Oral erythroplakia has not been studied as intensively as oral leukoplakia.

56 Erythroplakia is defined as a red lesion of the oral mucosa that cannot be characterized as any other definable lesion (Figure 13). The lesion comprises an eroded red lesion that is frequently observed with a distinct demarcation against the normalappearing mucosa. Clinically, erythroplakia is different from erythematous OLP as the latter has a more diffuse border and is surrounded by white reticular or papular structures. Erythroplakia is usually nonsymptomatic, although some patients may experience a burning sensation in conjunction with food intake. A special form of erythroplakia has been reported that is related to reverse smoking of chutta, predominantly practiced in India.63 The lesion comprises well-demarcated red areas in conjunction with white papular tissue structures. Ulcerations and depigmented areas may also be a part of this particular form of oral lesion.
Diagnosis

The diagnostic procedure of oral leukoplakia and erythroplakia is identical (Figure 14).57,64 The provisional diagnosis is based on the clinical observation of a white or red patch that is not explained by a definable cause, such as trauma. If trauma is suspected, the cause, such as a sharp tooth cusp or restoration, should be eliminated. If healing does not occur in 2 weeks, biopsy is essential to rule out malignancy.
Pathology

The biopsy should include representative tissue of different clinical patterns. Hyperkeratosis without any other features of a definable diagnosis is compatible with homogeneous oral leukoplakia. If the histopathologic examination leads to another definable lesion, the definitive diagnosis will be changed accordingly. However, there is no uniform depiction of an oral leukoplakia and the histopathologic features of the epithelium may include hyperkeratosis, atrophy, and hyperplasia with or without dysplasia. When dysplasia is present, it may vary from mild to severe. Dysplasia may be found in homogeneous leukoplakias but is much more frequently encountered in nonhomogeneous leukoplakias55,6567 and in erythroplakias.68 Epithelial dysplasia is defined in general terms as a precancerous lesion of stratified squamous epithelium characterized by cellular atypia and loss of normal maturation short of carcinoma in situ (Figure 15). Carcinoma in situ is defined as a lesion in which the full thickness of squamous epithelium shows the cellular features of carcinoma without stromal invasion.69 A more detailed description of epithelial dysplasia is presented in Table 6. The prevalence of dysplasia in oral leukoplakias varies from 1 to 30%, whereas the majority of erythroplakias display an atrophic epithelium with dysplastic features.68
Management

Oral leukoplakia is a lesion with an increased risk of malignant transformation, which has great implications for the management of this oral mucosal disorder. Since alcohol and smoking are well-established risk factors for the development of oral squamous cell carcinomas, measures should be taken to influence the patients to discontinue such habits. Cold-knife surgical excision, as well as laser surgery, is widely used to eradicate leukoplakias and erythroplakias but will not prevent all premalignant lesions from malignant development.7074 On the contrary, surgery has been strongly questioned as squamous cell carcinomas are almost equally prevalent in nonsurgically treated patients as in patients subjected to surgery.55 This may be explained by genetic defects in clinically normal mucosa and is supported by a concept referred to as field cancerization. 75 Field cancerization is caused by simultaneous genetic instabilities in the epithelium of several extralesional sites that may lead to squamous cell carcinomas. However, in the absence of evidenced-based treatment strategies for oral leukoplakias, surgery will remain the treatment for oral leukoplakias and erythroplakias. Malignant transformation of oral leukoplakias has been reported in the range of 1 to 20% over 1 to 30 years.62,76,77 Based on a recent review of available European epidemiologic data, the incidence has been calculated not to exceed 1% per year.78 Sixteen to 62% of oral carcinomas have been reported to be associated with leukoplakia at the time of the diagnosis, 7981 and in an Indian house-to-house survey, 80% of oral cancers were reported to be preceded by oral precancerous lesions or conditions. 82 Until biomarkers are developed, management of oral leukoplakias and erythroplakias has to rely on traditional clinical and histopathologic criteria. Homogeneous oral leukoplakia entails less risk for malignant transformation than do nonhomogeneous leukoplakias and erythroplakias. Presently, no consensus has been developed regarding management and follow-up of oral leukoplakias and erythroplakias. A general recommendation may be to reexamine the premalignant site irrespective of surgical excision every 3 months for the first year. If the lesion does not relapse or change in reaction pattern, the follow-up intervals may be extended to once every 6 months. New biopsies should be taken if new clinical features emerge. Following 5 years of no relapse, self-examination may be a reasonable approach.

Oral Submucous Fibrosis

is a chronic disease that affects the oral mucosa as well as the pharynx and the upper two-thirds of the esophagus.84 There is substantial evidence that lends support to a critical role of areca nuts in the etiology behind submucous fibrosis.85
Etiology and Pathogenesis

There is a dose dependence between areca quid chewing habit and the development of this oral mucosal disorder. Areca nuts contain alcaloids, of which arecoline seems to be a primary etiologic factor. 86 Arecoline has the capacity to modulate matrix metalloproteinases, lysyl oxidases, and collagenases, all affecting the metabolism of collagen, which leads to an increased fibrosis. 87 During the development of fibrosis, a decrease in the water-retaining proteoglycans will occur in favor of an increased collagen type I production. 88 There is also evidence of a genetic predisposition of importance for the etiology behind submucous fibrosis. Polymorphism of the gene, which is coding for tumor necrosis factor a (TNF-a), has been reported to promote the development of the disorder. Fibroblasts are stimulated by TNF-a, thereby participating in the development of fibrosis.89 Aberrations of other cytokines of importance are transforming growth factor b and interferon-c, which may lead to increased production and decreased degradation of collagen. A genetic predisposition is also supported by association-specific human leukocyte antigen (HLA) molecules, such as HLA-A10, -B7, and DR3.90
Epidemiology

Areca nutderived products have several hundred million consumers in the southern parts of Asia. Regional variations exist regarding the preference of the areca nut use, which also accounts for variation in the affected sites. Oral complications are most commonly observed on the lips, buccal mucosa, retromolar area, and soft palatal mucosa.91 The habit of chewing betel quid, containing fresh, dried, or cured areca nut, and flavoring ingredients is widespread in India, Pakistan, Bangladesh, and Sri Lanka and in immigrants coming from these regions.92 Tobacco is often used in conjunction with betel quid. The habit is more common among women in some geographic areas, which is also reflected in the gender distribution of submucous fibrosis. The global incidence of submucous fibrosis is estimated at 2.5 million individuals. 93 The prevalence in Indian populations is 5% for women and 2% for men.90 It seems as if age groups below 20 years of age more often contract submucous fibrosis. This is reflected in the advertisement of areca nut products, which is directed against younger age groups. Following the introduction of this marketing strategy, the incidence of submucous fibrosis has increased 10 times between 1980 and 1993.87
Clinical Findings

The first sign is erythematous lesions sometimes in conjunction with petechiae, pigmentations, and vesicles. 85 These initial lesions are followed by a paler mucosa, which may comprise white marbling (Figure 16). The most prominent clinical characteristics will appear later in the course of the disease and include fibrotic bands located beneath an atrophic epithelium. Increased fibrosis eventually leads to loss of resilience, which interferes with speech, tongue mobility, and a decreased ability to open the mouth. The atrophic epithelium may cause a smarting sensation and inability to eat hot and spicy food. More than 25% of the patients exhibit also oral leukoplakias.94
Diagnosis

The diagnosis of submucous fibrosis is based on the clinical characteristics and on the patients report of a habit of betel quid chewing. An international consensus has been reached where at least one of the following characteristics should be present95: $ Palpable fibrous bands $ Mucosal texture feels tough and leathery $ Blanching of mucosa together with histopathologic features consistent with oral submucous fibrosis (atrophic epithelium with loss of rete ridges and juxtaepithelial hyalinization of lamina propria)
Pathology

The early histopathologic characteristics for submucous fibrosis are fine fibrils of collagen, edema, hypertrophic fibroblasts, dilatated and congested blood vessels, and an infiltration of neutrophilic and eosinophilic granulocytes.96 This picture is followed by a down-regulation of fibroblasts, epithelial atrophy, and loss of rete pegs, and early signs of hyalinization occur in concert with an infiltration of inflammatory cells. Epithelial dysplasia in submucous fibrosis tissues appeared to vary from 7 to 26% depending on the study population. 9799
Management

Products derived from areca nuts are carcinogenic, regardless of tobacco use as an adjunct. Thus, treatment of submucous fibrosis should be focused on cessation of the chewing habits. If this is successfully implemented, early lesions have a good prognosis as they may regress.94 A plethora of treatment strategies have been tried, such as topical and systemic steroids, supplement of vitamins and nutrients, repeated dilatation with physical devices, and surgery.100 None of these treatments have reached general acceptance as the long-term results are dubious. Malignant transformation of oral submucous fibrosis has been estimated in the range of 7 to 13%87 and the incidence over a 10-year period at approximately 8%.98

Immunopathologic Diseases Oral Lichen Planus

Lichenoid reactions represent a family of lesions with different etiologies with a common clinical and histologic appearence.101 Histopathologic examination does not enable discrimination between different lichenoid reactions but may be used to distinguish lichenoid reactions from other pathologic conditions of the oral mucosa. Oral lichenoid reactions include the following disorders: $ Lichen planus $ Lichenoid contact reactions $ Lichenoid drug eruptions $ Lichenoid reactions of graft-versus-host disease (GVHD) Oral lichenoid contact reactions (LCRs) are included with allergic reactions since these lesions represent a delayed hypersensitivity reaction to constituents derived from dental materials or flavoring agents in foods.
Etiology and Pathogensis

The etiology of OLP is not known.101 During recent years, it has become more evident that the immune system has a primary role in the development of this disease.102 This is supported by the histopathologic characteristics of a subepithelial bandformed infiltrate dominated by T lymphocytes103 and macrophages and the degeneration of basal cells known as liquefaction degeneration (Figure 17). These features can be interpreted as an expression of the cell-mediated arm of the immune system being involved in the pathogenesis of OLP through Tlymphocyte cytotoxicity directed against antigensexpressed by the basal cell layer. Autoreactive T lymphocytes may be of primary importance for the development of oral lichen planus (Composition 7).104 These cells cannot discriminate between inherent molecules of the body and foreign antigens. Activation of the autoreactive T lymphocyte is a process that may arise in other parts of the body than the oral mucosa and may not even occur in concert with the onset of the mucosal lesion. Most likely, it is not one single peptide that has the potential to evoke the inflammatory response but several depending on the specificity of the autoreactive T lymphocyte. The conclusion that follows from this reasoning is that it is complicated to identify a single etiologic factor behind OLP.104 Other factors, such as stress, may also be of importance to establish the inflammatory process. It is not unusual that patients report that they have been exposed negative social events some months before to the onset of the disease. Altogether, this makes the etiology behind OLP a multifactorial process comprising events that may take place at different time points.