White and Red Lesions of the Oral Mucosa

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1 White and Red Lesions of the Oral Mucosa Maryam Jessri, Hani Mawardi, Camile S. Farah, and Sook-Bin Woo Abstract There are several conditions that can present as white or red macular, papular, and/or plaquelike lesions of the oral mucosa. Based on etiology, red and white lesions of the oral cavity can be divided into developmental, reactive, infectious, immune-mediated/autoimmune, and M. Jessri Division of Oral Medicine and Dentistry, Brigham and Women s Hospital, Boston, MA, USA Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA School of Dentistry and Oral Health Centre of Western Australia, University of Western Australia, Perth, WA, Australia maryam.jessri@gmail.com; mjessri@partners.org H. Mawardi Faculty of Dentistry, King Abdulaziz university, Jeddah, Saudi Arabia Division of Oral Medicine and Dentistry, Brigham and Women s Hospital, Boston, MA, USA hmawardi@kau.edu.sa C.S. Farah (*) School of Dentistry and Oral Health Centre of Western Australia, University of Western Australia, Perth, WA, Australia camile.farah@uwa.edu.au S.-B. Woo Division of Oral Medicine and Dentistry, Brigham and Women s Hospital, Boston, MA, USA Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA swoo@rics.bwh.harvard.edu; swoo@partners.org # Springer International Publishing AG 2017 C.S. Farah et al. (eds.), Contemporary Oral Medicine, DOI / _16-1 potentially malignant and malignant conditions. Whiteness of the oral mucosa can be caused by changes in the epithelium such as keratinization of normally nonkeratinized mucosa (such as the buccal mucosa), increased keratinization of normally keratinized mucosa, abnormal keratinization of the epithelium, thickening of the epithelium, and epithelial edema. Fibrosis and/or reduced vascularity of the underlying mucosa may also lead to whiteness which tends to appear deep without discernible surface alterations. Some of the more common causes of redness (erythema) of the oral mucosa include reduced keratinization of the oral epithelium, epithelial atrophy, erosion or inflammation, and vascular dilatation or proliferation. Generally, the prevalence of red and white oral lesions increases with age. Based on diagnostic and inclusion criteria and characteristics of the population, prevalence of oral mucosal lesions has been reported in 2 84% of the population (Do et al. 2014). A large proportion of red and white lesions are benign. However, the most common premalignant condition in the oral cavity is a white plaque (leukoplakia), and this must be managed expeditiously and appropriately. Many conditions can be accurately diagnosed with careful history taking and clinical examination. However, a biopsy is often necessary for a definitive diagnosis. This chapter discusses the clinical features of these white and red lesions, how to distinguish between them, and how to manage them. 1

2 2 M. Jessri et al. Keywords White lesions Red lesions Premalignant lesions Mucosal pathology Benign mucosal pathology Developmental conditions Reactive conditions Potentially malignant lesions Malignant lesions Oral squamous cell carcinoma Contents Introduction... 2 Developmental Conditions... 2 Fordyce Granules White Sponge Nevus (Cannon White Sponge Nevus, Familial White Folded Dysplasia) Hereditary Benign Intraepithelial Dyskeratosis (Witkop Disease)... 4 Reactive Lesions... 4 Chemical Desquamation... 4 Leukoedema... 5 Smokeless Tobacco Keratosis... 5 Morsicatio Mucosae Oris (Chronic Bite Keratosis)... 7 Benign Alveolar Ridge Keratosis... 8 Contact Stomatitis... 9 Nicotinic Stomatitis (Stomatitis Nicotina) Hairy/Coated Tongue Infections Candidosis Oral Hairy Leukoplakia Immune-Mediated and Autoimmune Conditions Benign Migratory Glossitis (Geographic Tongue, Erythema Areata Migrans, Migratory Stomatitis) Desquamative Gingivitis Plasma Cell Gingivostomatitis (Plasma Cell Orificial Mucositis) Oral Lichen Planus Lupus Erythematosus Oral Graft Versus Host Disease Erythema Multiforme Precancerous and Cancerous Lesions Leukoplakia and Proliferative Verrucous Leukoplakia Erythroplakia Oral Submucous Fibrosis Actinic Cheilitis (Actinic Cheilosis, Solar Cheilosis, and Farmer s Lip) Oral Squamous Cell Carcinoma Conclusion and Future Directions Cross-References References Introduction This chapter focuses on red and white macular, papular, and plaque lesions of the oral mucosa. There are many conditions in this chapter which overlap with entities discussed in other chapters. For instance, oral lichen planus and lichenoid lesions will only be discussed briefly here as there is a full-length chapter elsewhere in this textbook dedicated specifically to this topic. Likewise, the topic of oral candidosis is covered in great detail in the chapter on Oral Fungal Infections, and malignant lesions are covered in the chapter on Oral Mucosal Malignancies. The conditions described in this chapter are divided by etiology as follows: Developmental conditions Reactive conditions Infections Immune-mediated and autoimmune conditions Potentially malignant and malignant lesions Developmental Conditions Fordyce Granules Fordyce granules are benign sebaceous glands commonly found in the oral cavity that have a high prevalence of up to 80%, and as such they are generally considered to be a normal variation of the oral mucosa. However, their density and prevalence are reportedly higher in individuals with hyperlipidemia and Muir-Torre syndrome (Ponti et al. 2015). Fordyce granules are a variation of the normal oral phenotype. However, because of increased prevalence around puberty, as well as with increase in age, some authors suggest hormonal influence in their etiopathogenesis although it is more likely that they become fully expressed when patients reach adulthood (Choudhry et al. 1992).

3 White and Red Lesions of the Oral Mucosa 3 Fig. 1 Fordyce granules. Yellow papules on the left buccal mucosa Fordyce granules are seen in 80% of the general adult population with no particular gender predilection. They present as multiple asymptomatic, yellow or yellowish-white, 1 3 mm macules and papules, most commonly seen on the buccal mucosa, and vermilion of the upper lip. They are generally bilateral and symmetrically distributed (Fig. 1). Occasionally, some of the sebaceous glands may become hyperplastic and papular (up to 3 5 mm in size) so that the patient or oral health care provider may become more aware of them. Fordyce granules require no treatment other than recognition of the condition and reassurance of the patient. A biopsy is not usually required because of their typical appearance and distribution. Sebaceous hyperplasia is not uncommon, but sebaceous adenoma is rare (Izutsu et al. 2003). White Sponge Nevus (Cannon White Sponge Nevus, Familial White Folded Dysplasia) White sponge nevus is a rare autosomal dominant disorder with highly variable expressivity that affects the oral and other mucosae but not the skin. White sponge nevus is caused by mutation in genes associated with keratin-4 (KRT4) or keratin-13 (KRT13) resulting in keratin instability and abnormal aggregation of tonofilaments which in turn promotes abnormal proliferation and thickening of the oral epithelium (Rugg et al. 1995; Shibuya et al. 2003). The lesions of white sponge nevus appear at birth, early childhood, or adolescence and usually present in a bilateral, symmetric fashion as asymptomatic, thick, white, spongy plaques, usually on the buccal mucosa, ventral tongue, lip mucosa, and soft palate (Songu et al. 2012). There may also be esophageal, upper airway, and genital lesions, but the skin is not affected. Diagnosis is established through a biopsy because other conditions such as chronic traumatic keratoses may appear clinically similar. Patients should be reassured that this is a benign inherited condition that will persist throughout life. There is no effective treatment. Cases that have reportedly responded to antibiotics or antibacterial mouth rinses are not likely to represent this condition but instead a reactive keratosis.

4 4 M. Jessri et al. Hereditary Benign Intraepithelial Dyskeratosis (Witkop Disease) Hereditary benign intraepithelial dyskeratosis (HBID) is a rare autosomal dominant disorder presenting with bulbar conjunctival and oral plaques. It was first identified in 1960 and predominantly affects descendants of Haliwa-Saponi Native Americans in North Carolina (Cummings et al. 2008). Recent haplotype analysis of families with HBID showed a possible role of duplication of chromosome 4q35, which may trigger uncontrolled cell proliferation and premature keratinization of the epithelium (Allingham et al. 2001). HBID manifests at birth or early childhood with no gender predilection. Oral lesions are generally asymptomatic and present as non-tender, spongy, white plaques on the buccal mucosa, lips, ventral surface of the tongue, and floor of the mouth, usually in a bilateral fashion. Ocular lesions present as white-gray gelatinous plaques on the bulbar conjunctiva, and these may be asymptomatic, or patients may experience irritation, frequent lacrimation, a feeling of a foreign body in the eye, and photophobia. Corneal vascularization may lead to blindness in rare cases. One unusual feature of HBID is worsening of symptoms in spring and summer. A biopsy is usually required to confirm the diagnosis and rule out other conditions such as white sponge nevus or even frictional keratosis. Patients should be reassured that HBID is a benign inherited condition that will persist throughout life. There is no effective treatment. Reactive Lesions Chemical Desquamation Superficial chemical desquamation of oral mucosa occurs in response to exposure to chemical irritants present in mouth rinses and toothpastes, and it is also referred to as oral epitheliolysis. Harsher chemicals such as aspirin or other chemicals used in dentistry such as methacrylate cause more coagulations, erosions, and ulcers (irritant contact stomatitis) because of substantial inflammation and should be differentiated from superficial chemical desquamation. Chemical desquamation is induced by various irritants including, but not limited to, mouthwashes with high-alcohol content (such as Listerine (Johnson and Johnson, NJ, USA) and Pro-Health (Crest, Procter & Gamble Co., OH, USA) and strongly flavored toothpastes (Francalanci et al. 2000). Such caustic dentifrices can lead to coagulation and detachment of the most superficial 2 3 layers of epithelial cells which slough off yet leave behind intact thinner epithelium. In vitro studies have shown desquamation of human oral mucosa within 24 hrs following exposure to dentifrice resulting in an inflammatory response characterized by upregulation of IL-1β, downregulation of IL-8, and TNF-α secretion (Mostefaoui et al. 2002). Chemical desquamation is more common in adults because they tend to use dental products that have stronger additives. It presents as painless, wispy, gray-white threads, and membranous material that can be easily peeled off or spontaneously slough, leaving behind normal mucosa (Fig. 2). Chronic exposure may be associated with leukoedema or cheilitis.

5 White and Red Lesions of the Oral Mucosa 5 Fig. 2 Chemical desquamation from a mouth rinse: sloughing of the superficial layers of epithelium leaving behind normal-looking mucosa Lesions resolve on ceasing or changing the offending toothpaste or mouth rinse to a version without the offending chemical. Leukoedema Leukoedema, in its primary form, is common enough to be considered a variation of normal, with some studies reporting a prevalence of up to 90% especially in dark-skinned patients because of the color contrast between the milky-white leukoedema on darker mucosa. Leukoedema is the clinical term, while the pathologic process is keratinocyte edema. It is the result of fluid accumulation within keratinocytes, a process caused by mild local irritation, such as from cigarette or marijuana smoking, the use of some toothpastes and mouth rinses, and from physical trauma such as sucking (Heyl and Raubenheimer 1987). It is often seen at the periphery of contact desquamations or even frictional or factitial keratosis. Leukoedema is a condition of adults; however, it has been reported as early as 2 years of age in some patients and transiently in the sucking pads of infants (Madani and Kuperstein 2014). Its prevalence differs between gender and racial groups ranging from 0.96% to 90% of the population with the highest prevalence in African- American males (Madani and Kuperstein 2014; Pinto et al. 2014). Leukoedema presents as asymptomatic, white-gray translucent linear reticulations, most frequently seen on the buccal mucosa and to a lesser extent, the lip mucosa and ventral tongue. The complete disappearance of these pale reticulations upon stretching the mucosa (the so-called stretch test ) is a diagnostic feature (Fig. 3a, b). A biopsy is rarely necessary although the reticulations may be mistaken for those of lichen planus, prompting a biopsy. Stretching the mucosa and the disappearance of reticulations distinguish leukoedema from reticular lichen planus which is a keratotic lesion. The patient should be reassured as to the benign nature of the condition. If there is an associated smoking habit, it is a good opportunity to discuss habit cessation. Smokeless Tobacco Keratosis Smokeless tobacco (ST) keratosis describes oral changes caused by prolonged contact of the mucosa to ST products. This includes chewing

6 6 M. Jessri et al. Fig. 3 Leukoedema of right buccal mucosa. (a) Diffuse, filmy, slightly reticulated area on the right buccal mucosa. (b) Stretching the mucosa causes the lesion to disappear tobacco which takes several forms: loose leaf or shredded tobacco that may be sweetened and flavored, tobacco plug that also may be sweetened and sold as a compacted brick, or twist tobacco that is composed of tobacco leaves twisted into a rope from which sections can be bitten or cut off. Another common product is snuff composed of finely or coarsely ground, dry (that can be inhaled), or moist powdered tobacco (that is dipped ) and sold loose or in prepackaged sachets. Dissolvable tobacco tablets are also available. While the consumption rate of ST has remained stable among American women (1 in every 100), following a transient decrease between 1986 and 2000, ST is regaining popularity among American males (7 in every 100) (U.S 2014). In the 1980s, ST was thought to be strongly associated with the development of squamous cell carcinoma (Winn et al. 1981); however more recent studies have shown a low association (Rodu and Cole 2002). ST keratosis in its early stage is a form of contact irritation that develops at the site where the tobacco product is placed. Cessation of the habit leads to complete restoration of mucosa to its normal appearance. However, prolonged exposure for years may lead to the development of contact irritation lesion which is generally not reversible. Moist ST products with high alkalinity are more strongly associated with the development of contact irritation lesions. Although the term keratosis is conventionally used to describe this lesion, most ST lesions show predominantly edema of superficial epithelial cells often with only very focal or even no parakeratin formation. This is why many lesions resolve within days of habit cessation, especially in earlier stages of the condition. However, when leathery white plaques develop within these grayish edematous plaques after years or decades of use, the term leukoplakia could be applied despite its known etiology. The habit of using ST is particularly common among younger males (starting between 8 and 14 years of age) in many populations worldwide including North America, Northern Europe, and Asian countries. Early lesions appear as asymptomatic, soft, gray-white, poorly demarcated, edematous changes of the mucosa with parallel ridges, at the site of tobacco placement; lesions are not usually indurated or ulcerated (Fig. 4a, b). Common sites are the mandibular and maxillary vestibules. These lesions resolve within days to weeks of habit cessation. However, the use of ST at one site over years and decades may result in the development of well-demarcated, leathery, and often fissured white plaques of leukoplakia which will generally not resolve on discontinuation of the habit. Other oral changes associated with ST use include gingival recession, periodontal disease, caries, and occlusal wear (Kamath et al. 2014).

7 White and Red Lesions of the Oral Mucosa 7 Fig. 4 (a) Early smokeless tobacco lesion after 6 days of use: fissured, poorly demarcated slightly gray-white lesion of the lower lip and vestibule; there is no significant A biopsy is usually unnecessary but will show edema of superficial epithelial cells (similar to those seen in leukoedema) because of contact injury, while the mid- and lower epithelial cells are normal. However, once a leukoplakia has been established, the lesions should be biopsied to evaluate for dysplasia. Most ST lesions are readily diagnosed based on the history and clinical examination. The early gray-white and ridged lesions resolve with habit cessation within days to a few weeks. The dense white lesions of leukoplakia that develop after years of use generally do not resolve on habit cessation and have the potential for dysplasia and carcinoma similar to other leukoplakias. Pooled analysis of previous studies showed ST lesions have a weak association with oral cancer (OR = 1.81, 95% CI: 1.04, 3.17) compared with conventional cigarette smoking (Wyss et al. 2016). Morsicatio Mucosae Oris (Chronic Bite Keratosis) Morsicatio mucosae oris (MMO) or chronic bite/ frictional keratosis is a benign, trauma-induced lesion of the oral mucosa. MMO must be differentiated from leukoplakia which has malignant potential. keratosis. (b) Smokeless tobacco lesion showing poorly demarcated parallel pale gray-white ridges and folds in the vestibule (Courtesy of Dr. Jeffrey Stone, Lowell, MA, USA) As opposed to acute bite trauma which usually presents as an ulcer, MMO is caused by chronic trauma to the nonkeratinized mucosa that is usually associated with parafunctional habits, whether conscious or unconscious. This leads to parakeratosis and benign epithelial hyperplasia. This includes nibbling or sucking on the mucosa, as well as rubbing of the mucosa against dental prostheses or other hardware such as orthodontic braces and piercings. Similar lesions have been reported in the oral mucosa of the glassblowers (Schiodt et al. 1980). Its counterpart on the keratinized mucosa is benign alveolar ridge keratosis (see later). MMO is usually seen in individuals over the age of 35 and peaks in the fifth and sixth decades of life with a higher predilection for females (Woo and Lin 2009). The most common sites are the buccal mucosa (often appearing as an extension or accentuation of linea alba), the lateral/ventral tongue, and the lower lip mucosa. Most MMO lesions are bilateral, and more than half of patients do not report a history of such habits, or the habits may be nocturnal. The majority of cases present as asymptomatic, poorly demarcated, thickened, shaggy, white ragged papules and plaques that may be associated with focal areas of erythema or ulceration (Fig. 5a c). Often times, patients

8 8 M. Jessri et al. Fig. 5 Morsicatio mucosa oris (all images are from a single patient). (a) Poorly demarcated linear plaque along the bite line of the tongue. (b) Poorly demarcated red and white plaque along the linea alba region, with fading margins. (c) Poorly demarcated white papules and plaques of the right lower lip mucosa and contiguous buccal mucosa report being able to remove desquamated wisps of tissue from the surface of the lesion. A biopsy will exhibit histopathologic findings of reactive keratosis. MMO is a benign lesion, and patients should be reassured that these are reactive lesions usually caused by a parafunctional habit, whether conscious, unconscious, or nocturnal, with no malignant potential. However, all patients should have an examination of the muscles of mastication. Muscle tenderness suggests a clenching or bruxing habit with the potential for developing temporomandibular joint myofascial pain syndrome, and fabricating a night guard may be appropriate. However, using a habit-breaking device purely for managing MMO has not generally been successful in eradicating the lesions. Such devices themselves may cause the same frictional keratosis if the patient continues the habit and macerates the mucosa against the device. Benign Alveolar Ridge Keratosis Benign alveolar ridge keratosis (BARK) is a benign frictional/traumatic hyperkeratosis on keratinized alveolar ridge mucosa or the palatal mucosa (Natarajan and Woo 2008). Historically, BARK may have been classified under oral leukoplakia which implies potential for malignant transformation (Waldron and Shafer 1975; Napier et al. 2003). However, BARK is a distinct histopathologic and clinical entity that should be differentiated from other white keratinized lesions of the oral cavity and most importantly distinguished from leukoplakia because it has no malignant potential (Woo et al. 2014). It should also be

9 White and Red Lesions of the Oral Mucosa 9 Fig. 6 Benign alveolar ridge keratosis: poorly demarcated white plaque of the (a) right retromolar pad and (b) left retromolar pad differentiated from alveolar ridge keratosis which is not a specific histopathologic entity, but rather any keratotic lesion on the ridge, frictional, dysplastic, or cancerous (Chi et al. 2007). BARK is a benign, reactive lesion which results from mechanical trauma, likely from food crushed against the edentulous alveolar ridge mucosa. The oral mucosa responds with deposition of keratin and benign epithelial hyperplasia. It is the oral counterpart of the skin lesion, lichen simplex chronicus, a frictional/factitial keratosis, that shares similar histopathologic features. BARK is noted during the fifth to seventh decades of life, and males are more commonly affected (Natarajan and Woo 2008). It presents as an asymptomatic poorly demarcated white plaque, most commonly seen on the mandibular retromolar pad (often bilaterally), but also on the edentulous maxillary or mandibular alveolar ridge mucosa (Fig. 6a, b). The surface of a BARK lesion is often rough and slightly verrucous, which raises the specter of verrucous leukoplakia. A biopsy may be performed on suspicious lesions to establish the diagnosis, and the histopathologic features are specific. BARK is a benign lesion without potential for malignant transformation, and no treatment is required. Due to similarity in clinical presentation, BARK should be differentiated from leukoplakia which is a clinical entity that has malignant potential. Contact Stomatitis Lesions of contact stomatitis are red and/or white that are located where a known contactant has been placed. It can be divided into two main types: (a) Irritant contact stomatitis resulting from direct injury to the mucosa from an irritating substance placed against the mucosa, but with more damage than simple chemical desquamation (b) Allergic contact stomatitis or contact hypersensitivity reaction resulting from hypersensitivity to a component of the contactant A systemic hypersensitivity reaction to other agents such as foods or flavoring agents (such as phenolic compounds) is a different entity that may result in the swelling of the lip such as is seen in orofacial granulomatosis which is discussed elsewhere.

10 10 M. Jessri et al. Fig. 7 Contact stomatitis: (a) Diffuse, white translucent change of the ventral tongue in a female patient with year history of rinsing with 10% carbamide peroxide mouthwash. (b) Ventral tongue of the same patient, showing complete resolution of the lesion, 40 days after discontinuation of rinsing with 10% carbamide peroxide mouthwash Irritant contact stomatitis develops due to exposure of oral mucosa to a local chemical irritant that, depending on causticity, may lead to variable clinical findings. Long-standing contact with an irritant results in coagulation of the surface epithelial cells such as seen in smokeless tobacco lesions. More caustic agents such as aspirin, or dental materials such as methacrylate, lead to inflammation, erosion, and ulceration. Allergic contact stomatitis or contact hypersensitivity reaction develops as a result of a type IV hypersensitivity reaction to a contactant such as cinnamic aldehyde or peppermint in dentifrices and candies or mercury in amalgam restorations (Isaac-Renton et al. 2015). Irritant contact stomatitis is generally seen in adults because the pediatric population is unlikely to use strongly flavored dentifrices or smokeless tobacco or be involved in complex dental procedures. Mild irritant contact stomatitis may only result in patients sensing or observing a change in the color or texture of the mucosa, and patients may not seek care for this condition. An example is the asymptomatic, wrinkled, white lesions seen in smokeless tobacco use or reactive keratosis caused by mouthwash (Fig. 7a, b). For more caustic substances such as aspirin or methacrylate, changes develop within minutes to hours of contact. Erythema develops at the site of placement followed by variable gray-white changes from edema and coagulation of the epithelium and, depending on the length of exposure and strength of the contactant, painful ulceration (Spencer et al. 2016). This is usually easily diagnosed by taking a good history and correlating this with the clinical presentation; therefore a biopsy is not usually necessary. Allergic contact stomatitis or contact hypersensitivity reaction occurs in areas where there is direct contact with the offending agent, such as mucosal contact with amalgam, candies, or chewing gum. The area has a red and/or white macule or reticulated area that is poorly demarcated and that is usually sensitive or painful; ulcers may be present. One form of contact hypersensitivity reaction presents as desquamative gingivitis where the gingiva is diffusely bright red. A biopsy shows sheets of polyclonal plasma cells, and as such this condition is known as plasma cell gingivitis. In most cases, the diagnosis is readily arrived at because of the location and appearance of the lesion together with the history of contact with an offending agent. Removal of the offending contactant (such as replacing an amalgam with a composite restoration) may lead to resolution of the lesion. If in doubt, a biopsy should be performed to rule out other conditions such as

11 White and Red Lesions of the Oral Mucosa 11 Fig. 8 Nicotinic stomatitis: diffuse whiteness of the palatal mucosa with cobblestone appearance and red puncta (Courtesy of Dr. Ivan Stojanov, Case Western Reserve University, Cleveland, Ohio, USA) erythroleukoplakia. Contact hypersensitivity reactions may be lichenoid on histopathology. Irritant contact stomatitis: For chronic exposure to other mildly caustic substances, the lesions will resolve completely upon discontinuation of use of those products. If this is acute and caused by placement of aspirin or exposure to more caustic dental materials, topical steroid therapy (such as fluocinonide 0.05% gel or betamethasone dipropionate 0.05% ointment) may help to promote healing. Allergic contact stomatitis or contact hypersensitivity reaction: Once the biopsy has confirmed/established the nature of this lesion, removal of the contactant (such as amalgam) or cessation of the habit (such as eating candies or chewing gum) is a definitive therapy (Woo 2012). Topical steroids help resolve lesions more quickly, and topical anesthetics such as benzocaine help to ease pain. If the biopsy shows plasma cell stomatitis, patch testing may be helpful to identify the specific allergen. Nicotinic Stomatitis (Stomatitis Nicotina) Nicotinic stomatitis (NS) is an inflammatory condition of the hard palatal mucosa presenting as thickened and hyperkeratotic alteration of the palatal mucosa, commonly seen with pipe, cigar, or reverse smokers (Ramulu et al. 1973). Reverse smoking lesions which are the most severe form of nicotinic stomatitis have been classified by the WHO as an oral potentially malignant condition (Warnakulasuriya et al. 2007). NS is a misnomer because the lesions develop in response to the intense heat associated with smoking habits and not from nicotine. It is particularly prominent in reverse smokers because the heat from placing the lit end of the cigarette in the mouth is intense; this is a practice that is not infrequent in India and some Southeast Asian communities. It has also been reported in patients who habitually consume extremely hot beverages. As a result of chronic exposure to heat, the palatal mucosa becomes hyperkeratotic and thickened, and the orifices of excretory salivary ducts become inflamed. NS is more common in males in the fifth decade and older and is usually asymptomatic. The palatal mucosa is diffusedly whitened, and established lesions are fissured, with a cobblestone or dried mud appearance. The surface often contains scattered 1 3 mm, red punctuate papules that represent the inflamed orifices of minor salivary gland ducts (Fig. 8). Because these lesions are fairly uniform appearing and symmetric, any localized area that appears raised, warty, or fleshy must be viewed with suspicion and biopsied.

12 12 M. Jessri et al. Early NS lesions may regress on cessation of pipe smoking; however, patients with persistent lesions should be followed up regularly to monitor for malignant transformation, particularly reverse smokers (Saunders 1958; Alvarez Gomez et al. 2008; van der Eb et al. 1993). Hairy/Coated Tongue Hairy tongue (HT) is an acquired benign oral condition characterized by marked elongation of filiform papillae resulting in a hairlike appearance or a matted/coated appearance of the tongue dorsum. HT is caused by retention or accumulation of keratin on the filiform papillae and/reduced normal desquamation; the first is usually caused by dehydration and the second by poor diet (Manabe et al. 1999). In the first circumstance, patients have dry mouths where their salivary glands are producing less watery and more sticky, mucuscontaining viscid saliva so that keratin is retained. This is most frequently seen in patients who have salivary gland hyposalivation from taking anticholinergic medications, not drinking sufficient water, or with chronic anxiety or as a result of smoking tobacco. Less frequent causes of hyposalivation include head and neck radiation for cancer and Sjogren s syndrome. In the second circumstance, there is reduced mechanical desquamation of the keratin on the filiform papillae in individuals who consume mostly soft, processed foods and insufficient coarse foods such as fresh fruits and vegetables. This includes hospitalized patients, patients who are very ill, and those with poor diet. These lesions may be misdiagnosed as candidosis because of the whiteness of the tongue and because cultures may be positive for candida although that may merely represent normal oral carriage. HT is generally seen in adults because it is strongly associated with hyposalivation and chronic illness, and there may be a male predilection. It is usually asymptomatic and generally affects the anterior two-third of the tongue dorsum, sparing the lateral borders and the tip (Fig. 9a, b). These matted papillae may be stained by the natural color of foods, food dyes, tobacco, or pigment produced by pigment-producing bacteriae (chromogenic) on the tongue. Common Fig. 9 Hairy tongue. (a) Elongated yellow brown filiform papillae of the mid- and posterior dorsal tongue. (b) Two-month follow-up of the same patient after improving hydration and chewing fresh pineapple

13 White and Red Lesions of the Oral Mucosa 13 colors are brown, yellow, or black (hence, the term black HT). Prolonged contact with bismuth subsalicylate, an antacid, may also discolor the tongue dorsum (Gurvits and Tan 2014). Some patients report halitosis, dysgeusia, and/or a stale or metallic taste, symptoms that are often associated with a dry mouth (Gurvits and Tan 2014). The matted, hairy texture may cause gagging. If burning is present, the patient should be evaluated for oral candidosis which may look similar but will usually involve sites other than the tongue and does not usually have a diffuse, symmetric appearance on the tongue dorsum alone. This is particularly important in patients who are on antibiotics where it is important to distinguish between dehydration and/or poor oral intake from illness and the presentation associated with oral candidosis. HT is self-limiting with no serious sequelae, and patients should be reassured that they do not have an infection. Improved hydration, eating a diet containing fresh fruits and vegetables, and reducing habits that cause dehydration of the mucosa (such as smoking and using alcoholic mouth rinses) will improve this condition. Brushing the tongue gently with a soft toothbrush or gentle use of a tongue scraper helps to remove the retained keratin and promote desquamation, but should be used sparingly so as not to cause further irritation to the dorsal tongue epithelium. Anecdotal evidence suggests that eating acidic and fibrous foods such as pineapple may also reduce keratin retention, while brushing the tongue with diluted sodium hypochlorite solution can also be effective. Infections Candidosis Candidosis is the most common fungal infection in the mouth. Oral candidosis is most commonly caused by Candida albicans. This organism can be isolated from the oral cavity of 30 50% of the asymptomatic dentate population; this prevalence likely increases with age. This merely indicates carriage, and hence a positive carriage culture in the absence of clinical manifestations should not be interpreted as representative of an active infection (Tejani et al. 2016). Predisposing factors for candidosis include (a) alterations in the local environment, such as hyposalivation and use of topical steroids; (b) alterations in the systemic environment, such as use of systemic antibiotics and immunosuppressive agents; diabetes mellitus; hematinic deficiencies; intrinsic immunodeficiency syndromes or acquired immunodeficiency such as HIV/AIDS; and 3) positive candidal carriage. Other members of the Candida genus that can affect the oral cavity include C. guilliermondii, C. tropicalis, C. dubliniensis, C. krusei, and C. parapsilosis; however, they are less common in the general population and are more frequently seen in patients with HIV/AIDS. Candidosis occurs across a broad age range depending on clinical circumstances as outlined above. Patients may be asymptomatic but more often present with sensitivity and a burning sensation, or even pain, and sometimes dysgeusia (Sharon and Fazel 2010). Several clinical manifestations exist as follows: Pseudomembranous candidosis or thrush: This presents as white, curdy papules and plaques composed of tangled hyphae, yeast, and desquamated epithelial cells (Fig. 10a). These adherent papules and plaques may or may not be scraped off the mucosal surface leaving behind erythematous, often bleeding mucosa. Pseudomembranous candidosis often occurs after antibiotic therapy or high-dose steroid therapy in susceptible individuals and is common in those with HIV/AIDS (Reichart et al. 2000). When lesions are present diffusely on the tongue dorsum, they autoinoculate the palatal mucosa, and these are referred to as kissing lesions.

14 14 M. Jessri et al. Fig. 10 (a) Pseudomembranous candidosis: white plaques and papules and erythema involving the hard and soft palate. (b) Erythematous candidosis: erythema of the palatal mucosa beneath a denture. (c) Median rhomboid glossitis and angular cheilitis in an edentulous after antibiotic therapy. (d) Angular cheilitis: erythematous, macerated areas at the commissures Erythematous candidosis: As the name implies, it presents as erythematous, raw-appearing lesions of the oral mucosa and has been further subclassified based on the clinical presentation, anatomical site, or etiology as follows: Denture stomatitis or chronic atrophic candidosis characterized by sensitive or painful, well-delineated erythema limited to the denture-bearing areas, more commonly seen on the palatal mucosa (Fig. 10b). Median rhomboid glossitis or central papillary atrophy of the midline of the dorsum of the tongue characterized by an often ovoid area of depapillation and erythema just anterior to the foramen cecum (Fig. 10c). Angular cheilitis characterized by painful erythema and fissuring of the corners of the mouth (Fig. 10d). Reduced vertical dimension leads to dampness and maceration predisposing to candidal growth in this particular form of candidosis. This is often exacerbated by preexisting iron or vitamin B12 deficiency. This form of candidosis is often associated with concomitant infection with Staphylococcus aureus (Ohman et al. 1986; Smith et al. 2003). Hyperplastic candidosis: It presents as asymptomatic white plaques that cannot be scraped off. It is more common in the anterior buccal mucosa and lateral tongue. Hyperplastic candidosis may be associated with endocrinopathies and hairy leukoplakia.

15 White and Red Lesions of the Oral Mucosa 15 The diagnosis is usually established by the clinical appearance of the lesion or by identifying hyphae through a scrape and potassium hydroxide preparation or by cytologic examination. A biopsy is not usually necessary, but if performed, hyphae are readily identified. Topical and systemic antifungal medications are discussed elsewhere, including management of prostheses which act as fomites. In brief, topical therapy includes nystatin rinses and pastilles, clotrimazole and miconazole troches, and, in some countries, topical amphotericin. Combinations of antifungal agents and a topical steroid (such as nystatin and triamcinolone or clotrimazole and betamethasone) are useful for atrophic candidiasis related to dentures and for angular cheilitis. Treatment of concomitant Staphylococcus infections is with topical erythromycin. Systemic therapy includes fluconazole. Patients with recalcitrant disease should be evaluated for systemic disease such as diabetes mellitus or even HIV/AIDS. In patients treated with long-term systemic steroids or with recurrent infection episodes, prophylaxis regimens should be considered. Drug resistance to fluconazole may develop in patients on long-term antifungal therapy, and other agents include voriconazole, itraconazole, posaconazole, and echinocandins. Oral Hairy Leukoplakia Oral hairy leukoplakia (OHL) is a benign condition of the tongue caused by Epstein-Barr virus (EBV) and is most frequently seen in immunocompromised patients such as those with HIV/AIDS as well as in patients on immunosuppressive therapy such as organ transplant recipients (Bhayat et al. 2010). However, OHL has also been reported in immunocompetent individuals (Greenspan et al. 2016). OHL is caused by EBV infection within the mucosal epithelium, and biopsies show the presence of EBV-encoded RNA within the nuclei of epithelial cells. The current theory or etiopathogenesis suggests initial infection of basal epithelial cells with EBV followed by replication of EBV in the epithelial cells and B cells (Slots et al. 2006). Circulating cytotoxic T cells function to maintain a latent state of the virus during this process. In immunocompromised and immunosenescent patients, there is a natural decrease in the numbers of cytotoxic T cells leading to active replication and circulation of EBV-infected B cells (Slots et al. 2006). OHL in HIV/AIDS is generally seen in the fourth decade of life, and males are affected more frequently (male-to-female ratio 4:1) (Dongo et al. 2013; Stojanov and Woo 2015). Men who have sex with men with HIV seropositivity have the highest prevalence of OHL. OHL presents most frequently on the lateral borders of the tongue as an asymptomatic, white, adherent plaque with linear folds that run parallel to the long axis of the lateral tongue (Fig. 11). Other sites include the buccal mucosa, and lesions are generally bilateral. OHL is diagnosed by biopsy and confirmation of the presence of EBV by in situ hybridization studies. Oftentimes, there is secondary candidosis noted on the biopsy. OHL is a benign lesion and may be the first sign of HIV infection. As such, all patients carrying this diagnosis who are not known to be immunocompromised should have an HIV test and be evaluated for latent immunocompromise. Lesions resolve with antiretroviral therapy. Treatment with systemic valaciclovir and topical treatments such as 25% podophyllin resin, 1% penciclovir, or 5% acyclovir have shown some benefits (Walling et al. 2003; Moura et al. 2010). In patients with iatrogenic immunosuppression, OHL may resolve on reduction of immunosuppression. Candidosis should be treated with antifungal agents.

16 16 M. Jessri et al. Fig. 11 Hairy leukoplakia: white, adherent plaque with linear folds running parallel to the long axis of the left lateral tongue Immune-Mediated and Autoimmune Conditions Benign Migratory Glossitis (Geographic Tongue, Erythema Areata Migrans, Migratory Stomatitis) Benign migratory glossitis (BMG) is a chronic, benign inflammatory condition of the tongue characterized by relapsing-recurring loss of filiform papillae; it affects 1 2% of the population (Jainkittivong and Langlais 2005). Patients may seek professional advice because of the unusual appearance of the tongue or increased sensitivity of their mucosa to spicy or acidic food. The exact pathophysiology of BMG is unknown. However, it often occurs in atopic patients, namely, those with or have a history of asthma, eczema, hay fever, food sensitivities, and other allergies (Goregen et al. 2010). In the absence of atopy in the patient, a positive history of such conditions may be elicited in firstdegree relatives. It is also associated with psoriasis (especially the generalized pustular form) and Reiter disease. BMG lesions tend to flare when patients are under stress or are ill (Miloglu et al. 2009). BMG affects a wide age range; while some report it to occur mostly in individuals over the age of 40, others deem it to be more frequent in children with a decreasing prevalence with increasing age (Banoczy et al. 1975; Assimakopoulos et al. 2002). BMG has a female predilection (1.5:1), and patients may be asymptomatic or experience burning, soreness, and/or sensitivity especially upon eating acidic and spicy foods. It most frequently presents on the dorsal or ventral tongue. BMG typically begins as one or more depapillated areas on the dorsal tongue which enlarge to form slightly depressed, red patches with a white surrounding rim giving rise to an annular or circinate appearance. This results in a map-like pattern, hence the name geographic tongue (Fig. 12a, b). It is self-limiting and heals within a few days with a variable period of quiescence before it recurs. When sites other than the tongue such as the lip mucosa, floor of the mouth, or soft palate are affected, it is referred to as migratory stomatitis or stomatitis areata migrans (Fig. 12c). A biopsy is usually unnecessary if the history is typical but may be performed to confirm the diagnosis. If BMG is asymptomatic, no treatment is indicated, and patients should be provided information and reassurance. Symptomatic BMG lesions

17 White and Red Lesions of the Oral Mucosa 17 Fig. 12 (a) Benign migratory glossitis characterized by macular erythema with atrophy of filiform papillae and slightly elevated white, circinate borders. (b) Benign migratory glossitis characterized by patchy depapillation of the dorsum with only faint white rim. (c) Migratory stomatitis: white circular and linear lesions of the lower lip mucosa may be managed with 2% viscous lidocaine and/or liquid diphenhydramine in equal volumes for symptom control. Other agents may include topical steroids and antifungal medications. More severe cases may be treated with topical steroid rinses such as dexamethasone oral rinse or steroid gels and creams. Desquamative Gingivitis Desquamative gingivitis is a descriptive term that refers to gingival erythema that is usually diffuse, sometimes with noticeable peeling of gingival tissues. It is a clinical finding that has been associated with several disorders, some of which may represent true desquamation and loss of epithelium. Desquamative gingivitis is a clinical finding resulting from three main classes of disorders including: 1. Lichen planus or lichenoid mucositis 2. Autoimmune vesiculobullous disorders and,in particular, mucous membrane pemphigoid and less often pemphigus vulgaris (Scully and Porter 1997; Lo Russo et al. 2008) 3. Contact hypersensitivity reaction (such as plasma cell gingivitis which is often associated

18 18 M. Jessri et al. Fig. 13 Desquamative gingivitis: (a) diffuse erythema of the buccal attached gingiva without striations in a patient with lichen planus. (b) Diffuse erythema of the buccal attached gingiva in mucous membrane pemphigoid and (c) localized erythema of the buccal attached interproximal gingiva of the upper left central and lateral incisor teeth in a patient with pemphigus vulgaris with exposure to contactants such as flavoring agents in candies, chewing gum, or dentifrices) Of the three entities, lichen planus is the most common, and most patients experience mild to moderate oral sensitivity, pain, and bleeding on brushing (Lo Russo et al. 2009). Lichen planus, lichenoid lesions, and mucous membrane pemphigoid tend to occur in middle-aged females. Because of pain on brushing, there may be abundant materia alba on the teeth leading to even more inflammation and erythema. Desquamative gingivitis presents as brightly erythematous macular and/or diffuse areas of marginal and attached gingiva, usually on the buccal aspect, although the palatal and lingual gingivae may also be affected (Fig. 13a c). Ulcers and heaped-up remnants of ruptured bullae may be present at the edges of erythema. In most cases, patients are referred for biopsy or management because good plaque control has not resulted in resolution of lesions. A biopsy should be obtained from peri-lesional tissue; half should be sent in formalin for routine histopathologic examination, and the other half should be submitted either fresh if in a medical center or in Michel medium if the tissue is mailed, for direct immunofluorescence studies (Suresh and Neiders 2012). The histopathologic features vary depending on the diagnosis. In general, if the patient already has had a skin biopsy and a known diagnosis of a blistering disorder, it is usually unnecessary to perform an oral biopsy.

19 White and Red Lesions of the Oral Mucosa 19 Fig. 14 Plasma cell gingivostomatitis: manifesting as generalized moderate facial gingival erythema with mild edema in a 32-year-old female Management is directed toward treating the underlying condition. Patients should avoid the offending contactant if the diagnosis is contact hypersensitivity reaction. Management of lichen planus and autoimmune disorders is generally with topical steroids. This may be applied directly onto the mucosa or within custom trays. Intralesional steroid injections are helpful for large ulcers, and systemic therapy may be appropriate for more severe disease; this is discussed in the relevant chapters. Plasma Cell Gingivostomatitis (Plasma Cell Orificial Mucositis) Plasma cell gingivitis (PCG) also known as allergic gingivostomatitis is a rare, yet distinctive, benign inflammatory condition characterized by extensive infiltration of plasma cells within the connective tissue of the oral mucosa. The first cluster of cases was caused by hypersensitivity to a component of chewing gum (Kerr et al. 1971). Since then, flavoring agents such as cinnamaldehyde in chewing gum and toothpastes, mint candy, and herbs and spices have also been recognized as causative factors (Anil 2007). This is a condition of adults with no gender predilection. Patients report soreness and sensitivity especially on eating acidic and spicy foods and sometimes on brushing their teeth. The marginal and attached gingiva presents with diffuse, bright erythema with swelling, edema, and loss of stippling similar to the findings in desquamative gingivitis. Gingival bleeding is common because the epithelium is eroded and inflamed (Fig. 14). Although the gingiva is the most common site of involvement, other oral mucosal sites such as the buccal and palatal mucosa as well as extraoral sites such as the pharyngeal mucosa may also be affected. Conditions such as erythematous/erosive gingival lichen planus and mucous membrane pemphigoid, or even leukemia, may have the same clinical presentation. As such, a biopsy is always required to establish the diagnosis, and this shows sheets of polyclonal plasma cells. Similar to other hypersensitivity conditions, identifying the causative agent is of prime importance, and patch testing may be useful. Patients should keep a diary of possible exposures, especially to flavoring agents, and whether avoidance resolves lesions. Treatment modalities include topical and systemic steroids (Solomon et al. 2008). However, lesions will persist as long as the patient is exposed to the antigen. In cases of gross gingival enlargement (plasma cell granuloma), surgical excision is indicated for plaque control, followed by topical steroids.

20 20 M. Jessri et al. Oral Lichen Planus Lichen planus (LP) is a common chronic mucocutaneous condition that may affect the oral mucosa in more than half of the affected individuals (Altman and Perry 1961; Cheng et al. 2016). While concomitant presentation of cutaneous and oral LP is common, only 10 15% of patients with oral LP develop cutaneous lesions (Cheng et al. 2016). Vulovaginal-gingival and peno-gingival LP is a subgroup of LP collectively referred to as gingival-genital syndrome that is associated with HLA-DQB1*0201. This condition presents with desquamative gingivitis and often runs a more severe course sometimes with buccal mucosa fibrosis (Setterfield et al. 2006). LP is an immune-mediated condition in which basal cells are destroyed by cytotoxic CD8+ T cells (Lavanya et al. 2011). Although some consider oral LP to be an autoimmune disease, the target antigen has yet to be identified. Oral LP may be idiopathic, but lichenoid mucosal reactions indistinguishable from idiopathic LP may be seen in other conditions including: 1. Drug-induced hypersensitivity reactions to medications such as antihypertensive agents, including β-blockers, angiotensin-converting enzyme inhibitors, and diuretics (in particular hydrochlorothiazide) and nonsteroidal anti-inflammatory drugs (Yuan and Woo 2015) 2. Hepatitis C especially in patients with HLA-DR6 living around the Mediterranean Sea (Carrozzo et al. 2005) 3. Contact hypersensitivity to amalgam restorations 4. Chronic graft versus host disease 5. Thyroid disease (or medications to treat thyroid disease) (Garcia-Pola et al. 2016) Because oral LP may be associated with a variety of other conditions, some authorities suggest that oral LP is not a single specific disease but rather a mucosal reaction with a characteristic clinical and histopathologic phenotype. Oral LP is more commonly seen in women (male/ female 1:2 3) in the sixth decade (De Rossi and Ciarrocca 2014). The WHO diagnostic criteria for lichen planus was modified in 2003 and again in 2016 (van der Meij and van der Waal 2003; Cheng et al. 2016). Typical oral LP is almost always bilateral and symmetric and affects the buccal mucosa, tongue, and attached gingiva. Lesions may be classified into the following, often overlapping categories: Reticular/keratotic (classic) oral LP is characterized by mostly asymptomatic white intersecting loops and lines forming Wickham striae or papules on a variably erythematous background (Cheng et al. 2016). Lesions are generally bilateral and involve the buccal mucosa, tongue dorsum and ventrum, lip mucosa, and gingiva; this may be associated with erythema (Fig. 15a c). Erythematous/erosive oral LP frequently involves the gingiva and presents as red, erythematous areas of mostly buccal (and less commonly palatal and lingual) gingiva which is commonly referred to as desquamative gingivitis (Fig. 13a). Ulcerative oral LP presents as ulcerated oral mucosa with a yellow fibrin membrane usually with a surrounding erythematous rim and subtle peripheral reticulations (Fig. 16a d). Atrophic oral LP is best seen on the tongue dorsum where there is loss of the filiform and fungiform papillae and there is diffuse keratosis or white papules. Bullous oral LP is extremely rare, and most bullae break down to form erythematous/erosive oral LP. Oral LP that presents with bilateral, symmetric striations occurring at the typical oral sites may not require biopsy. Cases that are asymmetric with questionable striations should be biopsied, and erythematous/erosive lesions presenting as desquamative gingivitis should also have a portion of the biopsy submitted for direct immunofluorescence studies to rule out mucous membrane pemphigoid and other autoimmune

21 White and Red Lesions of the Oral Mucosa 21 Fig. 15 Reticular lichen planus of (a) right buccal mucosa, (b) left buccal mucosa, and (c) dorsum of the tongue presenting primarily as poorly demarcated keratotic papules vesiculobullous disorders. Plaque-type oral LP occurring as a solitary white plaque or a plaque within more typical oral LP should be viewed with suspicion, and biopsy is always indicated. It should be noted that many oral dysplasias present with a histopathologic features of lichenoid inflammatory infiltrate, but this should not be automatically construed as dysplasia arising in oral LP. Symptomatic cases are managed with topical steroid gels, creams, and rinses. More severe cases may require systemic steroid therapy in conjunction with hydroxychloroquine, mycophenolate mofetil, or tumor necrosis factor inhibitors. In cases of oral contact lichenoid hypersensitivity reactions, removal of the causative agent such as an amalgam restoration may resolve the lesions (Yuan and Woo 2015). Malignant transformation has been reported in % of oral LP although some of such cases had a history of smoking. Lupus Erythematosus Systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE), and subacute cutaneous lupus erythematosus (SCLE) are subsets of lupus erythematosus (LE) which is a chronic multisystemic autoimmune disorder that often presents with oral lesions (Nico et al. 2011; Tsokos 2011; Ranginwala et al. 2012). LE is an autoimmune disease, and a combination of genetic, hormonal, and environmental factors (e.g., smoking and exposure to ultraviolet light) may contribute to its development or progression (Tsokos 2011). Genetic predisposition plays a pivotal role in pathogenesis of LE, and this includes single-gene deficiencies that affect the immune system (Rullo and Tsao 2013). Antibodies produced in this condition target doublestranded DNA, histones, and ribonucleoproteins and are deposited in several organs including the

22 22 M. Jessri et al. Fig. 16 Ulcerative lichen planus (all images are from a single patient): reticulated, erythematous, and ulcerated (yellow fibrin membrane) of the bilateral hard palate (a and b) and buccal mucosa (c and d) kidney, liver, joints, skin, and mucous membrane resulting in protean clinical presentations (Ippolito et al. 2011). LE generally affects women of childbearing age (female:male 8 10:1) (Tsokos 2011). The oral mucosa can be affected in the absence of skin lesions in up to 20% of patients with DLE and 45% of patients with SLE (Lourenco et al. 2007; Nico et al. 2008). Involvement of oral mucosa is not a common finding in SCLE, and this has been attributed to the important role of UV light in pathogenesis of SCLE (Sontheimer 2005). Extraoral presentations of SLE in the head and neck area include a photodistributed or butterfly rash on the malar region, corresponding to the area of the face that is mostly exposed to the UV light. Cutaneous lesions of DLE present as atrophic plaques with follicular plugging and evidence of post-inflammatory hyperpigmentation. SCLE is the most photosensitive subtype of LE, and lesions mostly involve the sun-exposed area of the skin in the V-area of the neck, upper trunk, dorsum of the hands, and the shoulders (Sontheimer 2005). Oral lesions of LE cause pain and sensitivity and present as aphthous-like ulcers or poorly demarcated, red and white, reticulated lesions of the buccal, lip, and palatal mucosa (Lourenco et al. 2007) (Fig. 17a, b). An incisional biopsy and direct immunofluorescence studies are required to confirm the diagnosis. Granular deposition of IgG, IgM, and/or IgA at the basement membrane zone in biopsies taken from clinically normal skin for SLE, and taken from lesional tissue in DLE, is diagnostic (lupus band test). Serology is often positive for antinuclear antibody, anti-dsdna, anti-smith, anti-ribonucleoproteins, and anti-ssa. Oral lesions can generally be managed with topical steroids such as clobetasol or fluocinonide if

23 White and Red Lesions of the Oral Mucosa 23 Fig. 17 Oral presentation of lupus erythematous (both images are from a single patient). (a) Erythema with slight surrounding faint white reticulated lesion of the right hard palatal and (b) white reticulations and erythema of the left buccal mucosa lesions are localized, by steroid rinses such as dexamethasone, or by intralesional steroid injections. Systemic therapy is generally initiated and maintained by the patient s dermatologist or rheumatologist. Oral Graft Versus Host Disease Graft versus host disease (GVHD) is an immunemediated, multi-organ complication that occurs after allogenic hematopoietic cell transplantation (allo-hct) used for the treatment of hematological malignancies and diseases resulting in bone marrow failure (such as aplastic anemia). Historically GVHD was classified into acute and chronic categories based on time from transplantation, with acute GVHD occurring within the first 100 days posttransplantation and chronic GVHD as an extension of acute GVHD or developing de novo after 100 days. Current thinking, however, suggests that acute and chronic GVHD have distinct etiologies and clinical manifestations (Pavletic and Fowler 2012). Disparity in human leukocyte antigens (HLAs) between the donor and recipient is the most important risk factor for developing GVHD because of an alloimmune response by the donor s immune cells against the surface antigens of the recipient s cells which are mismatched (Vogelsang et al. 2003). The current guidelines recommend 8/8 match between donor and recipient HLA-A, HLA-B, HLA-C, and HLA-DRB loci (Lee et al. 2007b). Other factors such as sex, recipient s advanced age, source of progenitor cells, and intensity of conditioning regimen may also affect the severity of GVHD. Tissue damage from chemotherapy and radiation therapy during pretransplantation conditioning, infection, and immunosuppressive therapy results in the activation of antigen-presenting cells. Presentation of mismatched cell surface host antigens leads to activation and clonal expansion of donor lymphocytes which culminates in tissue destruction through pro-inflammatory cytokine production, resulting in acute GVHD which is an exaggerated inflammatory response (Ferrara et al. 2009). The pathophysiology of chronic GVHD is poorly understood. One theory proposes chronic GVHD to be an end-stage presentation of alloreactivity in which donor T cells have differentiated into Th2 cells causing activation of B cells and production of autoantibodies. Alternatively, it has been postulated that poor/dysfunctional immunologic recovery results in altered selftolerance (Kataoka et al. 2001). Acute oral GVHD: This tends to occur within days to weeks of engraftment with erythroderma and sometimes skin blistering. The liver is often

24 24 M. Jessri et al. affected leading to jaundice, and involvement of the gastrointestinal tract leads to abdominal pain and diarrhea (Ion et al. 2014). The oral mucosa is affected in less than 10% of patients with a median age of 49 years and a 2:1 male-to-female ratio (Ion et al. 2014). Patients report pain, sensitivity, or a burning sensation. It is characterized by marked oral mucosal erythema and/or desquamation often accompanied by ulcers and resembles chemotherapy and neutropenic ulcers except that (1) the keratinized tissues of the hard palatal mucosa and tongue dorsum are often affected and (2) patients are engrafted and no longer neutropenic. A skin biopsy establishes the diagnosis, although hypersensitivity to medications is an important differential diagnosis. Chronic oral GVHD: Lichenoid and sclerodermatous skin involvement, keratoconjunctivitis sicca, liver disease, obstructive lung disease, gastrointestinal disease, and genital disease with fibrosis are frequently encountered. Unlike acute GVHD, the oral mucosa is affected in 50 70% of patients with chronic GVHD (Mays et al. 2013). Patients may present with sensitivity, pain, and burning of the mucosa. There is both xerostomia and hyposalivation caused by destruction of salivary gland parenchyma. The National Institutes of Health (NIH) has devised clinical and histopathological criteria for scoring chronic GVHD for standardization of diagnosis (Treister et al. 2010). The diagnosis is usually made on clinical evaluation alone, and a biopsy is not usually necessary. Oral chronic GVHD has three common findings: (a) Mucosal lesions that are lichen planus-like with lacey, white reticulations, erythema, and ulcerations. The most common sites are the buccal mucosa, lip mucosa, and tongue mucosa although any mucosa may be involved (Fig. 18a c). (b) Superficial mucoceles of the palatal and buccal mucosa which are occasionally symptomatic (Fig. 19). (c) Dry mucosa with little to no floor-of-mouth pooling. Less frequent findings include: (a) Scarring and fibrosis leading to trismus and loss of the vestibule, especially in longstanding disease (b) Rampant caries from hyposalivation (c) Development of oral dysplasia and squamous cell carcinoma likely due to chronic immunosuppression As with other similar lesions in the mouth, these take the form of leukoplakia and its variants, erythroplakia, ulcers, and mass lesions. The risk of developing secondary cancer is greater in patients surviving 10 or more years after allo- HCT transplant (Demarosi et al. 2005). and Future Directions Acute GVHD is managed with calcineurin inhibitors (cyclosporine or tacrolimus), high-dose steroids, sirolimus, and mycophenolate mofetil. Chronic GVHD of the oral mucosa is usually successfully managed with a combination of topical steroids, topical tacrolimus, intralesional steroid injections, and/or systemic steroids and immunosuppressive therapy, depending on the severity of oral disease and the extent of involvement of the skin and other organ systems. Ulcers should be cultured to rule out herpes simplex virus infection. Hyposalivation is managed with frequent sips of water, and cholinergic agents, such as pilocarpine and cevimeline, and topical fluoride applications are helpful for the prevention of caries. Scarring and trismus can be managed with stretching exercises with/without stretching devices, intralesional steroid injections, and surgery to release fibrotic bands. Regular follow-up is essential for early detection of dysplasia and squamous cell carcinoma. There is ongoing research into managing GVHD by using targeted therapies to reduce cytokine production, modulate the activity of antigenpresenting cells, and control T-cell numbers and activity.

25 White and Red Lesions of the Oral Mucosa 25 Fig. 18 Oral chronic graft versus host disease (all images are from a single patient). (a) Diffuse erythema involving more than 75% of the right buccal mucosa. (b) Diffuse erythema and linear ulceration of the left buccal mucosa. (c) Erythematous and diffuse keratotic changes of the hard palate with multiple superficial mucoceles (Courtesy of Dr. Nathaniel Treister, Harvard School of Dental Medicine, Boston, MA, USA) Erythema Multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction with mucocutaneous manifestations. It is considered distinct from Stevens-Johnson syndrome and toxic epidermal necrolysis which are necrolytic syndromes with the latter being the more severe form (Bastuji-Garin et al. 1993). Fig. 19 Superficial mucocele (arrow) on the hard palatal mucosa of a patient with oral chronic graft versus host disease EM is a hypersensitivity reaction primarily to an infectious agent with more than 70% of cases associated with herpes simplex virus (HSV) infection, as well as with M. pneumonia infection usually in children (Sun et al. 2003; Schalock et al. 2006). Hypersensitivity to medications such as antibiotics (e.g., penicillins and sulfonamides), anticonvulsants (phenytoin), or analgesics (NSAIDs) forms a minority of cases (Sanchis

26 26 M. Jessri et al. et al. 2010; Langley et al. 2016). Asymptomatic (subclinical) reactivation of HSV may also cause this condition. In addition, some have considered a role for genetic predisposition to EM with HLA DQ3, HLA-B35, HLA-A33, HLA-DR53, and HLA-DQB1*030 being associated with recurrent EM (Schofield et al. 1994). Adults between the age of 20 and 40 are most commonly affected, with 20% of the cases occurring in children with a slight predilection for females. As discussed above, a large proportion of patients have a recent history of HSV infection. EM is categorized into minor and major types and chronic recurrent oral erythema multiforme. In minor EM, there is little-to-no mucous membrane and minimal (10%) skin involvement; the major type however is characterized with more extensive mucous membrane and skin involvement. Chronic recurrent oral EM is nearly always associated with HSV infection, and patients may experience several episodes a year (Farthing et al. 2005). Erythematous pruritic papules appear on the skin of the extremities, some of which develop typical target, bull s eye, or iris lesions. Such lesions are generally less than 3 cm in diameter and are composed of a central necrotic and erythematous disc surrounded by a pale edematous ring and an outer circle of dusky erythema (Auquier-Dunant et al. 2002). Cutaneous lesions progress centripetally to involve the trunk. The oral mucosa is affected in 20 70% of patients, and these present as painful ovoid or irregular ulcers on any mucosal surface with a background of moderate to severe erythema. Hemorrhagic crusts of the lip vermilion are a common but are not an invariable finding (Fig. 20a d) (Farthing et al. 2005). While cultures for HSV are usually negative in EM patients, elevated serum IgM and IgG (at least four times over baseline) to HSV is supportive of the diagnosis. Lesional tissue may also be positive by polymerase chain reaction for HSV. For the diagnosis of M. pneumonia, detection of IgM for plasma membrane antigens protein 1 and protein 116 by enzyme immunoassay is the most sensitive (Lee et al. 2017). A careful history taking and bloodwork as mentioned above are essential for establishing whether the trigger is infectious or medication-induced. EM is self-limiting and, management is directed toward pain control with topical anesthetics and analgesics, supportive care such as hydration, and promotion of healing of mucocutaneous lesions with topical and/or systemic steroids. Daily antiviral therapy has been shown to prevent recurrent EM in patients with viral trigger, and this in itself may be a useful diagnostic tool (Tatnall et al. 1995). Precancerous and Cancerous Lesions Leukoplakia and Proliferative Verrucous Leukoplakia Leukoplakia is a clinical diagnosis defined by WHO as a white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for oral cancer (Warnakulasuriya et al. 2007). It is the most common premalignant (potentially malignant) condition of the oral cavity. Because all other known disorders that carry no increased risk for oral cancer must be ruled out, the diagnosis of leukoplakia is, by definition, one of exclusion. While some lesions may be ruled out on clinical features alone, others will require a biopsy for definitive diagnosis. Many conditions already discussed earlier in this chapter are white but not leukoplakias. Approximately 40% of true leukoplakias show histologic evidence of dysplasia, carcinoma in situ, or invasive squamous cell carcinoma (SCC). The other 60% will show hyperkeratosis or parakeratosis, acanthosis, or atrophy, with or without inflammation; these have been given the name keratosis of unknown significance (KUS). Risk factors for the development of intraoral leukoplakia are similar to those for oral SCC and as such include cigarette smoking, excessive alcohol consumption, areca nut use, personal or familial history of cancer or cancer therapy, chronic

27 White and Red Lesions of the Oral Mucosa 27 Fig. 20 Recurrent erythema multiforme secondary to reaction to fluconazole (all images are from a single patient): (a) crusting of the upper lip with ulceration of the wet-dry border of the upper lip, extending to upper labial mucosa. (b) Ulceration of the right hard palate with diffuse erythema. (c) Erythema and ulceration of the tongue dorsum. (d) Ulceration of the right ventral tongue immunosuppression, age, and some syndromes (such as dyskeratosis congenita). Other risk factors include ultraviolet light damage for lesions of the vermilion and human papillomavirus in a small number of cases (Bagan et al. 2010; Woo et al. 2013). Regardless of histologic grade, oral leukoplakia has a heterogeneous molecular profile and exhibits loss of heterozygosity at 3p and/or 9p which is associated with an increased risk of malignant transformation (Rosin et al. 2000; Lingen et al. 2011; Gomes et al. 2015). Aneuploidy and hypermethylation have been reported in oral dysplastic lesions, and aneuploidy has been positively associated with higher histopathologic grade of dysplasia (Lingen et al. 2011). Mutation and loss of heterozygosity of TP53 and loss or overexpression of p53 is a frequent molecular finding in dysplastic leukoplakias (Rosin et al. 2000; Lingen et al. 2011). Although inactivating mutations in TP53 are generally considered driver mutations in carcinogenesis, overexpression of p53 is due to stabilizing mutations in the gene that prolongs the half-life of the protein (Lingen et al. 2011). Overexpression of matrix metalloproteinase 1 and 9 mrna has also been associated with the progressive phenotype of dysplastic lesions (Jordan et al. 2004). Leukoplakia most often presents as a solitary localized white plaque and less commonly as multifocal or extensive lesions that affect contiguous sites. Oral localized leukoplakia (OLL): OLL constitutes 85% of all oral potentially malignant disorders with a global prevalence of 2 4%. It usually affects individuals in the sixth decade of

28 28 M. Jessri et al. life or older, with increasing prevalence with increasing age. The male/female is approximately 2 3:1, and 38 62% of lesions occur in smokers (Woo et al. 2014; Maia et al. 2016; Naveen- Kumar et al. 2016). It is generally asymptomatic, and the tongue, gingiva, buccal mucosa, and palatal mucosa are the most commonly affected sites (Liu et al. 2012). Leukoplakia is classified as follows: 1. Homogenous leukoplakia. This presents as a well-demarcated, uniform white plaque that is often fissured (Fig. 21a). 2. Nonhomogenous leukoplakia. This takes several forms. a. Verrucous leukoplakia which has, at least focally, a rough surface and may be leathery in appearance; this also tends to have a welldemarcated border and often occurs on the gingiva (Fig. 21b). b. Nodular leukoplakia which has, at least focally, a nodular surface and is also well demarcated, although this may be difficult to distinguish from, or coexist with, verrucous leukoplakia, and it may be useful to combine verrucous and nodular leukoplakia into a single category. c. Erythroleukoplakia. This has areas of erythema within the leukoplakia that may be patchy or speckled (speckled leukoplakia); the erythematous component is generally not well demarcated (Fig. 21c). The rate of progression to oral cancer has been reported to be 1 7% for homogenous leukoplakia, 4 15% for verrucous leukoplakia, and 18 47% for erythroleukoplakia (Hsue et al. 2007; Liu et al. 2012; Anderson and Ishak 2015). However, morsicatio mucosae oris and benign alveolar ridge keratosis which have no malignant potential may be historically included in the category of leukoplakia resulting in dilution and underrepresentation of the true prevalence of dysplasia and progression to cancer (Woo et al. 2014; van der Waal 2015). In general, true leukoplakias do not regress but show progression and enlargement over time either noticeably or at a barely perceptible rate. The appearance of the lesion may also change from being homogenous to nonhomogenous and from being soft to being firm and indurated. Proliferative verrucous leukoplakia (PVL): Although the WHO considers PVL to be a subset of conventional localized leukoplakia, there are many differences between the two which may warrant classifying it separately (Table 1). PVL is characterized by relentlessly progressive involvement of the oral mucosa by white plaques, often verrucous and fissured, at multiple, noncontiguous sites, or it may present as a single large lesion with or without involvement of contiguous sites; a size of 3 cm 2 is often used as a criterion for this diagnosis in a single large lesion (Fig. 22a d). Although the average age at diagnosis of PVL is in the seventh decade, most patients will report that lesions have been present for years prior (Bagan et al. 2010, 2011). A homogenous form of PVL may exist but would be rare. As its name suggests, the most common form is the verrucous/nodular form. However, proliferative erythroleukoplakia is a variant that is often mistaken for oral lichen planus because of its widespread, often bilateral nature, with red and white areas, and sometimes trabecular keratosis that may be mistaken for reticulations. As such, the less specific term proliferative leukoplakia may be a more appropriate name for this condition. All patients with leukoplakia must be biopsied to establish a definitive diagnosis. Lesions that may have been clinically diagnosed as leukoplakia may in fact be histopathologically frictional keratosis, candidosis, or some other white lesion. In one study, this constituted approximately 75% of all clinical leukoplakias (Woo et al. 2014). Between 39% and 53% of localized leukoplakias show evidence of epithelial dysplasia or neoplasia at the time of diagnosis, and almost one third of dysplastic lesions progress to form invasive cancer (Brouns et al. 2014; Woo et al. 2014). In lesions that are large, multiple biopsies should be performed such as from a white area, from a red area, and from an indurated area (Parashar 2014; Gomes et al. 2015). In one study of incisional biopsies and subsequent excision of oral leukoplakias, 29% of the patients with

29 White and Red Lesions of the Oral Mucosa 29 Fig. 21 (a) Homogenous localized leukoplakia: sharply demarcated white plaque of the right buccal mucosa that showed moderate dysplasia (Courtesy of Dr. Nathaniel Treister, Harvard School of Dental Medicine, Boston, MA, USA). (b) Erythroleukoplakia of the right dorsal and ventrolateral tongue that on excision revealed a squamous cell carcinoma. (c) Verrucous leukoplakia of the right ventrolateral tongue single-site biopsy and 12% of the patients with multiple-site biopsies were deemed underdiagnosed. In addition, 12% of patients with single-site biopsy and only 2% of patients with multiple-site biopsies had unexpected carcinoma which were diagnosed in later resection of the lesions (Lee et al. 2007a). A recent systematic review of the literature showed patients with PVL to have undergone at least nine biopsies during their follow-up period (mean: 7 years; range: years) (Abadie et al. 2015). Sequential biopsies are essential for monitoring lesions of PVL because most lesions begin as KUS and progress to dysplasia and invasive cancer over decades (Parashar 2014; Abadie et al. 2015). and Future Directions Localized leukoplakia exhibiting keratosis of unknown significance: KUS lesions should be reevaluated by the clinician to determine whether they may represent reactive/frictional keratoses. Criteria for reactive lesions include poor demarcation, lack of fissuring, location at a site that can easily be traumatized, waxing and waning nature with even complete resolution, and then recurrence. Discussion with the pathologist is very helpful. If the clinical lesion is one of a true leukoplakia, narrow excision or ablation should be considered if the lesion is small, so that surgery is minimally morbid, and if the patient is young.

30 30 M. Jessri et al. Table 1 Comparison between localized leukoplakia and proliferative leukoplakia Feature Leukoplakia Proliferative leukoplakia Demographics Older males Older females Association with smoking High association with smoking (38 62%) (Maia et al. 2016; Naveen-Kumar et al. Low association with smoking (up to 42%) (Cerero- Lapiedra et al. 2010) 2016) Distribution Single site Multifocal or extensive contiguous sites Common sites Tongue, gingiva, and buccal mucosa Gingiva, alveolar mucosa, and palatal mucosa Histopathology at first biopsy ~ 40% dysplastic or SCC <10% dysplastic or SCC Mostly verrucous hyperplasia or KUS Risk of malignant transformation Architecture Overall: 1 15% Annual: 1 3% Overall: % Annual: 10% Could be homogenous or nonhomogenous Mostly nonhomogenous, usually verrucous/nodular or erythroleukoplakic Management Excision or ablation Difficult to manage because of the extent of the lesion; follow-up and excision of invasive cancers as they develop SCC squamous cell carcinoma, KUS keratosis of unknown significance Fig. 22 Proliferative verrucous leukoplakia. (a) Partially demarcated, white plaque on maxillary buccal gingiva. (b) Well-demarcated verrucous white plaque on the palatal mucosa. (c) Involvement of ~50% of the right buccal mucosa with a poorly demarcated, fissured, fairly homogenous white plaque. (d) Partially demarcated plaque of the mandibular buccal gingiva and vestibule

31 White and Red Lesions of the Oral Mucosa 31 Research on the molecular changes in KUS would help clarify whether they exhibit similar genomic alterations as dysplasia or even SCC. Localized leukoplakia with dysplasia: Some believe that mild dysplasias may regress, and as such, watchful waiting is appropriate (Lodi and Porter 2008). It is more likely that mild reactive epithelial atypia that may be seen in frictional keratoses and in other benign inflammatory conditions has been diagnosed as mild dysplasia and, as such, regressed with treatment or spontaneously. Some believe that even moderate-tosevere dysplasias do not require treatment. However, molecular studies have shown that these carry similar mutations as SCC (Lingen et al. 2011).Assuch,theyarenotlikelytoregress and more likely to progress, although the time to development of SCC varies greatly from patient to patient (Dost et al. 2014). OLL with moderate-to-severe dysplasia should be excised with clear margins if clinically appropriate (such as young patients with small lesions), and all patients should be followed up indefinitely for recurrence or the development of new leukoplakias at a noncontiguous site. Recurrence hasbeenreportedinapproximately7 38% of lesions based on the definition of leukoplakia, site, and treatment (such as laser ablation vs. resection) (Lodi and Porter 2008; Kuribayashietal.2012). Patients with leukoplakia exhibiting carcinoma in situ and invasive SCC should be referred to a cancer center for management. Proliferative verrucous leukoplakia: Periodic multisite biopsy especially of verrucous, erythematous, indurated, and bulky areas is recommended. Areas that show moderate-tosevere dysplasia should be monitored closely or excised if possible, although in most cases, it is not possible to obtain margins free of dysplasia, and dysplastic cells repopulate the surgical site. Areas that show carcinoma in situ or invasive carcinoma require complete excision with the understanding that the margins should be free of carcinoma, but will likely not be free of dysplasia or KUS. Within 4 12 years of follow-up, 74% of PVL progress to cancer (Cabay et al. 2007). Because many initial biopsies show KUS, this is evidence that KUS lesions are precancerous although without the histopathologic phenotype of dysplasia. Adjunctive aids such as the use of toluidine blue or autofluorescence techniques may be useful in such targeted cases and especially for followups. However, findings must be interpreted with caution because of low specificity of such tools (Bhatia et al. 2013; Bhatia et al. 2014). More detail about these devices is found in the chapter on Oral Mucosal Malignancies. Research on the molecular changes in PVL, especially the earlier lesions that show only KUS, would help clarify whether they exhibit similar genomic alterations as dysplasia or even SCC. If so, targeted therapy may be useful for the management of this condition. Erythroplakia Erythroplakia is a premalignant lesion characterized by a red plaque and is strongly associated with dysplasia and squamous cell carcinoma (Warnakulasuriya et al. 2007). According to WHO definition, erythroplakia is a fiery red patch that cannot be characterized clinically or pathologically as any other definable disease (Axell et al. 1984; Warnakulasuriya et al. 2007). Therefore, similar to leukoplakia, the diagnosis of erythroplakia is based on exclusion of other red lesions of the oral cavity (Shafer and Waldron 1975). This is a premalignant condition. Similar to oral squamous cell carcinoma, smoking, excessive alcohol consumption, personal or familial history of cancer, male gender, advanced age, history of cancer therapy, and prolonged immunosuppression are the major risk factors for developing erythroplakia (Shafer and Waldron 1975). Erythroplakia is uncommon, and as such there is limited data on its molecular characteristics although mutations in TP53 have been reported (Reichart and Philipsen 2005; van der Waal 2009).

32 32 M. Jessri et al. Fig. 23 Erythroplakia of the right maxillary edentulous alveolar ridge Oral erythroplakia is most commonly seen in the middle aged and the elderly with a substantially higher predilection for males (Reichart and Philipsen 2005). Lesions are usually asymptomatic, and the most commonly involved sites include the floor of the mouth, tongue, soft palate, and buccal mucosa. Erythroplakic lesions appear as smooth or granular, velvety plaques with generally well-demarcated margins (Fig. 23). All require biopsy, and over 70 90% of lesions exhibit carcinoma in situ and invasive squamous cell carcinoma (Shafer and Waldron 1975; Mashberg and Feldman 1988). Lesions that exhibit dysplasia or squamous cell carcinoma require excision or resection. Malignant transformation occurs in 14 50% of cases (Reichart and Philipsen 2005). As such, close follow-up of the patient for life is recommended. Oral Submucous Fibrosis Oral submucous fibrosis (OSF) is an insidious, potentially malignant lesion caused by chewing areca nut, with 7 13% of cases exhibiting transformation to squamous cell carcinoma (Pindborg et al. 1984; Murti et al. 1985). It is characterized by progressive mucosal fibrosis that can affect most of the oral cavity including the lips and buccal mucosa resulting in trismus. In advanced cases, fibrosis of the upper third of esophageal mucosa may result in dysphagia. Areca, which is the endosperm of Areca catechu palm tree, is commercially available in South Asia as the main component of betel quid and gutkha which are used for their stimulant or psychoactive properties (Arakeri and Brennan 2013). Betel quid ( paan ) is composed of the Piper betel leaf wrapped around the chopped areca nut, chopped tobacco leaves, and other components such as slaked lime and spices. Gutkha is increasingly replacing betel quid in popularity. It is usually sold in prepackaged sachets and is composed of areca nut, powdered tobacco, slaked lime, catechu (acacia extract), and flavorings. Areca nut contains alkaloids (the most potent of which is arecoline), flavonoids, and copper, all of which interfere with collagen metabolism (Tilakaratne et al. 2006). Chronic exposure to alkaloids induces synthesis of interleukin 6, tumor necrosis factor, and transforming growth factor beta (TGF-β) which modulate differentiation of fibroblasts resulting in accumulation of collagen (Rajalalitha and Vali 2005). Flavonoids such as tannins and catechins stabilize collagen molecules and inhibit collagenase through increasing the local concentration of cytokines and TGF-β (Arakeri and Brennan 2013). The high content of copper in areca nut upregulates lysyl oxidase which is essential to collagen crosslinkage (Arakeri and Brennan 2013).

33 White and Red Lesions of the Oral Mucosa 33 The carcinogenic properties of betel quid and gutkha are due to isolated or synergistic action of tobacco and areca nut (Nair et al. 2004; Arakeri and Brennan 2013). Carcinogenic effects of areca nut are attributed to polyphenols, alkaloids (most importantly, arecoline), metabolites of alkaloids (e.g., arecoline N-oxide), and areca nut-specific nitrosamines such as N-nitrosoguvacoline, N-nitrosoguvacine, 3-propionaldehyde, and 3-propionitrile (Angadi and Rao 2011; Kuo et al. 2015). In chronic exposure to such molecules, there is reduced cellular antioxidant glutathione resulting in increased oxidative stress and subsequent DNA damage which, when unrepaired, may lead to gene rearrangements and deletions implicated in carcinogenic process (Nair et al. 2004). If left unrepaired, DNA damage is a threat to genomic integrity, and their misrepair can potentially lead to activation of the apoptosis pathway, inducing chromosomal rearrangements, DNA deletions, and other deleterious mutations implicated in carcinogenic process. Although there is a dose-dependent relationship between chewing areca nut and the development of OSF, currently OSF is not only more common in younger individuals (in the second or third decade), but in addition younger patients (under 40 years of age) have been reported to develop OSF in response to shorter periods of exposure to areca nut compared to older individuals (Jacob et al. 2004; Ranganathan et al. 2004). OSF is more common in males. Often times, patients report pain, burning, and sensitivity in the mouth. The buccal mucosa, tongue, and soft palate are among the most commonly affected sites although in late stages, the disease might affect the entire oral mucosa and include the oropharynx. Clinical presentation of OSF depends on staging which is based on the degree of fibrosis and mouth opening (More et al. 2012). Early clinical lesions (stage 1) are characterized by stomatitis, including vesicle formation, petechiae, postinflammatory hypermelanosis, and ulceration. In moderately advanced lesions (stage 2), the mucosa has a marble-like pallor and fibrous bands that can be palpated in the buccal mucosa, and there is trismus (Fig. 24a c). Such fibrosis may be extensive in stage 3 disease (More et al. 2012). A biopsy should be performed when leukoplakia, erythroplakia, persistent ulceration, or a mass lesion is noted, suspicious for transformation to dysplasia and/or carcinoma. Currently, there is no cure of OSF, and it does not regress with cessation of the habit. Early stages of OSF can be treated with intralesional steroid injections (Arakeri and Brennan 2013). Patient with trismus may benefit from stretching the jaw using stacked tongue depressors or employing jaw rehabilitation devices to increase and maintain range of motion. Advanced cases may require surgical release of the fibrotic bands (Arakeri and Brennan 2013; Warnakulasuriya and Kerr 2016). OSF is a potentially malignant disorder that often displays evidence of dysplasia in the overlying epithelium with 7 13% of the patients developing oral squamous cell carcinoma. As such, close, long-term follow-up is recommended (Yoithapprabhunath et al. 2013). Actinic Cheilitis (Actinic Cheilosis, Solar Cheilosis, and Farmer s Lip) Actinic cheilitis (AC) is a disorder that commonly affects the vermilion border of the lower lip as a result of sun damage. It is considered a potentially malignant condition. Similar to actinic keratosis, which is a solitary keratotic and dysplastic lesion, AC develops due to chronic exposure of the lip vermilion to ultraviolet (UV) light, in particular UVB. UVB can cause mutations in tumor suppressor gene TP53 and other mutational events increasing the risk for developing squamous cell carcinoma. AC is normally seen in the middle-aged population with a strong predilection for Caucasian men (male/female of 10:1), and patients may report

34 34 M. Jessri et al. Fig. 24 Submucous fibrosis: (a) reduced mouth opening at 31 mm. (b) Diffuse whiteness with marbled-like pallor and macular erythema of right buccal mucosa with palpable fibrotic bands. (c) Diffuse whiteness of right ventrolateral tongue pain and/or sensitivity. Most patients relate a history of long-term sun exposure whether from work (such as farming or outdoor occupations) or from recreational activities (such as boating or golfing). Fair-skinned individuals (skin phototypes I and II) or those with a history of sunburns during childhood are at high risk for developing AC. The most frequent clinical findings include blurring of the vermilion-skin interface, dryness, fissuring, atrophy, scaly changes of the lower lip, and less commonly swelling and erythema (Fig. 25). Early lesions appear as pale, blotchy, smooth areas and/or dry fissures on the lower lip that slowly progress to form rough, scaly areas or firm keratotic papules and ulcers which may represent actinic keratosis or even squamous cell carcinoma. Lesions may also appear as leukoplakia or erythroleukoplakia (Camara et al. 2016). A biopsy to rule out dysplasia is indicated in cases with localized, scaly, or firm papules because this may represent actinic keratosis, which is by definition at least dysplastic if not outright squamous cell carcinoma (Camara et al. 2016). AC is an irreversible condition and has the potential for slow progression to squamous cell carcinoma. Patients should have regular follow-ups, limit sun exposure, and apply sunscreen routinely (Goldman 2015). Lesions exhibiting dysplasia may be treated with either topical therapies such 5-fluorouracil, imiquimod and cryotherapy, vermilionectomy, or laser ablation (Shah et al.

35 White and Red Lesions of the Oral Mucosa 35 Fig. 25 Actinic cheilitis characterized by blurring of the vermilion-skin border and moderate erythema and vascular ectasia with scattered faint white changes; this is particularly noticeable on the lower lip 2010). Squamous cell carcinoma is treated with surgical excision. Oral Squamous Cell Carcinoma Oral squamous cell carcinoma (OSCC) is the eighth most common cancer worldwide (Scully and Bagan 2009). OSCC may be preceded by or arise in a setting of leukoplakia, erythroplakia, or OSF. Considering the complexity and importance of a timely diagnosis and correct management in the prognosis of patients, OSCC has been discussed in greater detail in a separate chapter on Oral Mucosal Malignancies. Risk factors for developing OSCC are similar to that of oral epithelial dysplasia and include history of tobacco use, excessive alcohol consumption, areca nut use, history of cancer and cancer treatment, chronic immunosuppression and autoimmune disease, genetic and dietary factors, advanced age, male gender (likely related to habits), and human papillomavirus (HPV) infection (Warnakulasuriya et al. 2005; Scully and Bagan 2009). While tobacco use is perceived to be the major contributing factor in etiology of OSCC in low- and middle-income countries, HPV infection has been associated with pharyngeal and base-of-tongue cancer in younger populations with lower or no tobacco exposure (Sturgis and Cinciripini 2007). Environmental carcinogens such as benzopyrenes and nitrosamines from cigarette smoke and arecoline from areca nut cause OSCC and induce somatic mutations. Mutations in TP53, CDKN2A, PIK3CA, NOTCH, EGFR, and Wnt pathways have been reported in head and neck squamous cell carcinoma (Agrawal et al. 2011; Stransky et al. 2011; CancerGenomeAtlasNetwork 2015). Patients with familiar cancer syndromes such as dyskeratosis congenita, Fanconi anemia, and Bloom syndrome are at higher risk for developing oral squamous cell carcinoma because of inherited mutations (Savage 1993; van Monsjou et al. 2013; Sarode et al. 2016). Traditionally, OSCC affects older males (male-tofemale ratio 2:1) and often presents as leukoplakia, erythroplakia, PVL, nonhealing ulcers, or mass lesions (Fig. 26a, b). Lesions tend to be indurated and most often affect ventrolateral tongue and floor of the mouth. Early lesions are generally painless or have minimal symptoms, while advanced lesions may present with pain, paresthesia, or tooth mobility. Treatment of OSCC is highly dependent upon clinical staging. Once a tissue diagnosis is established, intraoral and extraoral imaging such as panoramic radiographs, computed tomography (CT), positron emission

36 36 M. Jessri et al. Fig. 26 Oral squamous cell carcinoma. (a) Erythroplakia of the floor of the mouth in a male patient with 40-year history of cigarette smoking (60 pack-years). Patient previously treated with T3N0 HPV-negative oropharyngeal squamous cell carcinoma, with recent diagnosis of lung carcinoma. Incisional biopsy of the erythroplakia revealed moderately differentiated invasive squamous cell carcinoma. (b) Erythroleukoplakia of the left tongue with thick exophytic plaques in a female patient with non-hodgkin lymphoma status post-allogenic stem cell transplant (10 years prior). An incisional biopsy of the lesion revealed invasive squamous cell carcinoma tomography (PET) scan, and magnetic resonance imaging (MRI) are used to determine clinical staging of the tumor. Stage I and II tumors generally have favorable prognosis and are typically treated with en bloc resection with or without lymph node dissection (Haddad et al. 2008). Many patients are diagnosed in late stages (stages III and IV) and are treated via a multidisciplinary approach including surgery and adjuvant or primary radiation and chemotherapy (Haddad et al. 2008). EGFR is overexpressed in most OSCC tumors, and consequently, cetuximab, a monoclonal antibody against EGFR, shows promise in the treatment of OSCC (Laimer et al. 2007; Dai et al. 2014; Martinez-Useros and Garcia-Foncillas 2015). Early diagnosis strongly impacts survival, and the 5-year survival rate is over 80% for stage I tumors and <30% for stage IV tumors. Patients should be followed up indefinitely because they are at high risk for developing a second malignancy. Conclusion and Future Directions Red and white lesions of the oral cavity include a wide variety of conditions; these range from reactive reversible conditions such as frictional keratoses to potentially malignant and malignant lesions such as oral leukoplakia. Lesions can be small and isolated or involve the entire mucosa. Similarly, lesions may be entirely asymptomatic or may result in mucosal sensitivity, burning, and in some cases severe pain. Management of oral lesions is based on their etiology and prognosis. Advances in basic science and, in particular, nextgeneration sequencing are improving our understanding of the etiology, development, and progression of malignant and potentially malignant lesions (Jessri and Farah 2014). As this is translated into clinical practice, it will lead to earlier and more accurate diagnosis, resulting in better management and targeted therapy in appropriate cases. Cross-References Clinical Evaluation of Oral Diseases Cutaneous Pathology of the Head and Neck Region Gingival Pathology Head and Neck Malignancies Interface Between Oral and Systemic Health Laboratory Medicine and Diagnostic Pathology Normal Variation in the Anatomy, Biology and Histology of the Maxillofacial Region Oral and Maxillofacial Fungal Infections