Chapter 38: Diseases of the Oral Cavity

Many dermatologic conditions, inflammatory, immunologic, infectious, or neoplastic, can also occur in the oral mucosa, with essentially similar clinicopathologic features. Occasionally, the mouth is the sole manifestation of a dermatologic condition as in the case with lichen planus and mucous membrane pemphigoid. There are also common conditions that are unique to the oral mucosa, such as recurrent aphthous stomatitis (canker sores) and geographic tongue. In this chapter, the reader will be introduced to the clinical characteristics, differential diagnosis, and management of common oral conditions.

Anatomy of the Oral Cavity

With the exception of the posterior one-third of the tongue, which is of endodermal origin, the epithelium that lines the oral mucosa derives mostly from ectoderm. In contrast to the skin, the oral epithelium exhibits different patterns of keratinization. For example:

• The masticatory mucosa (hard palate, gingiva, and alveolar mucosa) has keratinized or parakeratinized (retained nuclei in the stratum corneum) squamous epithelium.

• The tongue has parakeratinized, nonkeratinized, and specialized epithelia (papillae).

• The buccal mucosa and vestibule have nonkeratinized stratified or parakeratinized squamous epithelia, respectively.

The supporting connective tissue is of ectomesenchymal origin. Adnexal elements are not present in the connective tissue of the oral mucosa, with the exception of sebaceous glands, known as Fordyce granules/spots (Figure 38-1), which are present in 70% to 90% of individuals. However, the mouth has 800 to 1000 lobules of minor salivary glands, with the exception of the gingiva and the anterior aspect of the hard palate.

Categories of Oral Diseases

Clinically, oral lesions can be (1) ulcerated, (2) vesiculobullous, (3) maculopapular, (4) exophytic, papillary, or fungating, (5) nodular or polypoid, and (6) pigmented. Special attention should be given to lesions that are white (leukoplakic), or red (erythroplakic) patches or a mixture of the two (erythroleukoplakic) and lesions that are gray, black, or brown, as these lesions may be malignant or premalignant.

Oral ulcers have various etiologies, which include trauma, immunologic diseases, infections (bacterial, deep fungal, or viral), and neoplasms (squamous cell carcinoma, lymphoma, malignant salivary gland tumors, etc). They are generally painful, except for squamous cell carcinoma, which may be asymptomatic, when it presents as an ulcer.

Traumatic Ulcers

Introduction

Traumatic ulcers are usually the result of physical injury (eg, accidental biting during mastication, contact with sharp or broken cusps of teeth, and sharp food), and less often, thermal or chemical burn (eg, chemicals used during dental or surgical procedures, aspirin, alcohol, peroxide, and other acidic substances). Rarely, electrical injury can occur, especially in very young children who accidentally chew on an electrical wire.

Clinical Presentation

Traumatic ulcers frequently affect the tongue, lips, and buccal mucosa (Figures 38-2, 38-3, 38-4) and in cases of vigorous tooth brushing, small and often multiple ulcerations can occur on the gingiva. In general, traumatic ulcers present as round, ovoid or irregular, erythematous lesions usually covered by a pseudomembrane and surrounded by a white border that represents reactive epithelial regeneration.

Management

Traumatic ulcers heal after removal of the cause and depending on the size and the location; they usually heal within 1 to 2 weeks. Over the counter topical dyclonine hydrochloride, hydroxypropyl cellulose, lidocaine, or benzocaine can relieve the pain associated with ulcerations. Treatment with topical corticosteroids (gels are preferred over creams and ointments since they adhere better to the oral soft tissues) can be used in some instances. Chronic large ulcers may require topical steroids. Ulcers of the tongue may take more time to resolve due to the unique nature and composition of the tongue, which is, a movable muscle. Ulcerated lesions that last longer than 3 weeks without an obvious etiology should raise a clinician's suspicion of neoplasia, and these lesions should be biopsied with incisional or excisional techniques.

Recurrent Aphthous Stomatitis (RAS)

Introduction

Recurrent aphthous stomatitis (canker sores) is one of the most common oral mucosal lesions presenting with one or multiple ulcers NOT preceded by vesicles or bullae.¹ RAS affects between 5% and 60% (mean 20%) of people with a predilection for females, caucasians, and children of higher socioeconomic status.

Many predisposing factors have been implicated with the development of RAS. In some patients there is genetic predisposition with certain HLA types. Hypersensitivity to certain foods such as citrus fruits, chocolate, coffee, gluten, nuts, strawberries, tomatoes, medications (eg, -nonsteroidal anti-inflammatory drugs [NSAIDs], and beta blockers), sodium lauryl sulfate in toothpastes, smoking cessation, stress, trauma, infectious agents (eg, Helicobacter pylori, herpes simplex, and streptococci), and female hormonal changes have been associated with development of RAS.

Systemic diseases presenting with oral ulcers akin to RAS include nutritional deficiencies (iron, folate, and vitamin B complex), IgA deficiency, Behçet's disease, Sweet's syndrome (acute neutrophilic dermatosis), PFAPA syndrome (periodic fever, aphthae, pharyngitis, and cervical adenitis), inflammatory bowel disease, reactive arthritis (Reiter syndrome, cyclic neutropenia, and AIDS).

Clinical Presentation

RAS ulcers are mostly round or ovoid and generally painful. They are usually covered by a pseudomembrane and surrounded by an erythematous halo. There are three types of aphthae, minor, major, and herpetiform.

• Minor aphthae (Figure 38-5) are the most common form of RAS and typically present with recurring episodes of 1 to 5 small ulcers, less than 1 cm in greatest diameter. They predominantly affect the nonmasticatory mucosa and are usually seen in the anterior part of the mouth. They last 7 to 14 days, if left untreated.

• Major aphthae (Figure 38-6) are larger, deeper, last longer (2 to 6 weeks) and are very painful. Major aphthae are most frequently seen on the lips and the posterior oropharynx.

• Herpetiform RAS (Figure 38-7) is characterized by as many as 50 to 100 small ulcers and may clinically resemble ulcers of primary herpes simplex, thus the confusing term "herpetiform." Recurrences are usually closely spaced and lesions, although favoring the nonmasticatory mucosa, can be seen throughout the mouth.

Management

The treatment for RAS depends on the extent and degree of pain of the lesions. Some patients can tolerate the lesions and associated pain, but other patients have difficulty eating or even functioning during episodes. Over the counter topical anesthetics or protective bioadhesive products such as Orajel, Orabase, and Zilactin may be of some benefit. Fluocinonide or betamethasone dipropionate 0.05% gels can be used topically 2 to 3 times a day. They should be applied to early lesions at the onset of prodromal pain and tingling. Steroid solutions, such as dexamethasone 0.5 mg/5 mL, and prednisolone or betamethasone syrups may be used in patients who have widespread lesions. In hard to reach areas, such as tonsillar pillars, beclomethasone dipropionate aerosol spray can be used as an alternative. Systemic steroids can be used in patients with very painful major aphthae and in herpetiform lesions. Occasionally, systemic steroids are used in conjunction with topical steroids. RAS that does not respond to steroids should be referred to specialists who may prescribe dapsone, tacrolimus, thalidomide, tetracycline, levamisole, MAO inhibitors, and other medications as alternatives to steroids. Cauterization with silver nitrate and laser ablation are not recommended. Besides using medications to treat RAS, the clinician should review the eating habits of patients, which may be contributing to RAS. If indicated, an evaluation should be done for systemic diseases, which could be related to RAS.

Vesiculobullous lesions of the oral mucosa may be due to trauma, allergic reactions (Figure 38-8), infections (herpes simplex or zoster), or immune-mediated disease (pemphigus vulgaris and mucous membrane pemphigoid). Intact vesicles are rarely identified and generally vesiculobullous processes manifest as erosions and ulcerations as most blisters rupture spontaneously. Therefore, a clinician should specifically ask about the presence or absence of oral blisters when evaluating a patient with oral erosions and ulcerations.

Primary and Secondary Herpes Simplex (HSV)

Introduction

Oral HSV is generally due to HSV type I.² In rare cases, HSV type II may be the cause due to orogenital sexual contact. Primary infection by herpes simplex presents as gingivostomatitis (Figure 38-9). Direct contact with an asymptomatic individual shedding the virus in saliva, or with a person with recurrent infection such as herpes labialis are modes of transmission. The vast majority of individuals without antibodies against HSV type I, when infected, do not have clinical symptoms or signs. After the primary infection, the virus is transported to sensory or autonomic ganglia where it remains in a latent state.

Reactivation of the virus is responsible for recurrent disease which usually affects the lips (herpes labialis or cold sore) (Figure 38-10) or, intra-orally on the hard palate or gingiva (Figure 38-11). Perioral lesions may also occur on the skin of the nose, cheek, or chin. Triggering factors include immunosuppression, menstruation, stress, ultraviolet light, and local trauma. Prodromal symptoms (burning, itching, or tingling) occur in many patients.

Clinical Presentation

Primary HSV infection may present as acute gingivostomatitis in children and adolescents with multiple, 1 to 2 mm vesicles that rapidly rupture to form multiple small red, white, or yellow ulcerations throughout the mouth (Figure 38-9). The lips of the patients become crusted with serum and blood, and the gingivae are edematous and erythematous and covered with small ulcers. Patients may also have anterior cervical lymphadenopathy, chills, high fever (103 to 105°F), nausea, and irritability. Self-inoculation to the fingers, eyes, and genitals can occur. Older patients with primary disease may have pharyngotonsillitis. Recurrent herpes labialis presents as coalescing vesicles that rupture and subsequently crust. Without treatment complete healing occurs after 1 to 2 weeks. Intraoral recurrent herpes presents as small shallow and coalescing yellowish-white or erythematous ulcers preceded by vesicles that heal within 1 to 2 weeks.

Reactivation in immunocompromised patients such as HIV-positive³ and transplant patients may lead to a chronic herpetic infection that is persistent and characterized by atypical lesions that can mimic major aphthae or necrotizing stomatitis. In some patients these atypical ulcers harbor also cytomegalovirus co-infection. These patients should be referred to specialists for evaluation to confirm the diagnosis and to infectious disease specialists for management.

Management

Pediatric primary infections can be treated with palliative topical rinsing with 0.5% to 1% dyclonine hydrochloride and if needed with acyclovir suspension during the first 3 symptomatic days in a rinse-and-swallow mode (15 mg/kg or up to the adult dose of 200 mg daily for 5 days).

If needed, oral medications for primary and recurrent herpes simplex can be used. Table 38-1 lists selected treatment options for adolescents and adults. Topical medications are also available (Table 38-2).

Varicella (Chickenpox) and Herpes Zoster (Shingles)

Introduction

Varicella and herpes zoster are caused by the varicella-zoster virus (VZV). Varicella is the primary infection and patients present primarily with cutaneous lesions; however, oral lesions are not uncommon and may precede the skin lesions. Vesicular lesions usually appear on the lips and the palate and in contrast to primary herpes are generally painless. VZV establishes latency in the dorsal spinal ganglia.

Herpes zoster is the reactivation of VZV. The prevalence increases with age and occurs in 10% to 20% of infected individuals. Most affected patients have a single episode. Predisposing factors include stress, immunosuppression, treatment with cytotoxic medications, presence of malignancies, and older age. For head and neck cases, dental manipulation may be the trigger.

Clinical Presentation

The lesions of herpes zoster can affect the face and oral mucosa unilaterally and follow the path of the involved nerve (Figure 38-12). Since affected nerve endings can cross the midline, a few lesions can be seen on the other side of the midline. Patients present with very small vesicles that rupture and leave behind shallow painful ulcerations. Occasionally if the maxilla is involved, tooth necrosis and in rare cases bone necrosis can occur.

Management

Treatment for herpes zoster should begin as soon as the diagnosis is established. Valacyclovir 1 g 3 times a day for 7 days or famciclovir 500 mg 3 times a day for 7 days or acyclovir 800 mg 5 times a day for 7 days or acyclovir 800 mg 5 times a day for 7 days are the drugs of choice. Analgesics and antiepileptics (gabapentin and carbamazepine) and tricyclic antidepressants can be used for pain relief. Also oral corticosteroids are sometimes prescribed to older, immunocompetent patients (with no contraindications to steroids) to decrease the incidence of postherpetic neuralgia.

Mucous Membrane Pemphigoid (MMP) and Pemphigus Vulgaris (PV)

Introduction

Mucous membrane pemphigoid⁴ and pemphigus vulgaris⁵ are uncommon immunologic vesiculobullous diseases that can have oral manifestations. MMP (Figure 38-13), also known as cicatricial pemphigoid, generally involves only the mouth which is in contrast to bullous pemphigoid (the most common type of cutaneous pemphigoid) rarely presents with oral manifestations.

Clinical Presentation

In PV (Figure 38-14), oral lesions may be the "first to show and last to go" and oral mucosal involvement is seen in almost all cases. Lesions present as painful erosions or ulcerations preceded by vesicles. If intact vesicles are seen, MMP is more likely the diagnosis. This is because the vesicles in MMP are subepithelial and thus more deeply seated, in contrast to the vesiculobullous process in PV that is intraepithelial. Patients with PV rarely present with intact vesicles. It is important for the clinician to question the patient about a history of vesicles or bullae when multiple shallow ulcerations are identified in the mouth. Also, in patients presenting with PV, but more importantly with MMP, synchronous or metachronous ocular involvement may occur leading to scarring of the conjunctiva.

When the gingiva is involved in MMP and PV, the clinical presentation is that of mucosal sloughing and erosions. This is referred to as desquamative gingivitis and diffuse erythematous lesions covering most, if not all of the gingiva can occur (Figure 38-15). Desquamative gingivitis is a clinical descriptive term and not a diagnosis. In order of frequency, the underlying condition can be erosive lichen planus, MMP or pemphigus.⁶ Patients with oral PV can present occasionally with multiple shallow ulcerations of the free gingiva (Figure 38-16). Such lesions can persist after successful treatment of all other mucocutaneous lesions and achieving resolution is difficult.

In the differential diagnosis of immunologically mediated oral vesiculobullous and ulcerative processes one should include erythema multiforme, hypersensitivity reactions, angina bullosa hemorrhagica, linear IgA disease, and rarely, bullous lichen planus.

Management

Treatment for MMP depends on the severity of lesions and the areas affected. Topical steroids including fluocinonide, betamethasone dipropionate, or clobetasol propionate 0.05% gels may be used for mild disease. For widely distributed lesions, dexamethasone 0.5/5 mL rinse may be prescribed. Secondary candidiasis may develop as a side effect to topical corticosteroid treatment and can be treated with oral antifungal medications. Systemic therapy is typically required and is usually managed by a team approach with clinicians in clinical oral pathology, dermatology, and ophthalmology. These specialists often use systemic treatment with prednisone in more severe cases. Other systemic medications for the treatment of MMP include azathioprine, dapsone, and mycophenolate mofetil. Combination treatment for MMP with tetracycline 1 to 2 g/day and nicotinamide 1 to 2 g/day has been used as alternative to corticosteroids and the other immunosuppressive agents. For patients with gingival manifestations, excellent dental hygiene is important for good results. Also, the fabrication of customized trays by the patient's dentist as a vehicle for better delivery is recommended.

Treatment for oral lesions of PV is more complicated since the disease is widespread. Systemic treatment should start immediately after the diagnosis is established. Ideally, a patient with pemphigus should be treated by a physician with expertise in immunosuppressive therapy. Combination of systemic corticosteroids and immunosuppressive drugs such as azathioprine is chosen in many cases. Topical steroids may be used for persistent oral lesions.

Erythema Multiforme (EM) and Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)

Introduction

EM and SJ/TEN present with oral and cutaneous lesions.⁷ EM usually affects teenagers and young adults and is typically triggered by a herpes simplex infection or it may be caused by medications including antibiotics or anticonvulsants. SJS/TEN is commonly caused by medications and less commonly by infections. Chapter 23 has detailed information about these conditions.

Clinical Presentation

Oral lesions may precede or be concomitant with skin lesions, which present as erythematous papules and macules frequently having a target or targetoid appearance. EM and SJS/TEN have an acute onset and may be accompanied by malaise, fever, headache, and sore throat. In most patients the lesions usually occur in the nonmasticatory mucosa, the anterior part of the mouth with the gingiva, and hard palate being relatively spared. Oral lesions (Figure 38-17) usually start as erythematous patches, with or without vesicle formation, which ulcerate leaving extensive and painful erosions and ulcerations covered by pseudomembrane, as well as areas of necrosis. Many patients present with blood-crusted lips, which is a useful clinical sign (Figure 38-18). Besides oral and cutaneous lesions, patients can have genital, pharyngolaryngeal, esophageal, and bronchial lesions.

Management

It is important to identify any potential medication causes and treat any infection that may have caused EM or SJS/TEN. Patients with EM usually need just supportive care similar to that for the ulcerative disorders in this chapter. More severe cases may need systemic prednisone. Patients with suspected SJS/TEN should be referred for specialty care. Extensive oral and cutaneous involvement should be managed in a hospital setting, preferable in a burn unit. Patients with EM can usually be managed as outpatients with supportive care. See Chapter 23 for further information on management.

There is a wide variety of lesions that can present intraorally as macules, papules, or a combination thereof. Lesions with such patterns include geographic tongue, candidiasis, lichen planus/lichenoid lesions, leukoplakia, erythroplakia, and squamous cell carcinoma.

Geographic Tongue (Migratory Glossitis and Migratory Stomatitis)

Introduction

Geographic tongue⁸ is a common inflammatory disorder of primarily the tongue occurring in approximately 1% to 3% of the population. Some studies have shown increased prevalence in women. There is apparently a genetic predisposition and in some patients there is a family history. Lesions of geographic tongue may be encountered in patients with psoriasis and, according to studies, patients with psoriasis are up to four times more frequently affected than otherwise healthy patients.⁹ However, this association is not confirmed but other investigators.¹⁰ Other conditions that have shown an increased prevalence of geographic tongue include diabetes mellitus, reactive arthritis (Reiter's syndrome), and Down syndrome. Allergies, hormonal disturbances, and stress have also been associated with an increased prevalence of geographic tongue.

Clinical Presentation

Clinically, geographic tongue is characterized by a single or frequently several erythematous lesions occasionally surrounded by a white or yellow line representing epithelial hyperplasia (Figure 38-19). They vary in size and change shape and size, sometimes within hours. Lesions typically occur on the dorsum and ventral surfaces of the tongue, extending occasionally to the lateral aspects. When the dorsum of the tongue is affected, there is loss of lingual papillae. Symptomatic depapillation of the tongue may also be seen in anemia (eg, iron deficiency, pernicious), candidiasis, or diabetes mellitus. Thus, such conditions should be excluded in symptomatic cases that have clinically the appearance of geographic tongue.

In rare occasions lesions can be found in other parts of the mouth such as the buccal mucosa and the palate (Figure 38-20). However, these patients almost always have lesions on the tongue. In addition, lesions of migratory glossitis are often seen in conjunction with deep fissures on the tongue dorsum (fissured tongue) (Figure 38-21). Occasionally, patients report lesion-free periods.

Management

The lesions of geographic tongue are generally asymptomatic; however, tingling or burning sensation may be reported in association with spicy or acidic foods or brushing of the tongue with toothpaste. Other than reassuring the patient on the benign nature of geographic tongue, treatment is not necessary. For symptomatic patients, especially those who complain of burning sensation or pain, topical fluocinonide 0.05% gel may be used. Also there are case reports advocating the use of zinc sulfate 200 mg 3 times/day or vitamin B complex supplementations. A diagnostic biopsy may be performed in cases of inability to exclude geographic tongue from other conditions that may share similar clinical features including erythroleukoplakia.

Candidiasis

Introduction

Candidiasis of the oral mucosa is caused by C. albicans which presents in two forms, yeast and hyphae, the former being generally innocuous while the latter can invade the host tissue.¹¹ Other forms of Candida that can be identified in the mouth, however, far less frequently, include C. glabrata, C. tropicalis, C. krusei, C. parapsilosis, and C. dubliniensis. Among all fungal infections, oral candidiasis is by far the most common. The organism is present in the mouth of 30% to 50% of individuals without causing disease and its presence in the mouth increases with age. Factors that have been associated with the development of clinical disease include the immune status of the host, the strain of Candida, and the environment of the mouth. For example, patients with iron deficiency or pernicious anemia, on long-term antibiotics and steroids (topical, inhaled, or systemic), those with HIV infection or AIDS, and dry mouth can develop candidiasis. Smoking has also been related to the hyperplastic form of candidiasis. However, healthy individuals can also be affected.

Clinically, there are four forms of candidiasis: pseudomembranous, erythematous, hyperplastic, and mucocutaneous.

• Pseudomembranous candidiasis (thrush) is a common form and it is usually acute. It affects approximately 5% of infants and 10% of debilitated older adults as well as patients on long-term antibiotics or those with dry mouth or immunocompromised patients. The term pseudomembranous is misleading since there is no pseudomembrane present. Instead, creamy white or yellow, easily detached aggregates of yeast and desquamated epithelial cells are seen on the oral soft tissues (Figure 38-22) of the palate, buccal mucosa, and tongue. They are easily removed with a tongue blade, dry gauze or a cotton-tipped applicator leaving behind normal or erythematous oral mucosa. If bleeding occurs during this procedure, an underlying disease, such as lichen planus/lichenoid mucositis or a neoplastic epithelial process, should be suspected and excluded by biopsy. In most cases of thrush there are no symptoms; however, burning sensations and altered taste have been reported.

• Erythematous candidiasis is characterized by red patchy areas with minimal or no white plaques of fungal aggregates. Erythematous candidiasis can have several clinical presentations that include acute atrophic candidiasis, central papillary atrophy of the tongue (median rhomboid glossitis), angular cheilitis, and denture stomatitis.

  • Acute atrophic candidiasis (Figure 38-23) is usually seen in patients on long-term antibiotic treatment, with xerostomia, blood dyscrasias, or immunosuppression. Patients usually complain of a burning sensation (scalded mouth). When the tongue is affected, there is loss of the filiform papillae ("bald tongue").

  • Central papillary atrophy of the tongue, also referred to as rhomboid glossitis, is a mostly asymptomatic, chronic form of candidiasis, presenting as a depapillated, usually symmetrical area on the middle and posterior central aspect of the tongue that appears smooth or less frequently lobulated. Lesions may also occur on the palate ("kissing" effect) or the buccal mucosa (Figure 38-24). This is referred to as chronic multifocal candidiasis.

  • Angular cheilitis (perlèche) presents with fissures and cracks in the commissures of the lip (Figure 38-25). Typically it is seen in older patients with reduced vertical occlusal dimension (superior–inferior relationship of the maxilla to the mandible when the teeth are fully occluded), usually denture wearers, as well as patients with multifocal candidiasis. While in some instances only Candida is present, the majority of lesions harbor also Staphylococcus aureus, while some are caused only by this bacterium. Candida in angular cheilitis can spread to lips and perioral tissues.

  • Denture stomatitis refers to erythematous lesions in the areas covered by the dentures, or other removable dental prosthetic appliances, especially if they are continuously worn (Figure 38-26). These lesions are generally asymptomatic. Interestingly, a biopsy most often does not feature any evidence of fungus. In such cases candida is found in the pores of the dentures; however, similar lesions can be caused by bacteria.

• Hyperplastic candidiasis is an unusual form seen primarily in smokers. It is most commonly seen on the buccal mucosa (Figure 38-27) or the tongue. In this form of candidiasis, nonremovable white plaques are present. Although it is known that candida can induce epithelial proliferation, it is not entirely clear if some lesions of hyperplastic candidiasis represent leukoplakias suprainfected by candida. Occasionally, lesions disappear after antifungal treatment thus confirming the cause and effect role of candida in their development. Leukoplakias suprainfected with candida can also have a speckled appearance, that is, speckled mixed white and red lesions (speckled leukoplakia). In such instances, antifungal treatment may improve the appearance of the leukoplakia to a smoother, more homogenous white lesion.

• Mucocutaneous candidiasis¹² is a relatively rare immunologic disorder in which patients develop lesions affecting the mouth (hyperplastic candidiasis and other forms), nails, skin, and other mucosal surfaces. In some patients, mutations in the autoimmune regulator (AIRE) gene have been identified. Lesions appear early in life and persist. However, they are not invasive and they can be controlled with continuous antifungal treatment. There is also association of mucocutaneous candidiasis with endocrinopathies and rarely there is associated ectodermal dysplasia. Associated endocrinopathies include hypothyroidism, primary Addison's disease, diabetes mellitus, and hypoparathyroidism. In these patients there is increased risk for the development of oral or esophageal carcinoma.

Management

The treatment of oral candidiasis involves elimination of factors, if possible, that contribute to persistent infection. It is important for patients to maintain a high level oral hygiene. Topical treatments for adults include the following.

• Clotrimazole troches (imidazole agent) one 10 mg troche slowly dissolved in the mouth 5 times per day for 10 to 14 days.

• Nystatin oral (polyene agent) 1 or 2 lozenges (pastilles) 200,000 to 400,000 IU dissolved slowly in the mouth 4 to 5 times per day for 10 to 14 days.

• Itraconazole oral solution (triazole agent) 10 mL vigorously swished and swallowed twice daily for 1 to 2 weeks.

When systemic treatment is needed for adults, fluconazole (triazole agent) 200 mg tablets the first day and then 100 mg per day for 1 to 2 weeks should be the first choice. Depending on the form of the disease and in patients with resistant candida species, ketoconazole capsules (imidazole agent) 200 mg once or twice a day for 1 to 4 weeks or for 3 to 5 days after lesions resolve. Ketoconazole should not be used as initial therapy.

Oral Lichen Planus

Introduction

Oral lichen planus (OLP) is a relatively common chronic T-cell-mediated autoimmune disease affecting 1% to 2% of the population.¹³ In contrast to cutaneous lichen planus that is usually self-limiting, OLP is generally a chronic disease, which may be difficult to palliate and rarely spontaneously resolves. Also and more importantly, lesions of OLP may infrequently undergo neoplastic transformation thus causing morbidity and mortality. The premalignant potential has varies in studies between 0.4% and over 5%.

Patients with OLP may have concomitant extraoral manifestations and 15% of patients with OLP develop subsequently extraoral disease. The severity of OLP does not, in general, correlate with the extent of cutaneous disease. Also known is the association of OLP of the gingiva with vulvovaginal or penile LP.

OLP is seen primarily in the 5th and 6th decades of life and it is twice as common in females as in males. Lesions of OLP can also be seen in children and adolescents. Patients with OLP have higher levels of anxiety and those with erosive forms have higher depression scores. Also an association of OLP with hepatitis C has been reported.¹³

Clinical Presentation

There are three well-recognized forms: reticular, atrophic, and erosive. Reticular OLP (Figure 38-28) is the most common form and is characterized by multiple papules or plaques that coalesce forming striations (Wickham striae). Interestingly, lesions of reticular OLP rarely cause symptoms and frequently patients are unaware of their existence. Atrophic and erosive forms (Figure 38-29) are less common. However, these forms are the most frequently encountered in clinical practice because they cause varying degrees of discomfort. The erosive form is mostly used as a clinical term when ulcerated lesions are encountered. Histopathologically, true erosions are infrequently encountered. These forms may be associated with reticular lesions (Figure 38-30) and occasionally erythematous, atrophic, and ulcerated lesions feature radiating white striations. Rarely, vesicles and bullae (bullous LP) may be seen. The most frequent sites of OLP are the posterior buccal mucosa bilaterally, dorsolateral tongue, gingiva, palate, and lip vermillion. Occasionally, lesions of OLP are associated with candidiasis which alters their clinical appearance especially those of the reticular form. In cases of reticular OLP with candida superinfection, patients may complain of burning sensation. The characteristic striations of OLP are seen after the candida infection is treated.

The diagnosis of lichen planus is established clinically and histopathologically. The differential diagnosis includes the following.

• Contact hypersensitivity reaction to dental materials, flavoring food agents such as cinnamon or mints (Figures 38-31 and 38-32). In the later, characteristic Wickham striae are not encountered.

• Lichenoid drug reaction (Figure 38-33), graft versus host disease (GVHD), and oral lesions of lupus erythematosus may have similar or indistinguishable clinicopathologic features with lichen planus. Therefore the clinician should exclude such possibilities prior to establishing the diagnosis of OLP.

• Chronic ulcerative stomatitis and vesiculobullous diseases.

Management

Treatment of OLP is needed for the symptomatic forms. Patients with reticular OLP may be followed every 6 to 12 months. If patients are symptomatic, they may have a candida infection and antifungal medications should resolve the symptoms. Because of the autoimmune nature of LP and depending on the severity of lesions, topical and/or systemic corticosteroids may be indicated. Topical steroids including fluocinonide, betamethasone dipropionate, or clobetasol propionate 0.05% gels may be used. For widely distributed lesions, dexamethasone 0.5 mg/5 mL rinse may be used. Secondary candidiasis that may develop as a side effect to topical corticosteroid treatment can be eliminated by antifungal agents as described above. Topical tacrolimus ointment has been used in recalcitrant cases. Systemic treatment with prednisone may be needed in severe cases of erosive OLP. Other systemic medications that have been used for the treatment of OLP include azathioprine, dapsone, levamisole, and thalidomide.

Leukoplakia

Introduction

Leukoplakia is defined by the World Health Organization (WHO) as "a white patch or plaque that cannot be characterized clinically or pathologically as any other disease." It is a term that does not define a specific entity, but excludes a wide variety of white lesions that present distinct clinical and/or histopathologic characteristics. It is a strictly clinical term that should be used by clinicians to communicate the presence of a white lesion, are unaware of. Table 38-3 lists lesions that should be included and excluded from the term leukoplakia.

Note among those lesions, the entity referred to as hairy leukoplakia (Figure 38-34). This is a type of white lesion exhibiting specific clinicopathologic features, caused by Epstein–Barr virus (EBV). It is frequently suprainfected by candida and seen mostly in immunosuppressed patients and those with HIV/AIDS. This is but an example of the confusion that the term leukoplakia can cause.

Etiologic factors for the development of leukoplakic lesions include all forms of tobacco, alcohol abuse, ultraviolet light (for labial lesions), Candida albicans, sanguinaria (bloodroot, a plant used in some nonprescription products). Of these factors, tobacco is most frequently associated with the development of leukoplakias. It is known that around 80% of patients with leukoplakia are smokers and that heavier smokers have greater numbers of lesions and larger lesions compared to light smokers. Also, smoking cessation leads to a decrease in size or disappearance of leukoplakias in many patients. However, one should note that some patients with leukoplakias never smoked and that nonsmokers with leukoplakia have higher risk for the development of squamous cell carcinoma compared to smokers.

Leukoplakia is considered a premalignant lesion. However only 5% to 25% of the cases have definitive histopathologic criteria to support premalignancy (intraepithelial neoplasia). The premalignant nature of leukoplakia has been established by clinical investigations and long-term monitoring of lesions. These studies have confirmed a malignant transformation potential of about 4% to 5%, which increases in certain subtypes of leukoplakia (erythroleukoplakia, proliferative verrucous leukoplakia) to up to 47%. The progression and time of the development of histologically recognizable dysplasia in leukoplakic lesions are uncertain and occasionally invasive squamous cell carcinoma can occur without evidence of recognizable dysplasia.

The estimated prevalence of leukoplakia is between 1% and 4% and, recently, there appears to be gender parity, although in last years approximately 70% of the patients were males. The most frequent sites of occurrence are the vestibule and buccal mucosa followed by the palate, alveolar ridge, lower lip, tongue, and floor of mouth. The sites in the mouth in which leukoplakias present high risk for the development of dysplasia and squamous cell carcinoma are, in descending order the floor of mouth, ventrolateral tongue, lower lip, palate, buccal mucosa, vestibule, and retromolar mucosa.

Clinical Presentation

Clinically, leukoplakic lesions vary in clinical appearance from thin and homogeneous to thick irregular, leathery patches that may have distinct borders or blend with the surrounding tissues (Figures 38-35, 38-36, 38-37). Variations within the same lesion also occur. Occasionally, an erythematous component is present (erythroleukoplakia) (Figure 38-38). Such lesions have a higher risk for being dysplastic or invasive squamous cell carcinoma at the time of diagnosis. Proliferative verrucous leukoplakia (PVL),¹⁴ a subtype of leukoplakia, is characterized by the development of more than one lesions that exhibit various patterns of maturation even within the same patient (Figures 38-39A and B). Lesions of PVL have a very high risk for the development of verrucous or squamous cell carcinoma. They occur more frequently in women and less than one-third of the patients are smokers.

In the concept of oral premalignancy/squamous cell carcinoma one should include erythroplakia.²¹ This is defined as a red patch that cannot be clinically or pathologically diagnosed as any other condition (Figure 38-40). However, this definition is misleading because at the time of biopsy lesions of erythroplakia show severe dysplasia, carcinoma in situ, or invasive squamous cell carcinoma. Erythroplakia is less common than leukoplakia. It occurs in middle aged to older adults and the sites of predilection are the floor of mouth, tongue, and soft palate.

The gold standard for the diagnosis of clinically identified suspicious oral lesions is surgical biopsy.

Management

Surgical excision is the treatment of choice for leukoplakic lesions. Laser ablation is also used. Photodynamic therapy¹⁵ using 5-aminolevulinic acid is a promising alternative for treatment of dysplastic lesions. Cryosurgery and administration of 13-cis-retinoic acid have been used with limited results.

Oral Squamous Cell Carcinoma

Introduction

Oral cancer accounts for less than 3% of all cancers in the United States. Over 20,000 cases are diagnosed per year with more than 5000 patients dying of this disease annually. Oral squamous cell carcinoma (OSCC) represents approximately 95% of all types of malignancy affecting the oral cavity. Most patients are older than 60 years. However, there is an alarming increase in the number of younger patients without the traditional risk factors. Based on incidence rates less than 1% of men and women will be diagnosed with OSCC during their lifetime. The male-to-female ratio is approximately 2.5:1.

The major etiologic factors include tobacco and alcohol. All forms of smoked tobacco have been associated with increased risk. However, in smokeless tobacco, the association with the development of OSCC remains weak and controversial. In contrast, chewing of betel quid (paan, pan supari; combination of tobacco, areca nut, and slake lime) is a major cause for OSCC in the Indian subcontinent. Also, combination of heavy smoking and alcohol abuse results in a synergistic effect and increases the risk further.

Besides smoking and alcohol abuse, human papillomavirus (HPV) has been implicated in cases of tonsillar (oropharyngeal). However, association of HPV with the development of OSCC of the oral mucosa proper has not been determined. Squamous cell carcinoma with tumors is associated with HPV having a better prognosis.¹⁶ Patients with severe iron deficiency (Plummer–Vinson syndrome) have an elevated risk for development of esophageal and oropharyngeal squamous cell carcinoma.

Clinical Presentation

There is a variety of clinical appearances of OSSC. Tumors can be ulcerated, endophytic, exophytic, leukoplakic, or erythroleukoplakic (Figures 38-41 and 38-42). While some tumors are clinically obvious, there are occasions where lesions are small (Figure 38-43), painless, and mimicking inflammatory processes (Figure 38-44). Such is the case of lesions seen in association with dental prostheses or presenting as "inflamed" gingiva. In such cases, consultation with dental professionals may be necessary.

Management

Diagnostic biopsies should be obtained of all lesions that present with the aforementioned characteristics. Treatment of oral cancer involves a team of physicians that include ear, nose, and throat/oral surgery and maxillofacial specialists, oncologists, and prosthodontists.

Papillary, exophytic, or fungating lesions occurring in the oral mucosa include papillomas, verrucae vulgaris, condylomata accuminatum, lesions of multifocal epithelial hyperplasia (focal epithelial hyperplasia; Heck's disease), premalignant papillary, and verrucoid lesions as seen in proliferative verrucous leukoplakia, and papillary, verrucoid, or fungating variants of squamous cell carcinoma (Figure 38-45).

Oral papilloma is a common benign epithelial proliferation similar to common warts of the skin. It is presumed that most if not all of papillomas are induced by HPV. HPV 6 and 11 have been identified in almost half of oral papillomas. Children and young adults are most frequently affected and there is no gender predilection. Generally, they present as solitary epithelial proliferations exhibiting finger-like projections (Figure 38-46) or a cauliflower-like pattern. The most frequent sites are the tongue, palate, and lips. Occasionally, more than one site can be simultaneously affected (papillomatosis) especially in the immunocompromised patients.

Intraoral verruca vulgaris is uncommon. Occasionally, patients with cutaneous lesions also develop oral lesions (Figure 38-47).

Condyloma acuminatum can occur in the oral mucosa and has similar clinical and histopathologic characteristics of genital lesions. When identified in the mouth of children, sexual abuse is a concern and should be investigated.

Multifocal epithelial hyperplasia is an HPV-related proliferation (HPV 13 and 32) characterized by multiple papular or nodular epithelial proliferations that occasionally coalesce forming a cobblestone pattern (Figure 38-48). Patients may have 20 to 100 lesions that rarely reach 1.0 cm in size. Lesions are seen more frequently in children. However, adults can also develop lesions also, especially if there is contact with affected children. Frequent sites of involvement include the lips, tongue, and buccal mucosa. The diagnosis can be made clinically and microscopically.

The most common nodular or polypoid lesions of the oral mucosa are fibrous polyps (fibromas), mucoceles, and epulides.

Fibromas (fibrous hyperplastic lesions) present as sessile or pedunculated, rubbery, solitary tumors covered by normal-colored or hyperkeratotic (white) mucosa (Figure 38-49). Although trauma has been traditionally regarded as the cause of oral fibrous overgrowths, the etiology is unknown. Most lesions arise on the buccal mucosa, tongue, and lips, and their size rarely exceeds 1.5 cm. Most fibromas are asymptomatic, unless there is ulceration due to trauma. Most cases are seen in the 4th to 6th decades of life and females are twice as frequently affected as males. The observed higher frequency in females may be due to the fact that women are more concerned about their esthetics or oral health compared to males. Also, fibrous hyperplastic lesions may be seen on the alveolus of patients with ill-fitting dentures. Surgical excisional biopsy to confirm the diagnosis and to exclude other soft tissue tumors is recommended.

Mucocele¹⁷ refers to a clinically fluctuant nodular mass containing salivary mucus. It is either of extravasation type due to severing of a salivary gland excretory duct and spillage of mucus in the connective tissue, or retention type, resulting from obstruction of a salivary duct, the latter being less common. Extravasation-type mucoceles (Figure 38-50) are most frequently seen on the lower lip and less frequently the ventral surface of the tongue of children or young adults, or the palate and retromolar mucosa of older individuals. Retention-type mucoceles are seen in older adults on the upper lip, floor of mouth, and buccal mucosa. Thus, for a fluctuant lesion on the lower lip of a child or young adult, the diagnosis is most likely that of a mucocele until proven histopathologically otherwise. However, a fluctuant lesion of the upper lip in an adult is not an extravasation mucocele until proven otherwise. These lesions are typically retention mucoceles, or benign or malignant cystic salivary gland tumors.

There is an uncommon variant referred to as superficial mucocele seen on the posterior palate and buccal mucosa. They appear as single or multiple small translucent vesicles filled with clear saliva. The collection of mucus occurs in the surface epithelium. Multiple lesions, clustered or not, may be encountered in association with lichenoid disorders. In such cases, the differential diagnosis includes an immunologically mediated vesiculobullous disorder such as MMP. Rarely lymphangiectatic lesions may clinically mimic superficial mucoceles.¹⁸

Although they are indolent lesions, all mucoceles excised should be submitted for histopathologic evaluation to exclude the possibility of a cystic salivary gland tumor. Recurrence is infrequent, except those occurring on the ventral surface of the tongue (Figure 38-51) that have an approximately 20% to 25%.

Epulides are nodular soft tissue lesions typically on the gingiva and the alveolar mucosa. They include the following.

• Fibrous hyperplasia (fibromas)

• Fibrovascular inflammatory hyperplasia (usually but erroneously referred to as pyogenic granulomas, but they are neither pus-containing nor granulomatous) (Figure 38-52).

• Fibroblastic proliferation with ossification (peripheral ossifying fibromas) (Figure 38-53).

• Collection of multinucleated giant cells in association with proliferating mesenchymal cells in a hemorrhagic stroma (peripheral giant cell granuloma) (Figure 38-54). Combination of the last two can occur.

As a rule, fibrovascular inflammatory hyperplasias and peripheral giant cell granulomas are usually erythematous and hemorrhagic. Fibrous proliferations and peripheral ossifying fibromas are normal mucosa colored, except if they are traumatized and ulcerated. Excision of epulides is recommended and recurrence is not uncommon in peripheral ossifying fibromas (about 15%)¹⁹ and peripheral giant cell granulomas (10%).²⁰

Pigmented lesions of the oral mucosa²¹ are of two types: those related to melanin and those caused by other pigments, endogenous or exogenous, the latter mostly metallic in origin. Also, certain systemic medications may cause pigmented lesions in the oral mucosa by either an increase in melanin pigment or deposition of medication metabolites in the soft tissues. All oral pigmented lesions that cannot be related to a specific cause should be biopsied for diagnosis.

Melanin-Associated Hyperpigmented Lesions

• Oral (or ethnic) pigmentation, seen in darker-skinned individuals, varies in pattern, but is usually diffuse and bilateral with the color ranging from light to dark brown. The lesions are generally seen on the gingiva, buccal mucosa, lips, and tongue. Pinhead brown discolorations can be seen on the tips of the lingual fungiform papillae (Figure 38-55).

• Oral Melanocytic macules are the most common melanocytic lesions. They usually appear as single or multiple, well-demarcated, less than 1 cm, light or dark brown lesions usually on the buccal (Figure 38-56) and masticatory mucosa or on sun-exposed areas vermillion border of the lower lip (Figure 38-57). There is a female predilection.

• Intraoral melanocytic nevi are uncommon. They are usually acquired, and present as pigmented and less frequently as nonpigmented macular or papular or, rarely, nodular or polypoid lesions (Figure 38-58). They are generally small with most lesions being less than 1 cm. Two-thirds of the patients are women and the average age is 35 years. Most lesions occur on the hard palate, buccal mucosa, and gingiva. As is the case on the skin, there are three common histologic types, junctional, compound, and intramucosal, the latter being the most frequent type. Intraoral blue nevi have been also described, predominantly in the palate. Other rare forms, for example, Spitz, halo, combined, and congenital nevi have also been reported. Although there is demographic epidemiologic correlation between oral nevi and oral melanoma, there is no proof that intraoral nevi are a marker for the development of oral melanoma.

• Oral melanomas are very rare. They are usually macular, papular, or nodular and are most frequently pigmented, black, brown, or gray (Figure 38-59). Rarely red or non-pigmented melanomas are seen. The most frequent site is the masticatory mucosa and most patients are men. Most oral melanomas are clinically and histologically similar to acral lentiginous or nodular melanomas of the skin or a combination of the two.

• Melanoacanthoma is a rare, apparently reactive and, in most instances, self-limiting solitary or less frequently bilateral or multifocal process seen predominantly on the buccal mucosa of almost exclusively black individuals, primarily women.

• Smoker's, postinflammatory, and medication-related melanoses are reactive lesions. Smoker's melanosis is seen in heavy smokers and is considered a protective response by the epithelium to the harmful substances of tobacco. Postinflammatory melanosis is seen in chronic inflammatory diseases such as lichen planus, lichenoid mucositis, MMP, or PV. Hyperpigmentation occurs because of disruption of the basal cell layer leading to melanin accumulation in the connective tissue and within macrophages or stimulation of the epithelial melanocytes by inflammatory products (prostaglandins, leukotrienes, etc.) leading to an increase in melanin synthesis. Lastly, medication-related melanin hyperpigmentation (chloroquine and other quinine derivatives, phenolphthalein, estrogen, and AIDS-related medications) can present with oral manifestations. Females are more frequently affected probably due to interaction with sex hormones. Any site of the oral mucosa may be involved.

• Systemic conditions such as Peutz–Jeghers syndrome, PTEN hamartoma tumor syndromes, and Addison's disease may have oral and/or perioral melanin hyperpigmented lesions. In most instances the patients are aware of their condition and its clinical manifestations. Among such conditions one should include Laugier–Hunziker (Laugier–Hunziker–Baran) syndrome seen more frequently in females, in which patients develop multiple oral melanocytic macules and less frequently nail and vaginal lesions.

Non-melanin-Related Hyperpigmentations

These lesions are caused by either exogenous or endogenous pigments. Exogenous hyperpigmentations are mostly related to amalgam restorations (Figure 38-60). Lesions are usually located on the gingiva, alveolar mucosa, buccal mucosa, floor of mouth, and less often the tongue. The color is light to dark gray or even black depending on the amount and depth of the metal within the tissues. The size varies from few millimeters to 2 cm. The cause can be iatrogenic or traumatic. Particles of amalgam may be imbedded within the tissues during restorative procedures. Occasionally, metallic particles can be identified in dental radiographs as small radiopaque particles. Similar discolorations can occur from incidental or voluntary introduction of other metals such as graphite from pencil tips, tattoo ink, and chronic contact with charcoal toothpaste. Extrinsic staining of the oral tissues may also occur in smokers or coffee or tea drinkers (Figure 38-61). Lastly, breakdown products of bacteria may stain the gingiva. This usually occurs in children.

Chronic exposure to heavy metals such as bismuth, lead, gold, or silver can cause oral hyperpigmented lesions, but these days, such cases are rare. Finally metabolites of certain medications, the most frequent being minocycline, may cause diffuse discoloration of teeth, oral soft tissues, and bone. In most instances in minocycline-related hyperpigmentation the lesions are related to iron-chelated metabolites.

Lesions caused by endogenous pigments are usually related to blood extravasation (petechiae, ecchymoses, and hematomas) and products of hemoglobin degradation, that is, bilirubin and biliverdin. Trauma is the most common cause (Figure 38-62). The most frequently affected sites include the buccal mucosa, tongue, and palate. Direct trauma to a tooth or teeth may lead to pulpal necrosis and discoloration of affected teeth. Also, patients with hemorrhagic diathesis may develop multiple hemorrhagic lesions throughout the mouth. In such cases, thrombocytopenia is a frequent cause and should be excluded. Rare systemic conditions associated with non-melanin-associated hyperpigmented lesions of teeth and soft tissues include hemochromatosis, erythroblastosis fetalis and biliary atresia associated hyperbilirubinemia, beta thalassemia, and congenital erythropoietic porphyria.

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