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Pigmentation and Discoloration of Oral and Facial Tissues

Pigmentation and Discoloration of Oral and Facial Tissues

Pigmentation is a discoloration of the oral mucosa or gingiva due to the wide variety of lesions and conditions. Oral pigmentation has been associated with a variety of endogenous and exogenous etiologic factors. Also it can be explained as Oral mucosal discolouration, which ranges from brown to black may be due to superficial (extrinsic) or deep (intrinsic in or beneath mucosa) causes.

Types of Oro-maxillofacial Pigmentation

Extrinsic discoloration

Extrinsic discoloration is usually caused by extrinsic pigments. It is rarely of consequence and is usually caused by colored foods, drinks or drugs. Extrinsic discoloration usually affects both mucosae and teeth are discolored. Causes include the following:

• Foods and beverages, such as beetroot, red wine, coffee and tea.

• Confectionery, such as liquorice.

• Drugs, such as chlorhexidine, iron salts, griseofulvin, crack cocaine, minocycline, bismuth subsalicylate, lansoprazole and HRT.

• Tobacco: this may cause extrinsic discolouration, but can also cause intrinsic pigmentary incontinence, with pigment cells increasing and appearing in the lamina propria. This is especially likely in persons who smoke with the lighted end of the cigarette within the mouth (reverse smoking), as practiced mainly in some Asian communities. Tobacco is a risk factor for cancer.

• Betel: this may cause a brownish-red discolouration, mainly on the teeth and in the buccal mucosa, with an irregular epithelial surface that has a tendency to desquamate. It is seen mainly in women from South and Southeast Asia. Betel chewer’s mucosa epithelium is often hyperplastic, and brownish amorphous material from the betel quid may be seen on the epithelial surface and intra- and intercellularly, with ballooning of epithelial cells. Betel chewer’s mucosa is not known to be precancerous, but betel use predisposes to submucous fibrosis and to cancer.

Intrinsic staining

Causes for intrinsic hyperpigmentation are Increased melanin or number of melanocytes, or other materials. Intrinsic discolouration may have more significance than the extrinsic type. Normal intrinsic pigmentation is due to melanin, produced by melanocytes dendritic cells prominent in the basal epithelium.

Localized areas of pigmentation are usually caused by benign conditions:

• Embedded amalgam (amalgam tattoo)

• Embedded graphite (graphite tattoo)

• Other foreign bodies

• Local irritation/inflammation

• Melanotic macule

• Naevi

• Melanoacanthoma.

However, neoplasms, such as Kaposi sarcoma or malignant melanoma, are occasionally responsible. The anterior pituitary gland releases melanocyte stimulating hormone (MSH), which increases melanin production. Melanin pigmentation thus increases under hormonal stimulation, either by MSH, or in pregnancy, or rarely due to the action of adrenocorticotrophic hormone (ACTH), the molecule of which is similar to MSH, or under the influence of other factors (e.g. smoking). Thus in all patients systemic causes should be excluded, such as:

• Drugs; including smoking and the contraceptive pill

• Hypoadrenalism; there is increased ACTH production

• Peutz–Jeghers syndrome

• HIV infection

• Von Recklinghausen’s disease

• Albright syndrome

• Rarely, palatal pigmentation from bronchogenic carcinoma.

Amalgam Tattoo

Betel Stains

Peutz Jeghers Syndrome

List Causes of hyperpigmentation

Localized

• Amalgam, graphite, carbon, dyes, inks or other tattoos

• Ephelis (freckle)

• Epithelioid angiomatosis

• Kaposi’s sarcoma

• Malignant melanoma

• Melanoacanthoma

• Melanotic macule

• Naevus

• Pigmented neuroectodermal tumour

• Verruciform xanthoma

Multiple or generalized

Genetic:

• Racial

• Carney syndrome

• Complex of myxomas, spotty pigmentation and endocrine overactivity

• Laugier–Hunziker syndrome

• Lentiginosis profusa

• Leopard syndrome

• Peutz–Jeghers syndrome

Drugs:

• ACTH

• amiodarone

• antimalarials

• betel

• busulphan

• chlorpromazine

• clofazamine

• contraceptive pill

• ketoconazole

• menthol

• metals (bismuth, mercury, silver, gold, arsenic, copper, chromium, cobalt, manganese)

• methyldopa

• minocycline

• phenothiazines

• smoking

• zidovudine

Endocrine:

• Addison’s disease

• Albright’s syndrome

• Nelson’s syndrome

• pregnancy

Post-inflammatory

Others:

• Gaucher’s disease

• generalized neurofibromatosis

• haemochromatosis

• HIV disease

• incontinentia pigmenti

• thalassaemia

• Whipple’s disease

 

List the Causes of Pigmentation 

Melanin

Melanin, a nonhemoglobin derived brown pigment, is the most common of the endogenous pigments and is produced by melanocytes present in the basal layer of the epithelium. Melancocytes have a round nucleus with a double nucleus membrane and clear cytoplasm lacking desmosomes or attachment plates. Melanin accumulates in the cytoplasm, and the melanosome is transformed into a structureless particle no longer capable of melanogenesis. The number of melanocytes in the mucosa corresponds numerically to that of skin; however,in the mucosa their activity is reduced. Various stimuli can result in an increased production of melanin at the level of mucosa including trauma, hormones, radiation, and medications.Thyrosinase activity is present in premelanosome and melanosomes but absent in melanin granules.

Melanoid

Granules of melanoid pigment are scattered in the stratum lucidum and stratum corneum of the skin. Initially it was assumed melanoid was a degradation product of melanin, but more recently it has been shown that such a relationship is highly improbable. Melanoid imparts a clear yellow shade to the skin.3

Oxyhemoglobin and Reduced Hemoglobin

Oxyhemoglobin and reduced hemoglobin are pigments resulting from hemosiderin deposits.

The skin color is affected by the capillary and venom plexuses shining through the skin.

Carotene

Carotene is distributed in the lipids of the stratum corneum and stratum lucidum and gives a deep yellow color to the skin. It is found in higher concentrations in more women than in men. Pigmented lesions of the oral cavity are of multiple origin. Different classifications are used at this time. Some researchers divide the lesions into two main groups as either endogenous or exogenous lesions. Brocheriou et al.

subdivides pigmented lesions as follows:

• Non tumoral pigmentations

• Non melanin pigmented tumors or tumor like lesions

• Benign melanin pigmented tumors

• Malignant melanomas

In several articles on oral pigmentation, Dummett and others implicate many systemic and local factors as causes of changes in oral pigmentation.

Epidemiology

Oral pigmentation occurs in all races of man.There were no significant differences in oral pigmentation between males and females. The intensity and distribution of racial pigmentation of the oral mucosa is variable, not only between races, but also between different individuals of the same race and within different areas of the same mouth. Physiologic pigmentation is probably genetically determined, but as Dummett suggested , the degree of pigmentation is partially related to mechanical, chemical, and physical stimulation. In darker skinned people oral pigmentation increases, but there is no difference in the number of melanocytes between fair-skinned and dark-skinned individuals. The variation is related to differences in the activity of melanocytes.There is some controversy about the relationship between age and oral pigmentation. Steigmann and Amir et al. stated all kinds of oral pigmentation appear in young children. Prinz, on the other hand, claimed physiologic pigmentation did not appear in children and was clinically visible only after puberty.

Clinical Characteristics

The gingivae are the most frequently pigmented intraoral tissues. Microscopically, melanoblasts are normally present in the basal layers of the lamina propria.The most common location was the attached gingiva (27.5%) followed in decreasing order by the papillary gingiva, the marginal gingiva, and the alveolar mucosa.The total number of melanophores in the attached gingival was approximately 16 times greater than in the free gingival. The prevalence of gingival pigmentation was higher on the labial part of the gingiva than on the buccal and palatal/lingual parts of the arches.The shade of pigment was

classified as very dark brown to black, brown, light brown-yellow.3 Melanin pigmentation of the

oral tissues usually does not present a medical problem, but patients complain of black gums.

Classification and Differential Diagnosis

Oral pigmentation has been associated with a variety of lesions and conditions. Differential diagnosis of oral mucous membrane pigmentations are made according to the following situations:

A. Localized Pigmentations: Amalgam tatoo, graphite or other tattoos, nevus, melanotic macules, melanoacanthoma, malignant melanoma, Kaposi’s sarcoma, epithelioid oligomatosis, verruciform xanthoma

B. Multiple or Generalized Pigmentations

1. Genetics: Idiopathic melanin pigmentation (racial or physiologic pigmentation), Peutz-Jegher’s syndrome, Laugier-Hunziker syndrome, complex of myxozomas, spotty pigmentation, endocrine overactivity, Carney syndrome, Leopard syndrome, and lentiginosis profuse

2. Drugs: Smoking, betel, anti-malarials, antimicrobials, minocycline, amiodarone, clorpromazine, ACTH, zidovudine, ketoconazole, methyldopa, busulphan, menthol, contraceptive pills, and heavy metals exposure (gold, bismuth, mercury, silver, lead, copper)

3. Endocrine: Addison’s disease, Albright’s syndrome, Acanthosis nigricans, pregnancy, hyperthyroidism

4. Postinflammatory: Periodontal disease, postsurgical gingival repigmentation

5. Others: Haemochromatosis, generalized neurofibromatosis, incontinenti pigmenti, Whipple’s disease, Wilson’s disease, Gaucher’s disease, HIV disease, thalassemia, pigmented gingival cyst, and nutritional deficiencies

Systemic and Local Causes of Pigmentation

Many systemic and local factors are caused by changes in oral pigmentation. Some of the important factors are discussed below.

Amalgam Tattoo

The pigmentation of the oral mucous membrane by tooth restoration material (amalgam) is a

common finding in dental practice. Amalgam pigmentation is generally called amalgam tattoo.The lesion represents embedded amalgam particles and usually manifests itself as an isolated bluish or black macule in various areas of the mucosa. The color is usually described as black, blue, grey, or a combination of these. Almost half were located on the gingiva and alveolar mucosa, the mandibular region being affected more than the maxillary region. Almost half of the lesions were asymtomatic and were discovered during routine dental examination. The amalgam granules and fragments were found mainly in the lamina propria but were sometimes seen in the submucosa.

Pigmented Nevi

Pigmented nevi of the oral cavity are uncommon. The pigmented nevi are classified as intramucosal, junctional, compound, or blue according to their histological features. Nevi are seen particularly on the vermillion border of the lips and the gingivae. They are usually grey, brown, or bluish macules and are typically asymptomatic. Melanocytes are pigment producing cells characterized by the ability to syntesize via the enzyme dihydroxyphenylalanine (DOPA). A group of melanocytes (generally four or more) are in contact with the basal layer of the epithelium.

Oral Melanotic Macules

Oral melanotic macules are relatively rare oral mucosal lesions, analogous to skin freckles, due to the focal increase of melanin production.These melanotic macules have been variously termed ephelis, melonosis, lentigo, solitary labial lentigo, labial melanotic macule, and oral melanotic macule.The vermillion border of the lower lip is most commonly involved.The buccal mucosa, palate, and gingiva are less commonly affected. The color is usually described as grey, brown, blue, black, or a combination of these.Histologically, ephelis shows increased melanin pigmentation in the basal cell layer without an increase in the number of melanocytes; otherwise, the epidermis is normal.

Melanoma

Melanoma is a cancerous condition of the melanocyte. Special corpusles in this cell, known as melanosomes, contain the necessary enzyme (tyrosine) to transform amino acids into melanin. Melanocytes are found among the basal cells of the epidermis. Histopathogically, the mucosal epithelium is abnormal with large atypical melanocytes and excessive melanin. Malignant melanoma of the oral mucosa affects both sexes equally usually after 40 years of age. The great majority of the lesions (about 70-80%) occur on the palate, upper gingival, and alveolar mucosa.Initially there usually is a solitary small asymtomatic brown or black macule.

Physiologic Pigmentation

Physiologic pigmentation of the oral mucosa is clinically manifested as multifocal or diffuse melanin pigmentation with variable prevalence in different ethnic groups.2 Melanin is normally found in the skin of all people. In dark skinned persons the gingiva may contain melanin pigment to a greater extent than the adjacent alveolar mucosa. The melanin pigment is synthesized in specialized cells, the melanocytes, located in the basal layer of the epithelium. The melanin is produced as granules. The melanosomes are stored within the cytoplasm of the melanocytes, as well as in the cytoplasm of adjacent keratinocytes. Melanocytes are embryologically derived from neural crest cells that eventually migrate into the epithelium. If pigmented gingiva is surgically resected, it will often heal with little or no pigmentation; therefore, surgical procedures should be designed so as to preserve the pigmented tissues.

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome (intestinal polyposis) is a genetic disorder characterized by mucocutaneous pigmentation and hamartomas of the intestine.It manifests itself as frecklelike macules about the hands, perioral skin, and intraorally to include the gingiva, buccal, and labial mucosa. Pigmented spots are 1 to l0 mm in diameter. Pigmented spots are particularly found on the lower lip and buccal mucosa but rarely on the upper lip, tongue, palate, and gingiva.

Smoker’s Melanosis

Smoker’s melanosis is a benign focal pigmentation of the oral mucosa. It tends to increase significantly with tobacco consumption. Tobacco smokers have significantly more oral surfaces pigmented than non-tobacco users.Clinically, the lesion usually presents as multiple brown pigmented macules less than 1 cm in diameter, localized mainly at the attached labial anterior gingival and the interdental papillae of the mandible. Smoker’s melonosis is more common in females usually after the third decade of life.

Antimalaria Drug Use

Several antimalarial drugs are known to be capable of inducing intraoral melanin pigmentation. These drugs include: quinacrine, chloroquine, and hydroxychloroquine Longterm use may cause pigmentation of the oral mucosa. The pigmentation of the oral mucosa is described as slate-grey in color, bearing some resemblance to pigmentation caused by silver arsplenamine.

Minocycline Use

Minocycline is a synthetic tetracycline that is commonly used in the treatment of acne vulgaris.Although tetracycline causes pigmentation of bones and teeth, minocycline alone is also responsible for soft tissue pigmentation.It is usually seen as brown melanin deposits on the hard palate, gingiva, mucous membranes, and the tongue.

Heavy Metals

Heavy metals absorbed systemically from therapeutic use or occupational environments may discolor the gingiva and other areas of the oral mucosa. Bismuth, arsenic, and mercury produce a black line in the gingiva which follows the contour of the margin. Lead results in a bluish red or deep blue linear pigmentation of the gingival margin (Burtonian line). Exposure to silver causes a violet marginal line, often accompanied by a diffuse bluish-grey discoloration throughout the oral mucosa.

Addison’s Disease

Addison’s disease or primary adrenocortical hypofunction is due to adrenocortical damage

and hypofunction.Bronzing of the skin and increased pigmentation of the lips, gingivae, buccal mucosa, and tongue may be seen. Oral pigmentation may be the first sign of the disease.A biopsy of the oral lesions shows acanthosis with silver-positive granules in the cells of the stratum germinativum. Melanin is seen in the basal layer.

Periodontal Diseases

Periodontal diseases often produce discolorations of the oral mucosa. The pigmentation is worsened by gingivitis, which increases vascular permeability and allows the heavy metals access to the soft tissues.51 Melanin re-pigmentation is related to after surgical inury.

Hemachromatosis

Hemachromatosis (bronze diabetes) is a chronic disease characterized by the deposition of excess iron (ferritin and hemosiderin) in the body tissues, resulting in fibrosis and functional insufficiency of the involved organs. Hyperpig mentation may appear both in skin and mucous membranes (oral and conjunctiva). Gingival or mucosal pigmentation is reported to occur in 15 to 25% of patients with hemachromatosis. The oral mucosa shows diffuse homogeneous pigmentation of gray-brown or deep brown in about 20% of the cases. The buccal mucosa and the attached gingiva are the most frequently involved sites.

HIV Infection

In patients infected with human immunodeficiency virus (HIV), progessive hyperpigmentation of the skin, oral mucosa, fingernails, and toenails have been reported being related to primary adrenocortical deficiency and to zidovudine (azidothymidine) therapy in some cases.Clinically, oral pigmentation appears as irregular macules with brown or dark brown color. The tongue, buccal mucosa, and palate are the most commonly affected sites.

Classification of oral diseases of HIV- associated immune suppression (ODHIS)

         Present classification systems for HIV – associated oral lesions developed in the early 1990’s which was named as HAART. Patterns of oral conditions keep on changing very frequently. This highlights the need of new system.

Classification of oral diseases of HIV – associated immune suppression (ODHIS)

System should consider:

·         Changes in epidemiology of oral lesions

·         Therapeutics

·         Development of lesions and immune systems

·         Oral lesions to oral disease

Definition of Oral disease:  abnormality characterized by a defined set of signs and symptoms in the oral cavity, extending from the vermilion border of the lip to the oropharynx, with the exception of salivary gland disease

New Classification- Classification of oral diseases of HIV – associated immune suppression (ODHIS)

Group 1 – ODHIS associated with severe immune suppression (CD4<200 cells/mm³)

Group 2 – ODHIS associated with immune suppression (CD4<500 cells/mm³)

Group 3 – ODHIS assumed associated with immune suppression

A) More commonly observed

B) Rarely reported

Group 4 – Therapeutically-induced oral diseases

Group 5 – Emerging oral diseases

Oral diseases do not belong exclusively to one classification Group

Overlap may exist

Use of the New Classification

·         Identifying undiagnosed individuals

·         Provides additional rationale for HIV testing

·         Affects access and type of HIV-related healthcare

·         Provides clinical markers for therapeutic interventions and efficacy

Group 1. ODHIS associated with severe immune suppression (CD4<200 cells/mm³)

1.      Major recurrent aphthous ulcer

2.      Neutropenia-induced ulcers

3.      Necrotizing ulcerative periodontitis

4.      Necrotizing stomatitis

5.      Cytomegalovirus (CMV)

6.      Chronic HSV

7.      Histoplasmosis

8.      Esophageal, pseudomembranous, and hypertrophic candidiasis

9.      Oral hairy leukoplakia

10.   Kaposi’s sarcoma

11.   Idiopathic Necrotizing Stomatitis    

Hyperplastic candidosis

Oesophageal candidosis

Pseudomembranous Candidosis

Kaposi's Sarcoma

Histoplasmosis

Periodontitis

Neccotizing Sialometaplasia

Chronic HSV

Group 2. ODHIS associated with immune suppression (CD4,500 cells/mm3)

1.       Major recurrent aphthous ulcer

2.       Increased frequency, harder to treat, atypical location

3.       Erythematous candidiasis

4.       Salivary gland disease

5.       Drug induced low salivation

6.       Facial palsy

7.       Neuropathies

8.       Hyposalivation

9.       Human papilloma virus (HPV)

10.   Linear gingival erythema

11.   Non-Hodgkin’s lymphoma

12.   Linear Gingival Erythema

Aptheous Ulcer

HPV

Group 3. ODHIS assumed associated with immune suppression

More commonly observed

1.       Angular candidiasis

2.       Herpes labialis

3.       Intra-oral herpes

4.       Minor aphthous ulcers

Rarely reported

1.       Bacillary epithelioid angiomatosis

2.       Tuberculosis

3.       Deep-seated mycosis (except histoplasmosis)

4.       Molluscum contagiosum

5.       Varicella Zoster Virus (VZV)

6.       HSV Labialis

7.       Intra-oral Herpes

8.       Minor Aphthous Ulcers

Angular Chelitis with candidosis

Group 4. Therapeutically-induced oral diseases

Side-effect

·         Melanotic hyperpigmentation

·         Ulcers

·         Hyposalivation

·         Lichenoid drug reaction

·         Neutropenia-induced ulcers

·         Thrombocytopenia

·         Lypodystrophy-associated oral changes

·         Perioral paresthesia

·         Steven Johnson’s?

·         Exfoliative cheilitis?

Resistance-induced disease

·         Different Candida spp and strains

·         HSV

Antiretrovirals and Adverse Reactions

Antiretroviral Drugs

Indinavir

Saquinavir

Amprenavir

Nevirapine

Delavirdine

Efavirenz

Stavudine

Didanosine

Recurrent HSV

Adverse reactions of antiretroviral drugs

Oral ulcers

Stevens Johnson’s

Taste changes

Dryness

Perioral paresthesia

Thrombocytopenia

Ulcers – Medication Induced

Recurrent HSV

Group 5. Emerging oral diseases

1.       Human papilloma virus, several HPV types (may be associated with immune reconstitution)

2.       Erythema migrans

3.       Variants of Non-Hodgkin’s Lymphoma (NHL B-cell types)

4.       Epithelial neoplasms

5.       Aggressive interproximal dental caries

6.       Condyloma Accuminatum

7.       Squamous Cell Carcinoma

Oral Potentially Malignant Disorders

Courtesy : Guidelines for prevention and management of oral potentially malignant disorders Sri Lanka

Although oral cancer can arise denovo (without any precursor stage) very often it is preceded by the presence of some specific diseases involving the oral mucosa.

Terminology

·         Earlier OPMD were called as “pre cancerous lesions and pre cancerous conditions” , “Precursor lesions and conditions”.

·         Prefix “Pre” always denotes that these lesions and conditions will always transform into malignancy.

·         It is justifiable for the conditions like Proliferative verrucous leukoplakia which has a malignant transformation high as 70% and sublingual keratosis which has a malignant transformation of 35-45%.

·         But it is not for most of the Oral Potentially malignant lesions and condiditions (Eg:OLP which has a malignant transformation rate of less than 1%.

·         Most of them reverse to the healthy stage with the cessation of the causative agent or with the treatment.

·         Therefore, WHO workshop held in 2005 has introduced the term “Potentially” instead of “Pre”.

·         It conveys that not all lesions and conditions described under this term may transform to cancer.

Definition

Potentially Malignant Lesions

Area of morphologically altered clinical or histopathological oral mucosa, in which there is a higher risk of malignant transformation than other areas of the rest of the mucosa.

Potentially Malignant Condition

Generalized state of morphologically altered clinical or histopathological oral mucosa, in which there is a high risk of malignant transformation in any area.

Changes in terminology

In early working group of the WHO in 1978 proposed the the precancerous presentations in the oral cavity to be classified in to two broad catagories.

1.       Precancerous lesions

2.       Precancerous conditions

Definitions:

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

·         A precancerous condition is a generalized state associated with a significantly increased risk of cancer’.

This classification is done because of

·         The previous studies shown that the areas of tissue with certain alterations in clinical appearances identified at the first assessment as “Precancerous” have undergone malignant changes.

·         Some if these alterations, particularly red and white patches, are seen to co-exist at the margins of overt oral squamous cell carcinomas.

·         A propotion of these oral premalignant lesion and conditions share morphological and cytological changes observed in epithelial malignancies, but without frank invasion.

·         Some chromosomal, genomic and moleculer alterations found in clearly incvasive oral cancers are detected in these presumptive “precancer” stage

These were classified purely based on clinical observation

Criteria used for diagnosing dysplasia

Architecture

·         Irregular epithelial stratification

·         Loss of polarity of basal cells

·         Drop-shaped rete ridges

·         Increased number of mitotic figures

·         Abnormal superficial mitoses

·         Premature keratinization in single cells (dyskeratosis)

·         Keratin pearls within rete pegs

Cytology

·         Abnormal variation in nuclear size (anisonucleosis)

·         Abnormal variation in nuclear shape (nuclear pleomorphism)

·         Abnormal variation in cell size (anisocytosis)

·         Abnormal variation in cell shape (cellular pleomorphism)

·         Increased nuclear-cytoplasmic ratio

·         Increased nuclear size

·         Atypical mitotic figures

·         Increased number and size of nucleoli

·         Hyperchromasia

·         This took account of worldwide experience that oral precancer’ has clinically diverse appearances. A range of precancerous lesions and conditions was recognized in that report.

·         At the time these terms were coined, it was considered that the origin of a malignancy in the mouth of a patient known to have a precancerous lesion would correspond with the site of precancer.

·         On the other hand, in precancerous conditions, cancer may arise in any anatomical site of the mouth or pharynx.

·         But in 2005 clinical assembly of WHO

·         It is now known that even the clinically normal’ appearing mucosa in a patient harbouring a precancerous lesion may have dysplasia on the contralateral anatomic site (3) or molecular aberrations in other oral mucosal sites suggestive of a pathway to malignant transformation, and that cancer could subsequently arise in apparently normal tissue (4).

·         The current Working Group, therefore, did not favour subdividing precancer to lesions and conditions and the consensus view was to refer to all clinical presentations that carry a risk of cancer under the term “Potentially malignant disorders” to reflect their widespread anatomical distribution.

Etiology

No single factor has been identified as the causative factor for potentially malignant disorders.

But a number of high risk factors has been put forwarded which has greater than normal risk of

malignancy at a future date.

A. Extrinsic Factors

1. Tobacco in any form (smoking or chewing) is the single most major extrinsic cause (people who smoke more than 80 cigarettes per day have 17-23 times greater risk).

2. Alcohol regardless of beverage type and drinking pattern – synergistic action along with tobacco (risk of smokers who are also heavy drinkers is 6-15 times than that of abstainers).

3. Virus infection – HPV, EBV, HBV, HIV, HSV.

4. Bacterial infection – Treponema pallidum.

5. Fungal infection – Candidiasis.

6. Electro-galvanic reaction between unlike restorative metals.

7. Ultraviolet radiation from sunlight – associated with lip lesions.

8. Chronic inflammation or irritation from sharp teeth or chronic cheek-bite (tissue modifiers rather than true carcinogens).

B. Intrinsic Factors

1. Genetic (5% are hereditary).

2. Immunosuppression – organ transplant,HIV.

3. Malnutrition

Epidemiology and Prevalence

·         Average age of population affected with PMD’s are 50-69 years

In the Indian subcontinent the prevalence of oral cancer is the highest among all cancers in men even though it is only the sixth most common cancer worldwide.

·         It’s estimated that more than one million new cases are being detected annually in the Indian subcontinent.

·         92-95% of all oral malignancies are oral squamous cell carcinomas (OSCC).

Five-year survival for cancer is directly related to the stage at which the initial diagnosis is made.

·         Surgical treatment of oral cancer is considered among the most debilitating and disfiguring of all cancers. It produces dysfunction and distortions in speech, difficulty in mastication and swallowing, and affects the patient's ability to interact socially.

Histopathological stages in epithelial precursor lesion

Squamous hyperplasia

This may be in the spinous layer (acanthosis) and/or in the basal/parabasal cell layers (basal cell hyperplasia); the architecture shows regular stratification without cellular atypia

Mild dysplasia

The architectural disturbance is limited to the lower third of the epithelium accompanied by cytological atypia

Moderate dysplasia

The architectural disturbance extends into the middle third of the epithelium; consideration of the degree of cytological atypia may require upgrading

Severe dysplasia

The architectural disturbance involves more than two thirds of the epithelium; architectural disturbance into the middle third of the epithelium with sufficient cytologic atypia is upgraded from moderate to severe dysplasia

Carcinoma in situ

Full thickness or almost full thickness architectural disturbance in the viable cell layers accompanied by pronounced cytological atypia

Classification

Potentially malignant lesions

1.       Leukoplakia

2.       Erythroplakia

3.       Actinic Keratosis

4.       Palatal Keratosis

Potentially malignant conditions

1.       Oral Lichen Planus

2.       Oral Submucous Fibrosis

3.       Siderophenic Dysphagia(Plummer-Vinson syndrome)

4.       Syphiliitic leukoplakia

5.       Discoid Lupus erythematosus

6.       Epidermolysis bullosa

7.       Xeroderma pigmentosum

8.       Dyskeratosis Congenita

9.       Bloom syndrome

1.   Fanconi Anaemia

Leukoplakia

Leukoplakia is generally defined as a predominantly white lesion of the oral mucosa that cannot be clinically (or histopathologically) characterized as any other definable lesion

WHO Definition

A white plaque of questionable risk having excluded other known disease or disorders that carry no increased risk for cancer.

Leukoplakia is the most common potentially malignant lesion of the oral mucosa. The term leukoplakia is a clinical descriptor only. (The terms keratosis and dyskeratosis are histological features and should not be used as clinical terms). On the basis of the following clinical features a provisional diagnosis of leukoplakia is made when the lesion cannot be clearly diagnosed as any other disease of the oral mucosa with a white appearance.

Aetiology

·         Smoking

·         Betel Chewing

·         Alcohol Consumption

·         Other tobacco related habits

Clinical features

·         Leukoplakia can be either solitary or multiple.

·         Leukoplakia may appear on any site of the oral cavity.

·         The most common sites for leukoplakia are

buccal mucosa

Ø  alveolar mucosa

Ø  floor of the mouth

Ø  tongue

Ø  lips

Ø  palate

·         Generally two clinical types of leukoplakia are recognised: homogeneous and non-homogeneous, which can co-exist .

Homogeneous leukoplakia is defined as a predominantly white lesion of uniform flat and thin appearance that may exhibit shallow cracks and that has a smooth, wrinkled or corrugated surface with a consistent texture throughout ³.

This type is usually asymptomatic.

1.       Flat

2.       Corrugated

3.       Wrinkled (Sublingual Keratosis)-Malignant transformation 35-45%

4.       Pumice like

Non-homogeneous leukoplakia has been defined as a predominantly  white-and-red lesion "erythroleukoplakia") 

Ø  that may be either irregularly flat, nodular ("speckled leukoplakia) or

Ø  exophytic ("exophytic or verrucous leukoplakia").

1.       Verrucous

2.       Nodular

3.       Ulcerated

4.       Speckled

These types of leukoplakia are often associated with mild complaints of localised pain or discomfort.

·         Proliferative verrucous leukoplakia is an aggressive type of leukoplakia that almost invariably develops into malignancy. This type is characterised by widespread and multifocal appearance, often in patients without known risk factors.

·         Malignant transformation of PVL considered to be above 70%

·         In general, non-homogeneous leukoplakia has a higher malignant transformation risk, but oral carcinoma may develop from any leukoplakia.

·         Leukoplakia malignant transformation rate varies  3% – 45%

Diagnosis

Clinical diagnosis of Leukoplakia has the following  approaches.

·         Provisional Clinical Diagnosis: It is based on clinical features stated above on a single visit, using inspection and palpation as the only diagnostic means .

·         Definitive Clinical Diagnosis: It is based on clinical evidence obtained by lack of changes after identifying and eliminating suspected aetiologic factors during a follow-up period of 2-4 weeks (In some cases the time may be longer) .

·         Histopathologically Proven Diagnosis: Definitive clinical diagnosis complemented by biopsy in which, histopathologically, no other definable lesion is observed.

Clinical differential diagnosis includes the following disorders. See Table for details of differential diagnosis:

·         lichen planus (especially the plaque type)or lichenoid reaction

·         discoid lupus erythematosus

·         leukoedema

·         acute pseudomembraneous candidosis

·         white sponge naevus

·         frictional keratosis

·         chronic cheek biting (chewing) lesions (morsicatio buccarum),

·         smoker’s palate (leukokeratosis nicotina palate)

·         chemical injury

·         skin graft

·         hairy leukoplakia

Disorder	Diagnostic  features	Investigations
Lichen planus (plaque type)	Other forms of lichen planus (reticular) found in association	Biopsy consistent with lichen planus
Lichenoid reaction	Drug history, e.g. close to an amalgam restoration	Biopsy consistent with lichen planus or lichenoid reaction
Discoid lupus erythematosus	Circumscribed lesion with central erythema, white lines radiating	Biopsy consistent with DLE supported by immunofloresence and other investigations
Leukoedema	Bilateral on buccal mucosa, could be made to disappear on stretching (retracting), racial	Not indicated
Acute pseudomembranous candidosis	The membrane can be scraped off leaving an erythematous⁄raw surface	Swab for culture
White sponge nevus	Noted in early life, family history, large areas involved, genital mucosa may be affected	Biopsy not indicated
Frictional keratosis	History of trauma, mostly along the occlusal plane, an etiological cause apparent, mostly reversible on removing the cause	Biopsy if persistent after elimination of cause particularly in a tobacco user
Morsicatio buccarum (Chronic cheek biting)	Habitual cheek – lip biting known, irregular whitish flakes with jagged out line	Biopsy not indicated
Leukokeratosis nicotina palate (smoker’s palate)	Smoking history, greyish white palate	Not indicated
Chemical injury	Known history, site of lesion corresponds to chemical injury, painful, resolves rapidly	Not indicated
Skin graft	Known history	Not indicated
Hairy leukoplakia	Bilateral tongue keratosis. Specific histopathology with koilocytosis	EBV demonstrable on in situ hybridization

Reported risk factors of statistical significance for malignant transformation of leukoplakia, listed in an at random order (not applicable in the individual patient)

1.       Female gender

2.       Long duration of leukoplakia

3.       Leukoplakia in non-smokers (idiopathic leukoplakia)

4.       Location on the tongue and/or floor of the mouth

5.       Size > 200 mm²

6.       Non-homogeneous type

7.    Presence of C. albican

8.       Presence of epithelial dysplasia

Erythroplakia

Oral erythroplakia (OE) is considered a rare potentially malignant disease of the oral mucosa and is classically defined as ‘‘fiery red patch of the oral mucosa that cannot be characterized clinically or pathologically as any other definable disease”.

It must be noted that in case of a mixture of red and white changes such lesion is usually categorized as non-homogeneous leukoplakia (‘‘erythroleukoplakia”). The natural history of OE is unknown. It is not clear whether OEs develop de novo or they develop from oral leukoplakia through several intermediate stages of white/red lesions.

Aetiology:

Tobacco and alcohol use are considered important aetiologic factors. The possible role of C. albicans is at present still unclear. The etiology of OE reveals a strong association with tobacco consumption and the use of alcohol.

Epidemiology:

Prevalence figures of erythroplakia are only available from studies performed in South- and Southeast Asia and vary between 0.02% and 0.83%.

A recent case control study of OE from India reported a prevalence of 0.2%. A range of prevalences between 0.02% and 0.83% from different geographical areas has been documented³. OE is predominantly seen in the middle aged and elderly.   There is no distinct gender preference. One study from India showed a female:male ratio of 1:1.04.

Clinical features:

Lesions of OE are typically less than 1.5 cm in diameter but lesions larger than 4mm in diameter have been reported. ⁵ The clinical appearance may be flat or with a smooth or granular surface². The surface of OE is often depressed

below the level of the surrounding mucosa.⁶.  Any site of the oral and oropharyngeal cavity may become involved, usually in a solitary fashion. This solitary presentation is often helpful in clinically distinguishing erythroplakia from several other erythematous lesions affecting the oral mucosa, since these lesions occur almost always in a bilateral, more or less symmetrical pattern.⁷    See Table 2.2.1 for differential diagnosis of OE. OE is soft to palpation and does not become indurated or hard until an invasive carcinoma develops in it.  The soft palate, the floor of the mouth and the buccal mucosa are most commonly affected by OE.⁸ The tongue is rarely affected.⁹

OE is a diagnosis by exclusion. The term OE does not carry a histopathologic connotation. As for Oral leukoplakia the principle of provisional diagnosis and definitive diagnosis is also suggested for OE. Provisional diagnosis was defined as: ‘‘A provisional diagnosis of OE is made when a lesion at clinical examination cannot be clearly diagnosed as any other disease of the oral mucosa with red appearance’’. Definitive diagnosis was defined as: ‘‘A definitive diagnosis of OE is made as a result of identification, and if possible elimination, of suspected aetiological factors and, in the case of persistent lesions, histopathological examination’’.  OE is seldom multicentric and rarely covers extensive areas of the mouth.⁷

Histopathologically, erythroplakia commonly shows at least some degree of dysplasia and often even carcinoma in situ or invasive carcinoma..

 Histopathologically, it has been documented that in OE of the homogenous type, 51% showed invasive carcinoma, 40% carcinoma in situ and 9% mild or moderate dysplasia. Transformation rates are considered to be the highest among all OPMDs. Surgical excision is the treatment of choice. 

Prognosis and treatment

 In general, OE needs to be treated because of its high risk of malignant transformation. Besides, most erythroplakias are symptomatic. Surgery, either by cold knife or by laser, is the recommended treatment modality. As for excision of leukoplakia, no guidelines are available with regard to the width of the surgical margins. There are no data from the literature about the recurrence rate after excision of erythroplakias.

Red lesions that need to be considered in the differential diagnosis of oral erythroplakia (adapted from Reichart and Philipsen and Warnakulasooriya et al )

Nature of lesion	Lesion/ condition	Diagnostic features
Inflammatory⁄ immune  disorders	Desquamative gingivitis	Associated mostly with erosive /atrophic lichen planus in other areas
	Erosive/atrophic lichen planus	Reticular lesion/striae may be seen in peripheral areas; multiple sites
	Discoid lupus erythematosus	Circumscribed lesion with central erythema, white lines radiating
	Pemphigus , Pemphigoids	History of bullous eruption and rupture, wider & multiple areas involved
	Hypersensitvity reactions	History of exposure to allergen; wider area affected
	Reiter’s disease	Non gonococcal urethritis, arthritis
Infections	Erythematous candidiasis including  denture induced stomatitis	Found on palate and under denture
	Histoplasmosis	Raised /ulcerated lesion
	Tuberculosis	Usually ulcerative stellate appearance
Hamartomas⁄ neoplasms	Haemangioma	Blanching on pressure
	Lingual varices	Ventral aspect of tongue,symmetrical
	Telangiectasia	Multiple sites and skin involvement
	Oral purpura	Bleeding diatheses present
	Kaposi’s sarcoma	Seen mostly in HIV infected people

Palatal Keratosis

·         The lesion is unknown in sri lankan patients

·         Reported in south India Andhra Pradesh where people practice unusual method of smoking

·         Which the lighted end of cigar is held inside the moth

·         Resultant keratosis on the palate

Actinic Keratosis

·         Mainly found among fair skinned populations in sunny habitats(bright sun light)

·         Keratosis is preceded by inflammatory reactions

·         Mainly on lower lip

·         Erythematous changes accompanied by oedema, Vesciculation and occasionally bleeding

·         Developmet of lower lip cancer.

Oral submucous fibrosis (OSF)

Oral submucous fibrosis (OSF) is a potentially malignant disorder associated with burning sensation in the oral mucosa from the early stages and with a significant risk for malignancy. It is a chronic, insidious disease with a progressive fibrosis in the submucosal tissues leading to restriction in opening the mouth with the advancement of the disease.

The fibrosis initially affects the lamina propria of the oral mucosa and as the condition worsens, extends to the submucosa and the deeper tissues including oral musculature.  Consequently the elasticity of the oral mucosa is progressively lost. Variable rates of malignant transformation ranging from 4.5 to 7.6 percent have been reported. ^3,4

 No such data is available for Sri Lanka

Aetiology

Conclusive evidence now exists that the disease is caused by the consumption of areca nut. The condition predominantly affects populations of the Indian subcontinent and South East Asia who chew areca nut in betel quid or in flavoured formulations of the nut. Although the disease mostly affects people older than 40 years of age, younger people are increasingly seen to be affected, particularly those who consume flavoured areca nut products alone.

Alkaloids in Arecanut responsible for OSMF

1.       Arecoline

2.       Arecodine

3.       Guacoline

4.       Guacine

Pathogenesis

Unlike the other OPMDs described here,  the pathogenesis of OSF has been well elucidated.  Although a detailed discussion of the pathogenesis of OSF is beyond the scope of these guidelines, an understanding of this aspect of OSF is important.  Fibrosis and hyalinization resulting from increased amount of collagen in the  extracellular matrix of  sub epithelial tissues contribute to the important clinical features seen in this condition. It has been shown that either an increased collagen synthesis or reduced degradation of collagen may be responsible for the development of OSF. Alkaloids in areca nut, importantly, arecoline, have been implicated in stimulation of fibroblast proliferation while tannins in the nut appear to stabilize collagen structure that resists degradation by collagenases. Increased secretion of fibrogenic cytokines such TGF beta and imbalance  between  matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMMS) are responsible to altered collagen metabolism leading to fibrosis. The disease is associated with certain genetic groups than in others.¹

Clinical features

The clinical features that are diagnostic include:

·         Burning sensation of the oral mucosa

·         blanching and stiffening of the oral mucosa leading to limitation in mouth opening.

·         Widespread pallor of the oral mucosa

·         palpable fibrous bands in cheeks, along the faucial pillars,  soft palate and lips

·         tightening of the lips with resultant lack of their stretchability

·    depapillation of the dorsum of the tongue with restricted mobility of the tongue including protrusion

·        depigmentation of the mucosa particularly noticeable on the vermilion border of the  lips in a significant proportion of patients

·         vesiculation of the oral mucosa is sometimes described but not often seen.

·         Other potentially malignant disorder such as leukoplakia may be seen in longstanding OSF.

 

Diagnosis of OSF

Diagnosis can be made easily in established OSF based on the above clinical features. In early stages, however,  the diagnosis may be difficult to establish purely on clinical grounds and a biopsy may be necessary for the diagnosis. Biopsy is also necessary in advanced stages to determine the presence of epithelial dysplasia if there are clinically suspicious features.  The condition may need to be distinguished from other diseases that may exhibit  fibrosis and may cause limitation in mouth opening such as epidermolysis bullosa,  post-irradiation fibrosis, cicatricial pemphigoid,  progressive systemic sclerosis  etc. 

Staging of OSF

Unlike other OPMDs, OSF is a disorder that is associated with a functional disability. Attempts have been made to stage OSF using mainly clinical / functional  criteria ^2,5

 A staging scheme proposed by Kerr et al²  is a useful one and is shown in table

  

Disease Grading  of Oral submucous fibrosis (Kerr et al²)

Grade	Clinical and functional features
Grade 1 – Mild	Any feature of the disease triad for OSF ((burning, depapillation, blanching or leathery mucosa) present + inter-incisal opening >35 mm
Grade 2 – Moderate	Above features of OSF + inter-incisal limitation of opening 20–35 mm
Grade 3 – Severe	Above features of OSF + inter-incisal opening <20 mm
Grade 4A	OSF + other potentially malignant disorder on clinical examination
Grade 4B	OSF with any grade of oral epithelial dysplasia on biopsy
Grade 5	OSF + oral squamous cell carcinoma (SCC)

Treatment of OSF

There is no single satisfactory and evidence-based treatment method for curing the disease.  Physical and medical treatments have all been tried with claims of varying rates of success. Physical methods such as stretching exercises aimed at increasing mouth opening and medical treatments such as intra-lesional injection of corticosteroids have been reported. Intra lesional steroid (for example methyl prednisolone) injection is the widely practised treatment⁶ in most centres, especially for symptomatic cases with developing limitation in mouth opening associated with burning sensation.   Surgical methods aimed at severing the fibrous bands in advanced           stages have also been attempted but are associated with relapse. None of these methods has satisfied all criteria for randomised controlled trials².   Education and habit control among patients has been found to arrest the progress of the disease in early stages although this has not been proven by any randomised controlled trial.  Many of the patients suffering from OSF may be affected by iron deficiency anaemia and other nutritional deficiencies². A full blood count is recommended for every patient when the diagnosis of OSF is made. When deficiencies are detected, treatment must be instituted to correct them.

Lichen Planus

Oral lichen planus is a common chronic inflammatory mucocutaneous disorder that typically affects the skin and/or mouth .Lichen planus can also affect other non-oral mucosal surfaces such as the genitals.

OLP, the mucosal counterpart of cutaneous lichen planus, which is a chronic inflammatory disorder based on immunologic T cell mediated process.

OLP is a relatively common condition which affects 1%-2% of the population. The possible malignant transformation of OLP is still a subject of an ongoing controversy.

However the reported malignant transformation potential varies from 0.4% to 5%. This is a case of OLP that can be considered on the verge of malignant transformation on the basis of presence of severe epithelial dysplasia.

•   Affects 1%-2% of the population.
•   OLP lesions are commonly seen in 5^th and 6^th decades of life.
•   OLP affects women more than men.
•   Female : Male  ratio -1.4 : 1

Oral lichenoid reactions (OLR)

Considered  a variant of OLP, may be regarded as a disease by itself or as an exacerbation of an existing OLP, by the presence of medications (Lichenoid drug reactions) or dental materials (contact hypersensitivity)

 Clinical features

·         OLP usually present as bilaterally symmetrical lesion or multiple lesions.

·         Typically affects the buccal mucosa, dorsum and ventral surfaces of the tongue and/or gingiva.

·         Other mucosal surfaces can be affected but palatal involvement is particularly rare.

·         Oral lichen planus is often asymptomatic^1,3 although when there are areas of erosion or ulceration, the patient may have variable amounts of discomfort, being particularly troublesome when eating spicy or acidic type foods.

·         The variable clinical presentations of oral lichen planus comprise white patches, erosions, ulcers and, very rarely, blisters^1,3. The clinical presentation of lichen planus can be classified as follows:

Asymptomatic

◦       Reticular

◦       Papular

◦       Plaque like

Symptomatic

◦       Erosive/ Ulcerative

◦       Atrophic

◦       Bullous

ü  Reticular oral lichen planus – this is the most common presentation, manifesting as a network of white striations. These lesions are often painless, although patients may complain of a slight roughness or dryness to the affected mucosal surfaces.

ü  Plaque-like oral lichen planus – this manifests as areas of homogenous whiteness. This typically arises on the buccal mucosa or dorsum of tongue and may be more prevalent amongst those who are smokers.

ü  Papular oral lichen planus – this manifests as small white raised areas approximately 1-2mm in diameter. These again typically arise on the buccal mucosa and dorsum of tongue, although may also present on other mucosal surfaces. Erosive oral lichen planus – this is sometimes termed atrophic oral lichen planus. In this form there are areas of redness within the aforementioned white patches. Patients with this type of disease often complain of oral soreness

ü  Ulcerative lichen planus – there are frank ulcers within the areas of whiteness. Patients complain of continued soreness, this being particularly severe with spicy or acidic foods.

ü  Bullous lichen planus – this rare presentation manifests as small vesicles or blisters (bullae) within the white patches.

Patients with disease involving the gingiva may have areas of white patches or striae superimposed upon redness of the gums. The latter is often termed desquamative gingivitis and can be extremely painful.

There is little predictability as regards the frequency of non-oral disease in patients with oral lichen planus. Likewise the oral features may precede, accompany or follow lichen planus affecting other sites.

Etiolopathogenesis of OLP and OLR

The precise aetiology of this condition is unknown.

Cell mediated immune dysregulation has been associated with the pathogenesis of OLP.

The data suggests that OLP is a T-cell mediated autoimmune disease in which autocytotoxic CD8+ T cells trigger the apoptosis of Oral epithelial cells.

The nature of antigen is still uncertain.

However, several predisposing factors have been implicated in the pathogenesis of OLP and OLR.

Drugs

◦       Anti-malarials

◦       Non-steroidal anti-inflammatory drugs

◦       Angiotensin converting enzyme inhibitors

◦       Diuretics

◦       Beta blockers

◦       Oral Hypoglycemics

◦       Gold Salts

◦       Penicillamine

◦       Anti-Retrovirals

Dental Materials

ü  Dental Amalgam

ü  Composite and resin based         materials

ü  Metals (Eg:Nickel)

Chronic liver disease and            

Hepatitis C virus

Stress

Genetics

Tobacco chewing

Graft versus Host Disease

Diagnosis

·         The diagnosis of oral lichen planus is initially based upon the clinical presentation of bilateral white patches with or without erosions, ulcers or blisters, typically affecting the buccal mucosa, dorsum of tongue and gingiva⁵.

·         Biopsy with subsequent histopathological examination of affected tissue is essential to exclude other disease that may mimic oral lichen planus – such as lupus erythematosus⁵.

·         In addition, it is advantageous to undertake a biopsy to identify possible areas of cellular atypia (dysplasia) within the involved tissue.

Siderophenic Dysphagia (Plummer Vinson Syndrome)

Manifestation of severe iron deficiency anaemia

Reported in middle aged female

Presents with

·         Angular chellitis

·         A lemon tinted pallor of the skin

·         A depapillated, erythematous and painful tongue

·         Dysphagia due to post cricoids oesophagial stricture

·         Koilonychias(Spoon shaped nails)

Syphilitic Leukoplakia

Complication of tertiary syphilis

Dorsum of the tongue is the usual site

Treponema pallidum is the responsible organism

Discoid Lupus Erythematosus

Occur in two forms

·         Mucocutaneous – DLE

·         Systemic type-multisystem autoimmune involevement-SLE

Both cause oral ulcers

Female predominantly affected

Central erythema ,white spots or papules, radiating white striae at margins and peripheral telengiectasia and it may ulcerate

In SLE ulcers are more severe than DLE

Epidermolysis Bullosa

·         Uncommon inherited mucocutaneous vesiculo-bullous condition

·         Several subtypes with varying patterns of inheritance

·         The subtypes that produce oral lesions are

o   autosomal recessive non scarring letalis type

o   autosomal recessive scarring dermolytic type

·         Vesicles for on oral mucosa and face in reaction to mild trauma

·         Scarring may cause microstomia and obliteration of buccal mucosa, tongue may become fixed

Xeroderma Pigmentosum

Rare

Inherited autosomal recessive trait in which there is an inability to repair damge DNA caused by UV light and by some chemicals

Skin cancer and SCC on Lower lip, tip of the tongue

Fanconi Anemia

Fanconi anemia (FA) is a genetic disease with an incidence of 1 per 350,000 births, with a higher frequency in Ashkenazi Jews and Afrikaners in South Africa.

Fanconi's anemia is due to an abnormal gene that damages cells, which keeps them from repairing damaged DNA.

Dyskeratosis congenita

(DKC), also called Zinsser-Cole-Engman syndrome, is a rare progressive congenital disorder that in some ways resembles premature aging (similar to progeria). The disease mainly affects the integumentary system (i.e, the skin, the organ system that protects the body from damage), with a major consequence being anomalies of the bone marrow.

Mucosal leukoplakia occurs in approximately 80% of patients and typically involves the buccal mucosa, tongue, and oropharynx. The leukoplakia may become verrucous, and ulceration may occur. Patients also may have an increased prevalence and severity of periodontal disease.

Other mucosal sites may be involved (e.g., esophagus, urethral meatus, glans penis, lacrimal duct, conjunctiva, vagina, anus). Constriction and stenosis can occur at these sites, with subsequent development of dysphagia, dysuria, phimosis, and epiphora.