastic
    • Leukoplakia
    • Keratoses
    • Carcinoma
    C. Inflammatory
    1. Infective
    • Candidosis.
    • Hairy leukoplakia.
    • Syphilitic mucous patches and keratosis.
    • Koplik’s spots (measles).
    • Some papillomas.
    • Reiter’s disease.
    • Koilocytic dysplasia (papillomavirus).
    2. Non-infective
    • Lichen planus.
    • Lupus erythematosus.
    D. Congenital
    • Leukoedema.
    • Fordyce spots.
    • Inherited dyskeratoses.
    a. White sponge naevus.
    b. Focal palmoplantar and oral mucosa hyperkeratosis syndrome.
    c. Darier’s disease.
    d. Pachyonychia congenital.
    e. Dyskeratosis congenital.

1. Localised
2. Inflammatory
• Candidosis.
• Other mycoses.
• Lichen planus.
• Reiter’s disease.
• Graft versus host disease.
• Drugs.
• Epithelioid angiomatosis (Bartonella infection).
3. Reactive lesions
• Pyogenic granulomas.
• Peripheral giant cell granulomas.
4. Atrophic
• Geographic tongue.
• Lichen planus.
• Lupus erythematosus.
• Erythroplasia.
• Burns.
• Avitaminosis B12.
5. Purpura.
6. Vascular
• Telangiectases (Hereditary haemorrhagic telangiectasia or scleroderma).
• Angiokeratomas (Fabry’s disease).
• Angiomas.
7. Neoplasms
• Giant cell tumour.
• Squamous carcinoma.
• Kaposi’s sarcoma.
• Wegener’s granulomatosis.
8. Generalised
• Candidosis
• Avitaminosis B complex (rarely)
• Irradiation or chemotherapy-induced mucositis
• Polycythaemia

  • The red color of the lesions may be due to thin epithelium, inflammation, dilatation of blood vessels or increased numbers of blood vessels, and extravasation of blood into the oral soft tissues.
  • Underlying histological changes in red lesions:
  1. Dilated blood vessels.
  2. Sprouting of newly developed blood vessels.
  3. Thin overlying epithelium.
  4. Bleeding under the surface.

The concept of denoting some lesions or disorders of the oral mucosa as “precancerous” is based on the following evidence:

  • Areas of tissue with certain alterations in clinical appearances identified at the first assessment as “precancerous” have undergone malignant change during follow-up.
  • Some of these alterations, particularly red and white patches, are seen to co-exist at the margins of overt oral squamous cell carcinomas.
  • A proportion of these may share morphological and cytological changes observed in epithelial malignancies, but without frank invasion.
  • Some of the chromosomal, genomic and molecular alterations found in clearly invasive oral cancers are detected in these presumptive “precancer” or “premalignant” phase[s].

A precancerous lesion is “a morphologically altered tissue in which oral cancer is more likely to occur than in its apparently normal counterpart”

e.g.

  1. Leukoplakia
  2. Erythroplakia
  3. Mucosal changes associated with smoking habits.
  4. Carcinoma in situ
  5. Bowen’s disease
  6. Actinic keratosis, cheilitis and elastosis.

A precancerous condition is “a generalized state associated with a significantly increased risk of cancer.”

  1. Oral submucous fibrosis.
  2. Syphilis.
  3. Oral lichen planus.
  4. Lupus erythmatosus.
  5. Dyskeratosis congenital.
  6. Sideropenic dysplasia. 
  • In 2005, WHO abandoned the distinctions between precancerous lesions & precancerous conditions and to use instead the term “potentially malignant disorders” incorporating both the terminologies.
  • Potentially Malignant Disorders is defined by WHO (2005) as the risk of malignancy being present in a lesion or condition either at time of initial diagnosis or at a future date.

Potentially malignant disorders can be classified as:

  1. High Risk
  • Erythroplakia
  • Leukoplakia
  • Oral Submucous Fibrosis (OSF).
  • Erosive Lichen Planus.
  1. Life-style Related
  • Smokeless Tobacco Keratosis.
  • Reverse Smoker’s Palate.
  • Actinic Cheilitis.
  1. Infections
  • Hyperplastic Candidiasis.
  • Viral (HPV, HIV, EBV, HBV, HSV).
  • Tertiary Syphilis.
  1. Immunodeficiency
  • Solid Organ Transplantation.
  • Graft Versus Host Disease.
  • Chronic Cutaneous Lupus Erythematosus.
  1. Inherited Disorders
  • Xeroderma Pigmentosum.
  • Dyskeratosis Congenita.
  • Epidermolysis Bullosa.
  • Bloom Syndrome.
  • Fanconi’s Anemia.
  1. Clinical Methods
  • Vital staining – Toluidine Blue/Lugol’s Iodine
  • Vizilite
  • Brush Cytology
  1. Visualization Adjuncts Tissue Auto fluorescence
  • VELscope
  • In Vivo Confocal Microscopy
  1. Saliva-based oral cancer diagnostics
  • Molecular Methods
  • DNA Ploidy & Quantification of nuclear DNA content
  • Tumor Markers & Bio Markers
  1. PCR-Based diagnostic aids
  • Photo diagnosis
  • Auto fluorescence Spectroscopy
  • Fluorescence Photography
  • It is an imaging technique for various researches in cell biology with an advantage of optical sectioning and high resolution imaging.
  • In vivo confocal images from the oral cavity show the characteristic features such as nuclear irregularity which is used to differentiate OSCC from normal oral mucosa.
  • The principle is based on the fact that salivary composition is altered in patients with oral cancer.
  • Salivary transcriptome helpful in the detection of oral cancer.
  • Promoter hypermethylation patterns of TSG p16, O6- methyl guanine-DNA-methyltransferase, and death associated protein kinase are identified in the saliva of head and neck cancer.
  • High salivary counts of Capnocytophaga gingivalis, Prevotella melaninogenica and Streptococcus mitis is found in patients with OSCC.
  • DNA ploidy is the measurement of nuclear DNA content that provide a measurement of gross genetic to the daughter cells during mitosis or if some parts of chromosomes become detached, the chromosomal segregation becomes unbalanced and aneuploidy is seen which is observed in many cancers
  • Pre-malignant lesions such as oral leukoplakias, the nuclear DNA distribution patterns can be analyzed by flow-cytometry, showing different rates of dysplasia.
  • Used in the diagnosis and study of infectious diseases and malignancies associated with micro organisms.
  • PCR helps in the study of cancer and provide clearer understanding of
  • the pathogenesis of neoplasia.
  • PCR can be used to detect mutations in cancer-associated oncogenes (e.g., K-ras, Nras), tumor suppressor genes (e.g., p53, p16) etc.
  • The illumination of oral cavity tissue with UV-Visible light region results in the absorption of photons by fluorophores. It results in the excitation of fluorophores that causes emission of lower energy photons which are perceived as fluorescence from the mucosal surface.
  • The auto fluorescence spectroscopy system contains an optical fibre which is small and similarly generates wavelengths of variable excitations and consists of a spectrograph that collects the continuums of reflected fluorescence from the cellular structures and analyses the received information on a computer.
  • Auto fluorescence is typically caused by protoporphyrin and the variable concentration of blood components that vacillates proportionately during cancerous progression and retrogression.
  • Colposcopy (direct microscopy) provides three-dimensional images of the tissue surfaces examined with portable video cameras attached and viewed on a television monitor screen.
  • The colposcope is mounted with a green/blue filter to enable the inspection of alterations in vascularity and color quality as unfiltered white or yellow light diminishes the dissimilarity concerning the adjoining tissue and the arterioles. An optimum working distance of 200 mm for the focal length of the microscope is required.
  • Colposcopy of oral premalignant lesions had benefits in choosing a representative area of biopsy.
  • Lymph node hardness (elasticity) is a major criterion to differentiate between an inflammatory enlargement and a malignant enlargement.
  • Elastography assesses the behaviours of compliance of cellular structure.
  • The compression to tissues generates displacement or strain in the tissue structure and hence by measuring tissue strain, hardness of the tissue can be estimated.
  • The images obtained by elastography are evaluated before and after compression of cervical lymph nodes.
  • Raman spectroscopy delivers a factual, great – exactitude and sensitive procurement of the molecular tissue structure due to the particular interaction of cellular molecules with photons.
  • The spectral characters of lipids, nucleic acids and proteins functions as precise Raman biomarkers to differentiate between malignant and normal oral mucosal area.
  • Raman spectroscopy brings knowledge which is corresponding or even advanced to recognized procedures in oral carcinogenesis.
  • Photodynamic diagnosis (PDD) is based on the fluorescence generated by administration of an exogenous photoactivated compound that accumulates in cells with malignant potential, followed by appropriate photoirradiation.
  • Most promising photosensitizers for oral PMDs and oral cancer diagnosis is 5-aminolevulinic acid (ALA), which does not fluoresce itself, but can induce protoporphyrin IX (PPIX) fluorescence in tissue.
  • PDD in the oral cavity can be performed simply by rinsing with a 0.4% ALA solution for 20 min.
  • Topical application of excessive 5-ALA stimulates the production and intracellular accumulation of highly fluorescent PPIX in dysplastic and cancerous tissues, which is excited by brief exposure to light with a wavelength of 405 nm.
  • Fluorescent tissues are considered suspicious for malignant transformation and biopsy should be considered.
  • OCT produces cross-sectional images of tissue with a high spatial resolution of 10-20 μ
  • This technology employ back-scattered signals reflected from different layers within the tissue to reconstruct structural images, with the latter measuring sound rather than light.
  • The high spatial resolution of OCT enables “optical biopsy” and provides immediate and localized diagnostic information.
  • This technique is capable of imaging tissue depths of up to 1-2 mm and is thus considered suitable for imaging oral mucosal lesions.
  • As the normal human oral mucosa is very thin, ranging from 0.2-1 mm.
  • Fluorodeoxyglucose-positron emission tomography (FDG-PET) examination shows proficient precision and prognostic significance in defining lymphatic condition and thus helping in assessment and timely diagnosis of oral malignancy in affected patients.
  • PET/computed tomography (CT) can identify and distinguish surgical and radiation-induced variations from residual or recurrent neoplasias because cancerous cells uphold greater FDG for lengthier intervals of time as compared to infectious and inflammatory structures.

A tumor marker can be defined as a molecule that indicates the likely presence of cancer or can also be defined as one that provides information about the likely future behavior of an existing cancer (e.g. ability to metastasize or to respond to therapy).

  • It should have high sensitivity and specificity.
  • It should have high positive and negative predictive value.
  • It should be able to differentiate between neoplastic and non‑neoplastic disease and show positive correlation with tumor volume and extent.
  • It should predict early recurrence and have prognostic value.
  • It should be clinically sensitive, i.e. detectable at early stage of tumor.
  • Its levels should be preceding the neoplastic process, so can be useful for screening.
  • It should be easily assayable.
  • Screening for early malignancy.
  • Acting as a diagnostic aid for malignancy.
  • Determining prognosis in malignancy.
  • Predicting therapeutic efficacy.
  • Maintaining surveillance following surgical of the primary tumor.
  • Removal and monitoring therapy in advanced malignancy.

False elevation may occur in non‑neoplastic conditions as many tumor markers are proteins, over‑expressed not only by cancer cells but also by normal tissues.

  • Many tumor markers are not specific to a particular type of cancer.
  • Tumor marker levels are not elevated in every person.
  • No simple tests are yet available with sufficient sensitivity and specificity to detect the presence of a cancer.
  1. Epithelial markers
  • Cell surface markers – Histocompatibility.
  • Intracellular markers – Cytokeratins.
  • Basement membrane markers – Type 4 collagen.
  • Matrix markers – Tenascin.
  • Membrane antigen – Blood group antigens.
  1. Connective tissue markers
  • Intermediate filament proteins – Desmin.
  • Other filament proteins – Laminin.
  • Cellular enzymes – Amylase, lysozyme.
  • Cytoplasmic non‑filamentous non‑enzymatic proteins – Myoglobin, S100 Protein.
  • Membrane antigen – Leukocyte specific antigen.
  1. Salivary gland markers
  • Epithelial markers – Cytokeratins.
  • Myoepithelial cell markers – Actin, myosin.

Serum acinar cell markers – Salivary amylase.

  • Myoepithelial cells + acinar cells – S100 protein.

Albumin, Autoantibodies as tumor biomarkers, Catalase,CD44, CD59, Cofilin 1 (CFL1) and neural Wiskott–Aldrich syndrome protein (N‑WASP), Cancer antigen 125 (CA 125), Cytokeratins/keratins, CYFRA 21‑1, Endothelins, Glutathione, Interleukin‑1α,IL‑2β, IL‑6, IL‑8, Mac‑2 binding protein, SCC antigen, S100 calcium‑binding protein, Tissue polypeptide antigen, Tumor suppressor gene P53, Telomerase, TNF‑α, α‑Amylase.

  • Biomarkers are also defined as ‘‘a characteristic that is an objectively measured and evaluated indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to therapeutic intervention’’ .
  • Biomarkers could be analyzed in different analytes like blood and saliva.
  • Biomarkers help in predicting the preventive measures that could be formulated.
  • Aids in detection of various stages of oral malignant transformation.
  • Evaluates the molecular changes related to oral carcinogenesis.
  • Enhances the prognosis, diagnosis, and treatment of oral carcinomas.
  • Helps in manipulating the drugs used for the treatment of cancer.
  1. Based on biomolecules
  • DNA biomarkers
  • RNA biomarkers
  • Protein biomarkers.
  1. Based on disease state
  • Diagnostic biomarkers
  • Prognostic biomarkers.
  • Saliva is one of the most reliable tool for diagnosing oral squamous cell carcinomas because of their direct contact with oral cancer lesions.
  • Many salivary biomarkers in detection of oral cancer like:

Defensin-1, Intermediate filament protein (Cyfra 21-1), TPS (tissue polypeptide specific antigen), CD44, IL-8, IL-1b (interleukin), P53, OAZ-1(ornithine decarboxylase antizyme 1), SAT(permidine/spermine), IL-1b, IL-8, DUSP1(dual specificity phosphatase 1), miR-125a, miR-200a, miR-31(microRNA), IAP(inhibitor of apoptosis), CA-12(carcino antigen), SCC-Ag (squamous cell carcinoma antigen), CEA(carcino embryonic antigen), CA 19.9, CA128, M2BP (tumor antigen), MRP 14, CD 59, Profilm 1, catalase.

  • The World Health Organization (1978) has defined oral leukoplakia as a white patch or plaque which cannot otherwise be characterized clinically or pathologically as any other disease.
  • According to First International Conference on oral leukoplakia Malmo, Sweden oral leukoplakia may be define as “A white patch or plaque that cannot be characterized clinically or pathologically as any other disease and is not associated with any physical or chemical causative agent except use of tobacco.”
  • According to International Symposium, Uppsala, Sweden oral leukoplakia may be defined as “A predominantly white lesion of the oral mucosa that cannot be characterized as any other definable disease.”
  • The World Health Organization (1997) has defined oral leukoplakia as “A predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion.
  • Leukoplakia is more frequently found in men.
  • Occur on any mucosal surface.
  • Occurs in adults older than 50 years of age.
  • Approximately 70% of lesions are found on the buccal mucosa, vermillion border of the lower lip, and gingiva.
  • These lesions are less common on palate, maxillary mucosa, retromolar area, floor of the mouth, and tongue.
  • Lesions of the tongue and floor of the mouth account for more than 90% of cases that show dysplasia or carcinoma.

Two main clinical types of leukoplakia are:

  1.  
  2. Non-homogeneous.

A- Homogeneous lesions: Uniformly flat, thin and exhibit shallow cracks of the surface keratin. Risk of malignant transformation is relatively low.

B- Non homogeneous varieties include:

  1. Speckled

Mixed, white and red, but retaining predominantly white character.

  1. Nodular

Small polypoid outgrowths, rounded red or white excrescences.

  1. Verrucous

Wrinkled or corrugated surface appearance.

  1. Proliferative verrucous leukoplakia
  • First described by Hansen in1985.
  • High risk of transformation in oral carcinoma.
  • These lesions have extensive papillary or verrucoid white plaques that tend to slowly involve multiple mucosal sites in the oral cavity and to inexorably transform into carcinoma.
  • It slowly grows and has a high tendency to recur after treatment.
  • Brush biopsy.
  • Toluidine blue is an intravital staining for nucleic acids and abnormal tissue.
  • Chemiluminescence (reflective tissue fluorescence).
  • Biopsy.
  • Loss of polarity of basal cells.
  • More than one layer of cell with basaloid appearance.
  • Drop-shaped rete-ridges.
  • Increased nuclear-cytoplasmic ratio.
  • Nuclear hyperchromatism.
  • Enlarged nucleoli.
  • Increased number of mitotis.
  • Abnormal form of mitosis.
  • The presence of mitotic cells in the superficial epithelium.
  • Cellular and nuclear pleomorphism.
  • Irregular epithelial stratification.
  • Loss of intercellular adherence.
  • Keratinization of single cells or cell groups in the prickle cell layer.

Provisional (clinical) diagnosis

L: extent of leukoplakia

  • L0, no evidence of lesion
  • L1, ≤ 2 cm
  • L2, 2–4 cm
  • L3, ≥ 4 cm
  • Lx, not specified

S: site of leukoplakia

  • S1, all sites excluding FOM, tongue
  • S2, FOM and/or tongue
  • Sx, not specified

C: clinical aspect

  • C1, homogenous
  • C2, nonhomogenous
  • Cx, not specified

Definitive (histopatholgic) diagnosis

P: histopathologic features

  • P1, no dysplasia
  • P2, mild dysplasia
  • P3, moderate dysplasia
  • P4, severe dysplasia
  • Px, not specified

Staging

  • 1: any L, S1, C1, P1 or P2
  • 2: any L, S1 or S2, C2, P1 or P2
  • 3: any L, S2, C2, P1 or P2
  • 4: any L, any S, any C, P3 or P4

Lichen planus, leukoedema,cheek biting lesions, smokeless tobacco lesions,lupus erythematosus,hyperplastic or hypertrophic candidiasis,white sponge nevus, verruca vulgaris, hairy leukoplakia.

  1. Medical treatment

 

  1. Elimination of risk factors

    Ceasing of tobacco use is a prior action in case of tobacco associated leukoplakia.

  1. Carotenoids- 20 to 90mg/day of beta-carotene in time periods from 3 to 12 months.
  2. Lycopene- Lycopene is a carotenoid without provitamin A action. Dosages regimes from 4mg/day and 8mg/day for 3 months.
  3. Retinoic acid (Vitamin A) Systemic use with dosage of 300.000 IU of  retinoic acid. Tretinoin or isotretinoin in gel form (0.05% to 0.1%).
  1. Bleomycin- Bleomycin, a cytotoxic antibiotic, is an alternative treatment of oral leukoplakia. Topical 1% bleomycin applied once daily.
  2. Photodynamic therapy- Photosensitize (aminolevulinic acid-ALA) is administered systemically by intravenous injection or can be topically applied. After a short time it is collected in the target tissue and it is activated exposure to low-power visible light of a drug-specific wavelength. The result will be some reactive oxygen species which will induce damage to cell components (structural proteins, enzymes, DNA, and phospholipids).
  3. Surgical treatment
  4. Laser surgery- Benefits of the laser: the haemostatic effect and the limited scars post treatment. CO2 laser, neodymium: yttrium aluminum garnet (NdYAG) laser, and potassium-titanyl-phosphate (KTP).
  5. Conventional surgery – Refers to scalpel excision of the lesion followed by secondary healing in case of reduced mucosal defects or with a transposition of local mucosal flaps or even skin graft in case of large defects.
  6. Electrocoagulation- Can be used alone or as an adjuvant to scalpel surgery. It induces thermal damage in the surrounding tissues thus causing postoperative pain and edema and tissue scarring.
  7. Cryotherapy- It permits the destruction of lesion tissue by freezing in situ. It is carried out by either an “open” or a “closed” system.
  • The open-system cryotherapy is the direct application of cryogen on the lesion using a cotton swab or by an open spray.
  • The closed system of cryotherapy brings a greater degree of control with more complex and delicate apparatus. 

OSMF was first reported by Schwartz in 1952 while examining five Indian women from Kenya, which he called as “atrophica idiopathica (tropica) mucosae oris”. Later in 1953, Joshi from Mumbai re-designated the condition as OSMF, implying predominantly its histological nature. Its precancerous potential was first reported by Paymaster in 1956. Rao in 1962 suggested that OSMF is a localized condition of collagen disease.

Pindborg in 1966 defined OSMF as “an insidious chronic disease affecting any part of the oral cavity and sometimes pharynx. Although occasionally preceded by and/or associated with vesicle formation, it is always associated with juxta-epithelial inflammatory reaction followed by fibroblastic changes in the lamina propria, with epithelial atrophy leading to stiffness of the oral mucosa causing trismus and difficulty in eating.”

A. The Prodromal Symptoms (early OSF)

• Burning sensation on consuming spicy food.
• Appearance of blisters especially on the palate.
• Ulcerations or recurrent generalized inflammation of the oral mucosa.
• Excessive salivation.
• Defective gustatory sensation.
• Dryness of the mouth.
• Focal vascular dilatations manifest clinically as petechiae in the early stages due to hypersensitivity of the oral mucosa towards areca nut products.
• Pain in areas where submucosal fibrotic bands are developing when
palpated.

B. The advanced OSF

• Oral mucosa becomes blanched and slightly opaque and white fibrous bands appear.
• The oral mucosa is involved symmetrically and the fibrous bands in the buccal mucosa run in a vertical direction.
• Dense fibrosis causing fixation and shortening or even deviation of the uvula and soft palate.
• Dense fibrosis involving the tissue around the pterygomandibular raphae causes varying degrees of difficulty in mouth opening.
• Sometimes the fibrosis spreads to the pharynx and down to the pyriform
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.
• With progressing fibrosis stiffening of certain areas of the mucosa occurs leading to difficulty in opening the mouth, inability to whistle or blow 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.

A. Classifications based on clinical features of OSMF are as follows:

• JV Desa (1957)
• Pindborg JJ (1989)
• SK Katharia et al (1992)
• Lai DR et al (1995)
• R Maher et al (1996)
• Ranganathan K et al (2001)
• Rajendran R (2003)
• Nagesh and Bailoor (2005)
• Tinky Bose and Anita Balan (2007)
• Kiran Kumar et al (2007)
• Chandramani More et al (2011)

B. Classifications based on histopathological features:

• Pindborg JJ and Sirsat SM (1966)
• Utsunomiya H et al (2005)
• Kiran Kumar et al (2007)

Pindborg JJ in 1989 divided OSMF into three stages as follows:

  1. Stage I: Stomatitis with erythematous mucosa, vesicles, mucosal ulcers, melanotic mucosal pigmentation and mucosal petechiae.
  2. 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 mouth opening 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 mouth opening, 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 bud like uvula and sunken cheeks, not commensurate with age or nutritional status.
  3.  Stage III: Sequelae of OSMF are as follows:
  • Leukoplakia is found in more than 25% of individuals with OSMF.
  • Speech and hearing deficit may occur because of involvement of tongue and the Eustachian tube.

Chandramani More et al (2011):

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) as follows:
  1. Any one of the above stage along with other potentially malignant

disorders, e.g. oral leukoplakia, oral erythroplakia, etc.

  1. Any one of the above stage along with oral carcinoma.

Functional staging:

M1: Interincisal mouth opening up to or greater than 35 mm.

M2: Interincisal mouth opening between 25 and 35 mm.

M3: Interincisal mouth opening between15 and 25 mm.

M4: Interincisal mouth opening less than 15 mm.

  1. Areca alkaloids causing fibroblast proliferation and increased collagen synthesis

    Four alkaloids have been identified, arecoline, arecaidine, guvacine, guvacoline. Hydrolysis of arecoline produces arecaidine that has pronounced effects on fibroblast. Hydrolysis of arecoline in to arecaidine is necessary before fibroblast stimulation.

    Addition of slaked lime Ca(OH)2 to areca nut in pan (betel quid) facilitates hydrolysis of arecoline to arecaidine.

  2. Stabilization of collagen structure by tannins (and catachins polyphenols)
  3. Tannin present in areca nut reduces collagen degradation by inhibiting collagenases and proposed the basis for fibrosis as the combined effect of tannin and arecoline by reducing degradation and increased production of collagen respectively.

  4. Copper in nut and fibrosis
  5. The enzyme lysyl oxidase is copper dependent enzyme and play a key role in collagen synthesis and its cross linkage. Fibroblasts in OSF have not only increased lysyl oxidase activities but also specific growth characteristics. These different growth characteristics may either be due to the direct effect of ingredients of areca nut or secondary to inflammatory factors mediated by areca nut such as IL-1, TGF-β, IGF, EGF. Its production is controlled by various enzymes such as cyclooxygenase (COX). COX-2 expression was up regulated as early as half an hour, indicating this to be an early cellular response to arecoline at transcriptional level . COX 2 expression started to decrease when the arecoline was increased upto 160µg/ml, and this may be due to cytotoxicity.

  6. Fibrogenic cytokines
  7. There is demonstration of increased expression of fibrogenic cytokines namely TGF-β, platelet derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) in OSF tissues compared to normal. Disease process in OSF may be an altered version of wound healing.

  8. Genetic polymorphisms predisposing to OSF
  9. Studies showed that phenotype frequency of allele A6 of MICA, the G allele at position +49 of exon 1 was associated with OSF.

  10. Inhibition of collagen phagocytosis
  11. Degradation of collagen by fibroblast phagocytosis is an important pathway of physiological remodelling of the extracellular matrix (ECM) in connective tissue.  Reduction of phagocytic cells was strongly related to the arecoline levels in fibroblast.

  12. Stabilization of extracellular matrix
  13. Increased and continuous deposition of extracellular matrix may take place due to disruption of the equilibrium between matrix metalloprotinases (MMPs) and tissue inhibitors of matrix metalloprotinases (TIMP). OSF fibroblast produce more TIMP-1 protein than normal fibroblast, arecoline reduced the mmp-2 secretion and increase the TIMP-1 levels resulting in increased deposition of collagen in the extracellular matrix.

  14. Collagen related genes
  15. Collagen-related genes are altered due to ingredients in the quid. The genes CoL1A2, COL3A1, CoL6A1, COL6A3, COL7A1 have been identified as definite TGF-β targets and induced in fibroblasts at early stages of disease. The transcriptional activation of procollagen genes by TGF-β suggests that it may contribute to increased collagen levels in OSF.

  16. OSF as an auto immune disorder
  17. Increased levels of immune complexes and raised serum levels of IgG, IgA and IgM when compared with control groups have also been reported. Various HLA types, raised auto-antibodies and the detection of immune complexes tend to indicate an autoimmune basis for the disease.

Management of oral submucous fibrosis can be divided in to:

  1. Preventive measures.
  2. Nutritional support.
  3. Physiotherapy
    1. Kneading
    2. Muscle stretching exercise.
    3. Heat-short wave microwave diathermy.
  4. Medical management
    1. Corticosteroids.
    2. Peripheral vasodilators.
    3. Placental extracts.
    4. Recombinant human interferon gamma.
    5. Enzymes.
    6. Alternative medicine
      • Antioxidants
      • Immunised milk.
      • Turmeric
      • Combination regimen.

Modalities of corticosteroids used in the treatment

  1. Topical:
  • Triamcinolone acetonide 0.1% (Kenacort)
  • Betamethasone – 0.5% (Betnesol)
  1. Systemic :
  • Prednisolone – 20 mg/day (Wysolone)
  • Dexamethasone – 4mg/day (Dexona)
  • Triamcinolone – 12mg/day (Kenacort)
  1. Intralesional :
  • Dexamethasone – 4mg/ml (inj Dexona)
  • Triamcinolone -40 mg/ml (inj Kenacort)
  • Hydrocortisone – 25 mg/ml (inj Wycort)

Short acting drugs: Hydrocortisone intralesional injection 1.5cc given once a week for a duration of 12 weeks useful in early and mild cases.

Intermediate acting drugs: Topical triamcinolone acetonide 0.1% and local injection of triamcinolone acetonide.

Long acting drugs: Dexamethasone 4mg intralesional injections, is given biweekly, in combination with hyaluronidase gives better long term results. Betamethasone 4mg/ml intralesional injections biweekly, if given in combination with lycopene or hyaluronidase and vitamin E, it is more effective.

  • Pentoxifylline (Trental), a methylxanthine derivative has vasodilating properties. It increases mucosal vascularity.
  • It has anti inflammatory properties like altering fibroblast physiology, suppressing leucocyte function and stimulating fibrinolysis.
  • Its immuno-modulating actions include neutrophil degranulation, increasing leukocyte adhesion, promotes natural killer cell activity, release of peroxides, production of tumor necrosis factor and inhibits T and B cell activation.
  • Pentoxifylline 400 mg three times daily, resulted in improvement in mouth opening, tongue protrusion, and relief from perioral fibrotic bands.

Main effects of placental extracts are anti-inflammatory and significant analgesic effect, increase in blood circulation and tissue vascularity, an arrest of tissue growth stagnation, metabolic degenerative conditions, and lower immune response factor.

Placental extract injection 2ml intralesionally at weekly intervals for 10 weeks was found to be superior to cortisone. Combination of Dexamethasone, Hyaluronidase, and Placental extract gives better results than with a single drug.

γ-IFN has epithelial regulatory effect, it 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. Intralesional injection of γIFN (0.01- 10.0 U/mL) 3 times daily for 6 months.

  1. Chymotrypsin cleaves peptide amide bonds where the carboxyl side of the amide bond is a tyrosine, tryptophan, or phenylalanine of collagen fibers in OSMF. It acts as a proteolytic agent in the treatment of OSMF. Chymotrypsin (5000 IU), twice weekly submucosal injections for 10 weeks. Chymotrypsin (5000 IU), dexamethasone (4 mg) and hyaluronidase (1500 IU) twice weekly for 10 weeks sub-mucosally provide good results.
  2. Hyaluronidase degrades the hyaluronic acid matrix, lowers the thickness of intracellular cemental substances as well as activating definite plasmatic mechanisms. As a result, reprieve of trismus may be predictable through softening and diminishing of fibrous tissue. Intralesional injection of 1500IUwith 2% lignocaine twice daily give good results.
  3. 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.
  • Dose: 2mg of collagenase material dissolved in 1ml of distilled water for injection purposes.
  • Adverse reactions: Adverse reactions like pain swelling and trismus may be seen which is considered to be an allergic reaction of this agent.
  • Antioxidants act by reducing the free radical reaction that can cause DNA mutations and changes in lipid peroxidation of cellular membranes and changes in enzymatic activities.
  • Lycopene, 16mg, daily in two divided doses for 2 months or in combination with intralesional injections of betamethasone has shown marked improvement in mouth opening and associated symptoms.
  • Topical application of beta-carotene improves the integrity of oral epithelium as well as induces the redifferentiation of dysplastic epithelium. Six weeks of treatment with tablets containing mostly beta-carotene and vitamin E thrice daily, showed an effective increase in mouth opening and tongue protrusion in OSF.
  • Alpha- Lipoic Acid also called as thioctic has a good potential action of scavenging free radicals and it can dissolve in both water and fat. Alpha-lipoic acid 100 mg, 1 capsule per day for 30 days has shown reduction in burning sensation and improved mouth opening. 
  • Immunised milk is a type of skimmed milk produced from cows immunised with multiple human intestinal bacteria. It has good anti-inflammatory effect and contains modest amounts of Vitamin A, C, B1, B2, B6, B12, nicotinic acid, pantothenic acid, folic acid, iron, copper and zinc. Though chemically it is identical to commercial milk, it contains 20-30% higher concentration of IgG type I antibody.
  • Immunised milk powder, 45 gms, twice a day, for 3 months had shown significant improvement in symptoms of OSF.
  • Turmeric powder offers protection against benzopyrene, induces increase in micronuclei in circulating lymphocytes and it is an excellent scavenger of free radicals in vitro.
  • Turmeric oil (600mg), alcohol extracts of turmeric (3g) and turmeric oleoresin (600mg)  has effect on cytogenetic damage in patients suffering from OSF after daily intake for 3 months.
  • 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 accelerates healing, increases the extensibility of collagen fibers, provides pain relief and selectively raises the temperature in some well circumscribed areas.
  • Ultrasound of dose ranging from 0.6 to 2.0 W/Cm2 pulsed 1:1 or 1:2 ( 50% or 33.3 % duty cycle), Frequency of 3 MHz, 5cm diameter transducer head for 3 to 4 minutes to each side over the cheek for 15 consecutive days with permissible one day off each week.

Autologous bone marrow stem cell injections induce angiogenesis in the area of lesion which in turn decreases the extent of fibrosis thereby leading to significant increase in mouth opening.

Surgical modalities for OSMF are as following:

  • Simple excision of the fibrous bands can be done. However, this excision can result in contracture of the tissue and exacerbation of the condition.
  • Split-thickness skin grafting following bilateral temporalis myotomy or coronoidectomy.
  • Nasolabial flaps and lingual pedicle flaps can be performed.
  • Buccal fat pad is used as a grafting source. The buccal fat pad is a flexible and lobulated mass, simply accessible, and mobilized. 

The erbium chromium yttrium scandium gallium garnet (ErCr:YSGG) laser has a wavelength of 2780 nm, well absorbed by water and is used on oral soft tissue without creating thermal damage. However, in most of the cases, depends on the stage of disease and extent of oral involvement.

Anemia,  scleroderma.

  1. Oral Hairy Leukoplakia
  2. Candidiasis
  3. Mucous Patches
  4. Parulis.
  1. Oral hairy leukoplakia is commonly associated with HIV infection.
  2. Epstein-Barr virus (EBV) is causative agent in oral hairy leukoplakia.
  3. Involves the lateral border of the tongue but may extend to the ventral or dorsal surfaces.
  4. Lesions on the tongue are usually corrugated and may have a shaggy or frayed appearance.
  5. Also present as a plaque like lesion and often bilateral.
  1. Secondary syphilis develops within 6 weeks after the primary lesion characterized by diffuse maculopapular eruptions of the skin and mucous membranes.
  2. On the skin, it is present as macules or papules.
  3. In oral cavity, the lesions are usually multiple painless grayish white plaques overlying an ulcerated necrotic surface.
  4. Lesions occur on the tongue, gingiva, palate, and buccal mucosa
  5. Fever, sore throat, general malaise, and headache.
  6. The mucous patches resolve within few weeks.

They contain large numbers of spirochetes.

Uremic stomatitis is an uncommon complication of uremia that may occur as a result of advanced renal failure.

Four forms of uremic stomatitis:

(a) Ulcerative form

(b) Hemorrhagic form

(c) Nonulcerative pseudomembranous form

(d) Hyperkeratotic form.

Nonulcerative, pseudomembranous form and hyperkeratotic form appears as white lesions.

The nonulcerative pseudomembranous form presents as painful diffuse erythema covered by a thick whitish-gray pseudomembrane.

  • The hyperkeratotic form presents as multiple, painful, white hyperkeratotic lesions with thin projections.
  • Tongue and the floor of the mouth are more frequently affected.
  • Xerostomia, uriniferous breath odor, unpleasant taste, and a burning sensation.
  • Candidiasis and viral and bacterial infections are common oral complications.

Human body carries many germs like bacteria, protozoa, fungi, and viruses. When our immune system is working, it controls these germs. But when the immune system is weakened by disease or by some medications, these germs can get out of control and cause health problems. Infections that take advantage of weakness in the immune defenses are called “opportunistic.”

S.No.Opportunistic  infectionCauseWhen does it usually occur?
1CandidiasisFungus, Candida albicansCD4 < 200
2Cryptococcosis (Crypto)FungusCD4 < 50
3Pneumocystis pneumonia (PCP)FungusCD4 < 200
4Cytomegalovirus (CMV)VirusCD4 < 50
5Progressive multifocal leukoencephalo-pathy (PML)virusCD4 < 200
6Mycobacterium avium complex (MAC)BacteriumCD4 < 50
7Mycobacterium tuberculosisBacteriumCD4 < 200
8CryptosporidiosisParasiteCD4 < 100
9Toxoplasmosis (Toxo)ParasiteRare with CD4 < 200; usually in those with CD4 < 50
  • “Candidiasis” refers to a multiplicity of diseases caused by a yeastlike fungus, Candida, and is the most common oral fungal infection in humans.
  • Candida is predominantly an opportunistic infectious agent that is poorly equipped to invade and destroy tissue.

Proposed revised classification of Oral Candidosis.
A. Primary oral candidosis (Group I)
• Acute
Pseudomembranous
Erythematous
• Chronic
Erythematous
Pseudomembranous
Hyperplastic
Nodular
Plaque‑like
• Candida‑associated lesions
Angular cheilitis
Denture stomatitis
Median rhomboid glossitis
• Keratinized primary lesions superinfected with Candida
Leukoplakia
Lichen planus
Lupus erythematosus.
B. Secondary oral candidoses (Group II)
. Oral manifestations of Systemic mucocutaneous.
. Candidosis (due to diseases such as thymic aplasia and candidosis endocrinopathy syndrome).

  1. Drug/Medications
    • Broad spectrum antibiotics(example tetracycline).
    • Multiple antibiotic regimes.
    • Corticosteroids.
    • Cytotoxic agents.
    • Immunosuppressive agents.
    • Aniticholinergics( xerostomia producing).
  2. Endocrinopathies
    • Diabetes mellitus.
    • Hypoadrenalism.
    • Hypothyroidism.
    • Hypoparathyroidism.
    • Polyendocrinopathy.
  3. Hematologic Disorders
    • Aplastic anaemia.
    • Agranulocytosis.
    • Lymphoma.
    • Leukemia.
  4. Immunodeficiency
    • HIV disease.
    • Thymic alymphoplasia ( Nezelof’s syndrome).
    • Thymic hypoplasia (DiGeorge syndrome).
    • Severe combined immunodeficiency syndrome( swiss type).
    • Hyperimmunoglobulinemia.
    • E Syndrome.
    • Chronic mucocutaneous candidiasis.
  5. Leucocyte disorders
    • Myeloperoxidase deficiency.
    • Agranulocytosis/leucopenia/neutropenia.
  6. Malignancy
    • Leukemia.
    • Lymphoma.
    • Thymoma.
    • Advanced cancer.
  7. Nutritional deficiencies
    • Iron deficiency.
    • Folic acid deficiency.
    • Biotin deficiency.
    • Vitamin B deficiency.
    • Vitamin C deficiency.
    • Malnutrition.
    • Malabsorption
  8. Other
    • Radiation therapy.
    • Sjogren’s syndrome.
    • Pregnancy.
    • Xerostomia.
    • Old age.
    • Infancy.
    • Denture use.

Clinical lesions of candidiasis are following:

  • Pseudomembranous-white necrotic
  • Erythematous- red
  • Atrophic- red
  • Hyperplatic- white, red raised
  • Mixed- red/white keratotic/ white necrotic
  • Mucocutaneous- lip, angle
  • Esophagitis and other systemic

Normal count of candida in healthy individual is 200 to 500 cells per milliliter of saliva.

Candida albicans are recovered from 60% of dentate patient’s mouth over the age of 60 years. Species of oral Candida are: C. albicans, C. glabrata, C. guillermondii, C. krusei, C. parapsilosis, C. pseudotropicalis, C. stellatoidea, C. tropicalis.

  • Characterized by white patches on the surface of the oral mucosa, tongue, and elsewhere.
  • Lesions develop and form confluent plaques that resemble milk curds and can be wiped off to reveal a raw, erythematous and sometimes bleeding base.
  • These plaques made up of necrotic material and desquamated parakeratotic epithelia, penetrated by C. albicans yeast cells and hyphae
  • It presents as a red patch of atrophic or erythematous raw and painful mucosa.
  • Antibiotic sore mouth is a common form and should be suspected in a patient who develops symptoms of oral burning, bad taste, or sore throat during or after broad-spectrum antibiotics therapy.
  • Chronic iron deficiency anemia is also cause of this.

Chronic atrophic candidiasis includes:

  • Denture stomatitis (denture sore mouth).
  • Angular cheilitis.
  • Median rhomboid glossitis.
  1. Appears as a diffuse inflammation of the maxillary denture-bearing areas and sometimes associated with angular cheilitis.
  2. There are following clinical stages:
    • Type I- Localized simple inflammation or a pinpoint hyperaemia.
    • Type II- Erythematous or generalized simple type presenting as more diffuse erythema involving a part of, or the entire, denture-covered mucosa,
    • Type III- Granular type (inflammatory papillary hyperplasia) involves central part of the hard palate and the alveolar ridge.
  1. Negative pressure under the maxillary denture excludes salivary antibody.
  2. Closer adaptation of the maxillary denture and palate.

Angular cheilitis characterized by soreness, erythema and fissuring,  commonly associated with denture-induced stomatitis.

  • Reduced vertical dimension.
  • Nutritional deficiency (iron,vitamin B or folic acid).

Rare causes: Diabetes, Neutropenia, AIDS and co-infection with Staphylococcus and beta-hemolytic Streptococcus.

Midline glossitis, or glossal central papillary atrophy, is characterized by an area of papillary atrophy that is elliptical or rhomboid in shape, symmetrically placed centrally at the midline of tongue, anterior to the circumvallate papillae.

  • Chronic form of oral candidiasis: there is firm white leathery plaques on cheeks, lips, palate, and tongue.
  • The differentiation from other forms of leukoplakia is based on finding periodic acid–Schiff (PAS)–positive hyphae in leukoplakic lesions.
  • CHC also occurs as part of chronic mucocutaneous candidiasis, often with identifiable predisposing immunologic or endocrine abnormalities.

Chronic mucocutaneous candidiasis indentified by hyper plastic mucocutaneous lesions localized granuloma, and adherent white plaques on affected mucous membrane.

There are four categories of CMC:

  1. Familial CMC.
  2. Diffuse CMC.
  3. Candida endocrinopathy syndrome (CES).
  4. CMC of late onset.

Characterised by onset of persistent oral candidiasis, hyper plastic infection of nail folds in infancy.

Characterised by randomly occurring cases of severe mucocutaneous candidiasis with wide spread skin involvement and candida granulomas.

Characterised by onset of CMC during infancy or early childhood with hypoparathyroidism, hypodrenocorticism and other endocrine anomalies .

Associated with thymoma and other anomalies like myasthenia gravis, polymyositis, sqauamous cell carcinoma of lip, bullous lichen planus and hypogammaglobulinemia.

A. Smear Smears are taken from the infected oral mucosa with wooden spatulas and fixed immediately in ether/alcohol 1:1 or with spray fix. Dry preparations examined by Gram stain method and periodic acid Schiff (PAS) method. B. Swabs Swabs are seeded on Sabouraud’s agar (25ºC or room temperature), on blood agar (35ºC), on Pagano‑Levin medium (35ºC) or on Littmann’s substrate (25ºC). Incubation at 25ºC is done to ensure recovery of species growing badly at 35ºC. C. Biopsy Biopsy specimen should be sent for histopathological examination when chronic hyperplastic candidosis is suspected. D. Imprint culture technique Sterile, square (2.2 × 2.5 cm), plastic foam pads are dipped in peptone water and placed on the restricted area under study for 30-60 seconds. Thereafter the pad is placed directly on Pagano‑Levin or Sabouraud’s agar, left in situ for the first 8 hours of 48 hours incubation at 37ºC. Then, the candidal density at each site is determined by a Gallenkamp colony counter and expressed as colony forming units per mm2 (CFU mm‑2). E. Impression culture technique Taking maxillary and mandibular alginate impressions, transporting them to the laboratory and casting in 6% fortified agar with incorporated Sabouraud’s dextrose broth. The agar models are then incubated in a wide necked, sterile, screw‑topped jar for 48-72 hours at 37ºC and the CFU of yeasts estimated. F. Saliva Ask patient to expectorate 2 ml of mixed unstimulated saliva into a sterile, universal container and vibrate it for 30 seconds. The number of Candida expressed as CFU/ml of saliva is estimated by counting the resultant growth on Sabouraud’s agar using spiral plating or Miles and Misra surface viable counting technique. Patients with clinical signs of oral candidiasis usually have more than 400 CFU/mL. G. Paper Points An absorbable sterile point is inserted to the depth of the pocket and kept there for 10 sec and then the points are transferred to a 2 ml vial containing Moller’s VMGA III transport medium. H. Commercial identification kits The Microstix‑candida (MC) system consists of a plastic strip to which is affixed a dry culture area (10 mm × 10 mm) of modified Nickerson medium  and a plastic pouch for incubation. The O Yeast‑I dent system is based on the use of chromogenic substances to measure enzyme activities. Ricult‑N dip slide technique is similar to, but of higher sensitivity than MC system. I. Histological identification Demonstration of fungi in biopsy specimens may require several serial sections to be cut. The specific fungal stains such as PAS stain, Grocott‑Gomori’s methenamine silver (GMS) and Gridley stains are widely used for demonstrating fungi in the tissues. J. Physiological tests Used in definitive identification of Candida species involve determination of their ability to assimilate and ferment individual carbon and nitrogen sources. K. Phenotypic methods
      1. Serotyping
Serotyping is limited to the two serotypes (A and B), a fact that makes it inadequate as an epidemiologic tool. Yeast ‘Killer Toxin’ typing. Nine killer strains were used to developing a triplet code to distinguish between 100 strains of C. albicans and found 25 killer-sensitive types. ii. Morphotyping This method has been used in a study of the morphotypes of 446 strains of C. albicans isolated from various clinical specimens. iii. Biotyping This system comprised three tests, the APIZYM system, the API 20C system and a plate test for resistance to boric acid. This system was found to distinguish a possible 234 biotypes, of which 33 were found among the 1430 isolates of C. albicans taken from oral, genital and skin sites. iv. Protein typing Non‑lethal mutations of proteins during the yeast cell cycle yields proteins of differing physical properties between strains, which may be distinguishable by one or two dimensional gel electrophoresis. L. Genetic methods In arbitrarily primed polymerase chain reaction (AP‑PCR) analysis (synonym: randomly amplified polymorphic DNA (RAPD) analysis), the genomic DNA is used as a template and amplified at a low annealing temperature with use of a single short primer (9 to 10 bases) of an arbitrary sequence. M. Serological tests Serological tests for invasive candidiasis
        1. Detection of antibodies
        2. Slide agglutination
        3. Immunodiffusion
        4. Phytohemagglutination
        5. Coelectosynersis
        6. Immunoprecipitation
        7. A and B immunofluorescence
        8. Nonspecific Candida Antigens
        9. Latex agglutination
        10. Immunobloting
        11. Cell Wall Components
        12. Cell Wall Mannoprotein (CWMP)
        13. b‑(1,3)‑D‑glucan
        14. Candida Enolase Antigen testing.
        N.Immunodiagnosis The use of specific antibodies labelled with fluorescent stain permits causative organisms to be diagnosed accurately within minutes.
 Dosage form/strengthIndication
  1Miconazole cream 2% (OTC)Angular cheilitis
  2Clotrimazole cream 1% (OTC) (prescription)Angular cheilitis
  3Ketoconazole cream 2% (Prescription)Angular cheilitis
  4Nystatin ointment 100,000 units/gram (prescription)Angular cheilitis
  5Nystatin topical powder 100,000 units/gram (prescription)Denture stomatitis
  6

Nystatin oral suspension 100,000 units/gram (prescription)

Intraoral candidiasis
  7Betamethasone dipropionate clotrimazole cream (prescription)Intraoral candidiasis
  8Clotrimazole troches 10 mg (prescription)Intraoral candidiasis
  9Amphotericin B 100 mg/ml (prescription)Intraoral candidiasis
 Generic nameFormulation
  1

Amphotericin B

100 mg/ml oral suspension

  2

Clotrimazole

10 mg troche
  3Fluconazole

100 mg tablet

10 mg/ml oral suspension

40 mg/ml oral suspension

  4

Itraconazole

100 mg capsule

10 mg/ml oral suspension

  5

Ketoconazole

200 mg tablet
  6

Nystatin

100,000 units/ml oral suspension

200,000 units/ml pastille

500,000 units/ml tablet

100,000 units/ml vaginal table

The syndrome comprises of ill defined group of symptoms- Chronic fatigue, pre menstrual symptoms, poorly characterized gastro intestinal complaints, headache, rashes alleged to be due to low grade chronic gastro intestinal, oral or vaginal infection of candida.

Some patients with chronic candida infections develop secondary skin response characterized by localized or generalized sterile vesiculopapular rash that is allergic response to candida antigens. These reactions k/a monilids or Id reaction.

Also known as focal epithelia hyperplasia. Lesions appear as 0.1 to 0.5 cm fat, slightly raised whitish plaques with roughed surface on lips and cheeks.

According to WHO in 1978, oral erythroplakia is defined as “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.”

  1. It appears as flat or depressed and is sometimes found together with leukoplakia (erythroleukoplakia).
  2. Predominately occurs in the floor of the mouth, the soft palate, the ventral tongue and the tonsillar fauces. It is usually asymptomatic.
  3. Patients may complain of a burning sensation and ⁄ or soreness.
  4. Erythroplakia shows dysplastic features and often presents as ‘carcinoma in situ’ or ‘invasive carcinoma’ at the time of biopsy.
  • Erythematous candidiasis.
  • Early SCC.
  • Local irritation.
  • Mucositis.
  • Lichen planus.
  • Lupus erythematosus.

Lichen planus (LP) is a chronic mucocutaneous disorder of the stratified squamous epithelium that affects oral and genital mucous membranes, skin, nails, and scalp.

Word lichen planus derived from the Greek word “leichen” means tree moss and Latin word “planus” means flat.

Erasmus Wilson in 1866, described the disease and named it Lichen Planus.

Exact etiology is still unknown, but some factors are associated with it. These are as follows:

  1. Genetic background

Familial cases are rare. An association observed with HLA‑A3, A11, A26, A28, B3, B5, B7, B8, DR1, and DRW9.

  1. Dental materials

Silver amalgam, gold, cobalt, palladium, chromium and even non‑metals

such as epoxy resins (composite) and prolonged use of denture wear.

  1. Drugs

Oral lichenoid drug reactions triggered by systemic drugs like: NSAIDs, beta blockers, sulfonylureas, some angiotensin‑converting enzyme (ACE) inhibitors, antimalarials, contact allergens including toothpaste flavorings, especially cinnamates.

  1. Infectious agents
  • Hepatitis C virus (HCV)
  • Epstein Barr virus (EBV).
  • Human herpes virus 6 (HHV‑6).
  • Human immunodeficiency virus (HIV).
  1.  Autoimmunity.

  2. Stress.

  3. Diabetes and hypertension.
  • Lichen planus is a T-cell mediated disease autoimmune in nature where the CD8+ T-cells trigger the apoptosis of oral epithelial cells at the basal layer. Keratinocyte antigen expression and antigen unmasking are involved in the disease mechanism. It may be a self-peptide or a heat shock protein. Then subsequently T-cells migrate towards the basal keratinocytes during surveillance or chemochine mediated action. The antigen directly binds to the migrated CD8+ cells by the major histocompatibility complex-1 (MHC) on keratinocyte. Langerhans cells are increased in lesions of lichen planus and there is upregulated MHC-II expression. The CD4+ cells and interleukin-12 activate CD8+ T-cells that are involved in the apoptosis of keratinocytes through FasL mediated and tumor necrosis factor-alpha (TNF-alpha).
  • The vascular adhesion molecules receive the expression of the reciprocal receptors of infiltrating lymphocytes. This is the cytokine-mediated lymphocyte that contributes to the homing mechanism. Matrix metallo protease 9 are majorly involved in the tissue matrix protein degradation.
  • The chronic nature of the disease is contributed by the Regulated on Activation, Normal T-cell expressed and secreted that is, a member of “CC chemochine family”. This greatly recruits the mast cells and lymphocytes that results in degranulation, releasing chymase and TNF-alpha.
  • The heat shock proteins are also upregulated by the lesional keratinocytes of oral lichen planus. Inflammation that exists prior to the disease condition can contribute to the expression of heat shock protein.
  1. The lesions show white striations, which are slightly elevated, fine, whitish lines known as Wickham’s striae (Honiton lace).
  2. Usually affect buccal mucosa, ventral and lateral borders of tongue, gingiva and floor of the mouth.
  3. Lingual papillae become atrophied in the areas of involvement, and the resulting smooth surface accentuates the white striae.
  4. Gingival lesions present as fiery red areas affecting the entire width of attached gingiva called desquamative gingivitis.
  5. It is associated with intense sensitivity of gums to hot or spicy food or brushing of teeth with intense burning sensation to pain.
  6. Skin lesions described by the six p’s: Planar, plaque, pruritic, purple, polygonal, and papular.
  7. They may be discrete and gradually coalesce in to large plaques each covered with fine glistening scale.
  8. Early in onset of disease they appear red, soon they take on reddish purple or violaceous colour.
  9. Skin lesions commonly involve flexor surface of legs and arms, especially the wrists, forearms, inner aspect of thighs, trunk especially in sacral areas.
  10. Nail beds may also be affected with resultant ridging, thinning and subungual hyperkeratosis.
  11. Scalp involvement, if untreated can lead to scarring and permanent hair loss.
  12. Patients are often unaware of quiescent OLP, which may be present only with faint white striations, papules or plaques. Exacerbations of OLP have been linked to periods of psychological stress, anxiety or mechanical trauma. This phenomenon is referred as Koebner’s phenomenon.

Association of LP of vulva, vagina, and gingiva is recognized as vulvovaginal-gingival syndrome.

The combination of follicular LP with scarring alopecia of scalp and non-scarring alopecia of axilla and pubis or other areas is known as Graham-Little syndrome.

Triad of Diabetes mellitus, hypertension and oral lichen planus.

The red and white components of lesion can be part of following textures.

  1. Reticular

White fine striae/network can show annular/circular patterns. The striae often present with peripheral erythemous zone, which reflects sub epithelial inflammation. Most frequently observed bilaterally in buccal mucosa and rarely on mucosal side of lips.

  1. Papular

Present in initial phase of disease, clinically characterized by small white dots which in most times intermingle with reticular form.

  1. Plaque like

Homogenous well demarcated white plaque often but not always surrounded by striae.

  1. Erythematous/atrophic

Characterized by homogenous red area, striae are frequently seen at periphery. Some may exclusively display erythematous OLP of attached gingiva, which represents desquamative gingivitis.

  1. Erosive: Ulcerative, Bullous

Ulcerative and bullous are most disabling. Clinically present with fibrin coated ulcers surrounded by erythematous zone frequently displaying radiating white striae. Bullous lesions vary from 4 mm to 2 cm and rupture leaving erythematous zone.

  • Degenerative changes in basal keratinocytes frequently lead to pigmentary incontinence.
  • Gamma-aminobutyric acid (GABA) imbalance occurs in anxiety disorders and might be passed through the cranial nerve, stimulating production of melanocytes, resulting in excessive deposition in OLP. 

Direct Immunofluorescence

Fibrinogen and fibrin are deposited in a linear pattern in the BM zone. Colloid bodies contain fibrin, IgM, C3, C4 and keratin. Laminin and fibronectin staining may be absent in areas of heavy fibrin deposition and colloid body formation. This finding suggests BM damage in these areas.

Immunohistochemical (Ihc) Studies

Immunohistochemical staining using the antibody to the S-100 protein indicates an increase in langerhan cells in mid layer of the epithelium.

Biopsy

Histopathology

  • Liquefactive degeneration of the basal cell accompanied by apoptosis of the keratinocytes, a dense band-like lymphocytic infiltrate at the interface between the epithelium and the connective tissue.
  • Focal areas of hyperkeratinized epithelium (which give rise to the clinically apparent Wickham’s striae)
  • Occasional areas of atrophic epithelium where the rete pegs may be shortened and pointed (saw tooth rete pegs).
  • Eosinophilic colloid bodies (Civatte bodies).
    1. Topical agents
      • Corticosteroids

0.05% clobetasol propionate gel, 0.1% or 0.05% betamethasone valerate gel, 0.05% flucinonide gel, 0.05% clobetasol butyrate ointment or cream and 0.1% triamcinolone acetonide ointment.

      • Retinoids Isotretinoin gel 0.1%, topically administered Vitamin A, beta-all-trans retinoic acid all are effective.
      • Topical Tacrolimus

Tacrolimus ointment is available in two strengths: 0.1% and 0.03%. The 0.1% formulation twice daily is more effective in erosive lichen planus.

      • Intralesional injection Intralesional steroids such as triamcinolone acetonide (10– 20 mg/ml) injections can be effective and repeated every 2–4 weeks.
    1. Systemic Steroid Therapy

The oral dose of prednisone for 70-kg adult ranges from 10-20 mg/day for moderately severe cases to as high as 35 mg/day (0.5 mg/kg daily) for severe cases.

  1. Griseofulvin It is administered systemically in doses of 500mg/day to 1 gm/day.
  2. Azathioprine Azathioprine in doses of 50 to 100mg/day in combination with systemic steroids shows positive response.
  3. Efalizumab- Efalizumab therapy with initial dose of 0.7mg/kg followed by dose of 1.0 mg/kg per week for 5 week provide good results.
  4. Surgical excision, cryotherapy, CO2 laser, and ND:YAG laser have all been used in the treatment of OLP.
  5. Photo chemotherapy, uses ultraviolet A (UVA) with wavelengths ranging from the 320 to 400 nm, after the injection of psoralen (8-Methoxypsoralen, 0.4-0.6 mg/kg) is also used.

Lichenoid reactions were differentiated from lichen planus on the basis of:

  • Association with the administration of a drug, contact with a metal, the use of a food flavoring, or systemic disease.
  • Resolution of lesions when the drug or other factors were eliminated or  the disease was treated.

Drugs and Materials Implicated in Oral Lichenoid Reactions are:

  1. Antimicrobials
    • Dapsone.
    • Ketoconazole.
    • Para-aminosalicylic acid.
    • Sodium aminosalicylate.
    • Streptomycin.
    • Sulfamethoxazole.
    • Tetracycline.
  2. Antiparasitics
    • Antimony compounds (stibophen, stibocaptate).
    • Organic arsenicals.
    • Chloroquine.
    • Pyrimethamine.
    • Quinacrine.
  3. Antihypertensives
    • ACE inhibitors.
    • Chlorothiazide.
    • Hydrochlorothiazide.
    • Labetalol.
    • Mercurial diuretics.
    • Methyldopa.
    • Practolol.
  4. Antiarthritics
    • Aurothioglucose.
    • Colloidal gold (Europe only).
    • Gold sodium thiomalate, thiosulfate.
    • NSAIDs (Fenclofenac, ibuprofen,naproxen).
    • Ibuprofen.
    • Naproxen.
    • Phenylbutazone.
  5. Oral hypoglycemic agents
    • Chlorpropamide.
    • Tolazamide.
    • Tolbutamide.
  6. Uricosuric agents
    • Allopurinol
  7. Miscellaneous drugs
    • Iodides
    • Penicillamine
    • Quinidine sulfate
  8. Chemicals
    • Dental restorative.
    • Substituted paraphenylenediamines used materials in color film developers; dental casting alloys and amalgam restorations.
  1. Linea Alba (White Line)
  2. Frictional (Traumatic) Keratosis
  3. Cheek Chewing
  4. Chemical Injuries of the Oral Mucosa
  5. Actinic Keratosis (Cheilitis)
  6. Smokeless Tobacco–Induced Keratosis
  7. Nicotine Stomatitis
  8. Sanguinaria-Induced Leukoplakia

Variant of traumatic keratosis affecting the cheeks and lips can be seen in European glass factories and lesions regress with change of occupation.

Aspirin, silver nitrate, formocresol, sodium hypochlorite, paraformaldehyde, dental cavity varnishes, acid etching materials, and hydrogen peroxide.

  • Actinic keratosis is a premalignant epithelial lesion.
  • Occur due to long-term sun exposure.
  • 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, measuring < 1 cm in size.
  • The surface may be crusted and rough to the touch.
  • Surgery.
  • Topical chemotherapeutic agent 5-fluorouracil.
  • Seen in the area contacting the tobacco.
  • Area of involvement is the anterior mandibular vestibule, posterior vestibule.
  • Mucosal surface appears white and is granular or wrinkled a folded character may be seen (tobacco pouch keratosis).
  • Gingival recession with periodontal-tissue destruction in the immediate area of contact.
  • Numerous slightly elevated papules with punctate red centers that represent inflamed and meta plastically altered minor salivary gland ducts.
  • Nicotine stomatitis is completely reversible and resolve within 2 weeks once the habit is discontinued.
  • Sanguinaria extract, a mixture of benzophenanthridine alkaloids derived from the common bloodroot plant (Sanguinaria canadensis).
  • It used in oral rinses and toothpaste products.

Patients who used sanguinaria-based products on a routine basis present with white, velvety, wrinkled or corrugated patch of leukoplakia in the maxillary vestibule, involving both the attached gingiva and vestibular mucosa.

  • Seen in adults in the fourth to ninth decades of life.
  • Patients present with a white, velvety, wrinkled or corrugated patch of leukoplakia in the maxillary vestibule,attached gingiva and vestibular mucosa, anterior mandibular vestibule.
  • No appropriate treatment.
  • Initial biopsy is mandatory.
  • Complete discontinuation of Sanguinaria-containing product.
  • Cessation of tobacco or alcohol.
  1. Ectopic lymphoid tissue
  2. Fordyce’s granules
  3. Gingival and palatal cysts of the newborn and adult
  • BHT is benign, asymptomatic, and temporary.
  • It presents with black, green, or yellow pigmentation and elongated filiform papillae in a typical carpet-like appearance of the dorsum of the tongue.

BHT is associated with smoking, excessive coffee/tea or alcohol consumption, poor oral hygiene, xerostomia, oxidizing mouthwashes, medications (antibiotics, antipsychotics), and certain medical conditions (HIV, trigeminal neuralgia, malignancies).

  • Pseudo-BHT secondary to chemicals or food coloring.
  • Pigmented fungiform papillae of tongue.
  • Hairy leukoplakia
  • Congenital nevi.

Graft versus host disease (GVHD) is an immunoreaction that occurs when implanted T lymphocytes from the donor recognize cell surface antigens in the host and mediate cytotoxicity.

  • Acute (< 100 days after bone marrow transplantation).
  • Chronic (after day 100, post transplantation).

Divided into three stages:

  • First stage: Pre-treatment stage where chemotherapy, release of endotoxins following infection, blood transfusion, prior treatment and underlying diseases that affect endothelial and epithelial cells operate to induce the release of inflammatory cytokines, including interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α. This upregulates the expression of antigens and adhesion molecules on histocytes of target organs, including the skin, gastrointestinal mucosa and liver; thus, an immunoreaction with T lymphocytes of the donor occurs.
  • Second stage: Classified by the activation of donor T lymphocytes. Inconsistency of major histocompatability complex (MHC)-I antigens of the donor and recipient results in CD8+ cytotoxic T cell proliferation, while inconsistency of MHC-II antigens results in CD4+ T cell proliferation. Furthermore, T cells become polarized into CD4+ T helper1 cells that secrete IL-2 and interferon (IFN)-γ, which in turn cause T cell proliferation and the activation of natural killer cells.
  • GVHD: Occurs when IL-2 and IFN-γ activate donor mononuclear cells to produce large amounts of inflammatory cytokines, including IL-2 and TNF-α. The ‘cytokine-injury-cytokine’ cycle causes a waterfall-like development of inflammatory cytokines, which ultimately results in the clinical presentation of GHVD.

Acute GVHD:

  • Fever.
  • Rash.
  • Diarrhea.
  • Severe neutropenia or pancytopenia.
  • Normal or almost normal liver function and slightly abnormal renal function.

Skin lesions:

  • Epithelial segment becoming loose and keratinous.
  • Spinous layer becoming thinner and atrophic.
  • Skin processes disappearing.
  • Focal necrotic inflammatory scabs in the upper spinous layer.
  • Necrosis of single or aggregated keratinized cells in the inner spinous layer.
  • The mortality rate of acute GVHD is high.

Chronic GVHD:

  • Associated with lichenoid lesions that affect both skin and mucous membranes.
  • Oral lesions occur in 80% of cases.
  • Salivary and lacrimal gland epithelium also be involved.
  • Intraoral lichenoid lesions are extensive and involve the cheeks, tongue, lips, and gingivae.
  • Burning sensation of the oral mucosa.
  • Pyogenic granuloma on the tongue.
  • Stage I: Rash area of <25%, hemoglobin (Hb) level of 24.2–51.3 μmol/l and diarrhea of >500 ml or persistent nausea.
  • Stage II: Rash area of 25–50%, Hb level of 51.3–102.6 μmol/l and diarrhea of >1,000 ml or persistent nausea
  • Stage III: Rash area of >50%, Hb level of 102.6–256.5 μmol/l and diarrhea of >1,500 ml
  • Stage IV: Extensive erythrodermia accompanied with the formation of blisters, Hb level of >256.5 μmol and severe abdominal pain with or without intestinal obstruction.
  • Prevention by careful histocompatibility matching and judicious use of immunosuppressive drugs.
  • Topical corticosteroids and palliative medications for ulcerations.
  • Ultraviolet A irradiation therapy with oral psoralen.
  • Topical azathioprine suspension as an oral rinse and then swallowed, thereby maintaining the previously prescribed systemic dose of azathioprine.
  • Topical azathioprine.
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