2003, Vol.21, Issues 1, Oral Medicine and Oral Dermatology

Dermatol Clin 21 (2003) xi xii
Preface
Oral medicine/Oral dermatology
Roy S. Rogers III, MD Alison J. Bruce, MD Guest Editors
The past decade has heralded an improved understanding of the pathogenesis of many diseases, particularly those with an immunological basis. The development of immunofluorescence testing as a commonplace tool in the evaluation of dermatologic, mucous membrane, and other autoimmune disorders has significantly enhanced our understanding of immunologic disease processes and, in turn, allowed us to develop more targeted and scientific approaches to therapy. Diseases of the mouth and oral cavity are enormously troublesome to patients, impacting their ability to communicate and to interact socially and in the workplace, thus diminishing their quality of life. Many clinicians have shared their patients distress because oral diseases can be difficult to differentiate and, more specifically, to effectively manage. However, the enhancement of our understanding of oral disease and the strides made in more effective diagnosis and management of oral disorders has spurred new interest in the fields of oral medicine and oral pathology. Many physicians and dentists now share a keen interest in what has now become an exciting field of medicine. The increasing attendance at sessions reviewing oral disease at the Annual Meeting of the American Academy of Dermatology exemplifies this interest of dermatologists in oral medicine. The more generic Symposium on Disorders of the Mucous Membranes has been replaced by a symposium devoted specifically to oral medicine, and numerous smaller sessions
on oral medicine and oral dermatology topics have proliferated to meet the educational needs of those attending the Annual Meeting of the American Academy of Dermatology. The 20th World Congress of Dermatology, held in Paris in the summer of 2002, continued this theme. The Symposium on Diseases of the Oral Mucosa was filled, with overflowing lines of registrants outside the hall waiting for an empty seat. The European Academy of Dermatology and Venereology has instituted a Symposium on Diseases of the Oral Mucosa in its popular annual meeting. The desire of clinicians to understand and treat patients with distressing oral diseases has fostered this interest, and the depth of understanding of disease pathogenesis and treatment has allowed medical science to meet this interest. Previous issues of the Dermatologic Clinics have been devoted to discussion of oral disorders to enhance education of the dental and medical community; in this issue, the update on oral mucosal disease continues. In 1987, the Dermatologic Clinics published an issue on disorders of mucous membranes, which Dr. Rogers had the pleasure of editing, and, in 1997, on disorders affecting the oral cavity, which Dr. Rogers edited with Dr. Dale Miles, a dentist. In this issue, Dr. Alison J. Bruce, a dermatologist with a keen interest in oral medicine and oral dermatology, joins Dr. Rogers as co-editor. This issue is organized to explicate oral ulceration with articles on acute oral ulcers, viral diseases of the
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oral mucosa, recurrent aphthous stomatitis, complex aphthosis, and Behcets disease and pseudo-Behcets disease. White lesions of the oral cavity are discussed in articles on white lesions of the oral cavity, the clinical manifestations and treatment of oral lichen planus, the oral and genital variants of erosive oral lichen planus, oral psoriasis, and contract stomatitis reactions. Other conditions that produce a sore mouth are addressed in articles on denture sore mouth, diseases of the tongue, and the burning mouth syndrome. Specialized areas are addressed in articles on halitosis, pediatric oral medicine, and oral manifestations of systemic diseases, of genodermatoses, and of erythema multiforme. Colleagues from the field of dentistry have contributed substantially to this issue. Drs. Kupp and Sheridan, periodontologists, discuss denture sore mouth; Dr. Ayangco, a resident in periodontics, joins Dr. Rogers in discussing the oral manifestations of erythema multiforme; Drs. Messadi and Younai, oral medicine specialists, discuss halitosis; Drs. Parks and Lancaster, oral pathologists, review the oral manifestations of systemic diseases; and Dr. Zunt, another oral pathologist, reviews recurrent aphthous stomatitis. Drs. Ginat A. Mirowski and Drore Eisen are dually trained dentists and dermatologists who bring expertise and a special perspective to oral medicine and oral dermatology. Drs. Messadi, Waibel, and Mirowski review white lesions of the mouth, and Dr. Eisen contributes his perspectives and findings from the largest and most carefully documented series of patients with oral lichen planus. Drs. Eisen and Rogers discuss the genital lichen planus variants in men and women. Dermatologists have maintained a keen interest in the oral mucosal manifestations of many diseases and have developed a substantial base in oral medicine and oral dermatology. Dr. Bruce joins Drs. Byrd and Rogers in the article on glossitis and other tongue disorders, Drs. Hairston and Rogers on viral diseases
of the oral mucosa, Dr. Rogers in the article on acute oral ulcers, and contributes her own perspective on oral psoriasis. Drs. LeSeur and Yiannias discuss contact stomatitis, Drs. Hand and Rogers explicate the oral manifestations of genodermatoses, and Drs. Witman and Rogers review pediatric oral medicine. Drs. Drage and Rogers discuss evaluation and management of patients with the burning mouth syndrome. Drs. Jorizzo and Garton and Ms. McCarthy discuss Behcets disease and complex aphthosis, and Dr. Rogers shares his experience with patients referred to the Mayo Clinic with the diagnosis of Behcets disease who do not have that condition in the article on pseudo-Behcets disease. Our task as Guest Editors has been one of selecting topics to encompass oral medicine and oral dermatology, identifying and recruiting authors, reading each contribution, and identifying correlations with other contributions. This task has been made easier by the acceptance of the authors of the challenge to prepare the manuscript, by meeting that challenge with excellent manuscripts and illustrations, and by their dedication to meeting deadlines. The manuscripts were delivered to the efficient hands of Rebecca Schmidt at W.B. Saunders in Philadelphia, where she and her colleagues edited the final product. We owe a debt of gratitude to the contributors, Ms. Schmidt, and our secretaries at the Mayo Clinic, Mrs. Barbara Stowers and Mrs. Charlene Graff. Roy S. Rogers, III, MD Alison J. Bruce, MD Department of Dermatology Mayo Clinic 200 First Street SW Rochester, MN 55905-0001, USA E-mail addresses: rogers.roy@mayo.edu (R.S. Rogers III) bruce.alison@mayo.edu (A.J. Bruce)
Dermatol Clin 21 (2003) 1 15
Acute oral ulcers

Alison J. Bruce, MD*, Roy S. Rogers III, MD
Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Ulceration of the oral mucosa is a frequent occurrence producing painful aphthae, a term of ancient origin referring to ulceration of any mucosal surface. The oral mucous membranes are specialized frail membranes and are susceptible to erosion [1]. Fullthickness erosion of the epithelium into the lamina propria produces painful ulceration. Because oral ulcers are both common and painful, the clinician is often consulted for diagnosis and treatment. Etiologies range from minor irritation to malignancy and systemic disease. A practical approach to the diagnosis and management of oral ulcers allows the clinician appropriately to evaluate patients and institute therapy. In general, oral ulcers are painful and may be single or multiple, symmetric or irregular in shape. They usually have a central friable yellow-white exudative base with a surrounding rim of bright erythema. Once an ulcer forms, it is subject to repeated irritation from saliva and microflora, and the acute inflammatory stage may be followed by a pattern of chronic inflammation. Although there are many diverse causes, oral ulcers frequently demonstrate similarity both clinically and histologically. An algorithmic approach based on duration, recurrent nature, morphology, location, and systemic symptoms is useful in evaluating etiology (Fig. 1). Acute oral ulcers are of short-lived duration and 6 weeks is a reasonable point of differentiation between acute and chronic ulcers. The causes of chronic oral ulceration are multiple, ranging from malignancy to systemic disease and other chronic inflammatory or immunobullous disorders, such as pemphigus, paraneoplastic disease, mucous mem-
brane pemphigoid, and lichen planus. Discussion of chronic ulceration is beyond the scope of this article. Acute oral ulceration refers to ulcerative episodes of less than 6-weeks duration, and for ease of classification these should be categorized based on the pattern of behavior. Oral ulcers may occur as a single episode or be recurrent in nature representing a different spectrum of mucous membrane disease. An understanding of these differing patterns of oral ulceration aids in work-up and diagnosis (see Fig. 1).
Recurrent oral ulceration Trauma Oral trauma is one of the most common causes of recurrent oral ulcers. This results from mechanical, chemical, or thermal irritation of the mucosa. These are generally acute short-lived events producing painful ulcers, which heal readily within a few weeks without scarring. The ulcers may be recurrent if the inciting stimulus is not removed. Dental appliances, dentures, and orthodontic hardware may be causative in recurrent oral ulceration (Fig. 2) [2]. Dentures can produce pressure ulcers, which are typically small, less than 1 cm in size occurring on the crest of the alveolar ridge [3,4]. Irritation from a sharp or broken tooth is usually readily identifiable. Patients may also inadvertently produce traumatic ulcers through biting of the oral mucosa either accidentally or through unconscious oral habit [5]. This usually occurs on the loose buccal mucosa, lower lip, or tongue. Habitual cheek biting produces erosion along the bite line, which corresponds to the closure of the upper and lower teeth. Lesions above or below the bite line are typically not caused by cheek biting.
* Corresponding author. E-mail address: bruce.alison@mayo.edu (A.J. Bruce).
A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115
Fig. 1. Algorithm to evaluate acute oral ulcers that (A) are recurrent in nature, and (B) occur as an isolated episode.
Fig. 2. Recurrent ulcer on the labial mucosa secondary to trauma from an adjacent dental appliance.
Fig. 4. Minor aphthous ulcer with a small superficial kissing ulcer tucked in the alveolar sulcus.
Chemical irritation also produces ulceration as the result of exposure to acidic or basic substances. Occasionally nonsteroidal anti-inflammatory drugs, such as aspirin, which patients may hold in their mouth to relieve toothache, produce local ulceration (Fig. 3). There are many other over-the-counter medications that similarly damage the mucosa with prolonged contact [4]. Factitial injuries can be seen in children or psychologically disturbed patients who repeatedly pick at the gingiva with fingernails or other objects. Recurrent aphthous stomatitis Recurrent aphthous stomatitis (RAS), commonly known as canker sores, has been estimated to occur in as high as 20% of North American patients. RAS is reviewed elsewhere in this issue by Zunt. In most
cases, recurrent aphthous ulcers are limited to the oral mucosa and tend to be multifactorial in etiology rather than attributable to a single factor. Trauma, smoking, stress, hormonal influences, genetics, food allergies, infections, and immunologic factors are all suggested causes [6 11]. Recurrent aphthous stomatitis can be classified in two systems based on morphology, or clinical presentation. Using the first classification, Cooke [12] delineated three categories of RAS based on morphology. Minor aphthous ulcers are the most common form accounting for about 80% of cases. Typically, these ulcers are superficial in nature, small in size, usually less than 1 cm in diameter, few in number, occurring singularly or in groups, and heal within about 7 to 10 days without scarring (Fig. 4). The second subtype, major aphthous ulcers, otherwise known as periadenitis mucosa necrotica recurrens, or Suttons disease, occurs in about 10% of patients. These ulcers are larger in size, often over 1 cm in diameter, occurring either singly or as multiple lesions (Fig. 5). They are slower to heal and may
Fig. 3. Mucosal ulceration related to use of aspirin to relieve toothache.
Fig. 5. Major aphthous ulcer. A large deep and painful ulcer involving an extensive area on the labial mucosa.
A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115 Table 1 Diagnosis of oral ulcers based on morphology Morphology Discrete Diagnosis Trauma Minor and major RAS Syphilis Viral Herpetiform RAS Recurrent intraoral HSV Zoster Major RAS EM Syphilis Minor RAS Cyclic neutropenia
persist for several weeks, ultimately leaving a scar because of the extent of necrosis [13]. A third category, known as herpetiform ulcers, is a descriptor referring to the clustered morphology of lesions. It is unrelated to herpesvirus infection. Herpetiform ulcerations are large in number, ranging from 10 to 100 at a time and consist of multiple small lesions that ultimately coalesce becoming confluent into larger plaques. Because of the size and depth they may heal with scarring in 7 to 30 days (Fig. 6, Table 1). Although lesions of RAS differ in size and extent, they are similar in appearance with yellow central slough and surrounding erythematous halo. There may be a premonitory stage lasting approximately 24 hours followed by 2 or 3 days of intense pain and then gradual lessening of the pain as healing begins [14]. The second useful classification of RAS is clinical, based on severity of affliction. Simple aphthosis represents the more usual scenario of episodic lesions that are few in number, healing within 1 to 2 weeks, and recurring infrequently. Conversely, complex aphthosis is a more severe phenomenon presenting as a clinical picture of severe, numerous, large, deep lesions, which are persistent, slow to resolve, and associated with marked pain or disability. New lesions may typically develop as older lesions resolve such that patients are frequently seldom disease-free. Occasionally, RAS may be part of a multisystem disease, such as Behc ets syndrome; fever, aphthosis, pharyngitis, and adenitis syndrome; or mouth and genital ulcers with inflamed cartilage syndrome [15]. Because the mouth is the origin of the gastrointestinal system, RAS is also seen with chronic inflammatory bowel disease including Crohns disease, ulcerative colitis, or gluten-sensitive
Grouped
Large
Small
Abbreviations: EM, erythema multiforme; HSV, herpes simplex virus; RAS, recurrent aphthous stomatitis.
enteropathy [16]. Hematinic deficiencies of iron, folate, and vitamin B12 have also been linked to etiopathogenesis of aphthous stomatitis [17,18]. Although associated with these and other entities, such as menstrual irregularity or hematologic malignancy, only 40% of patients suffering from complex aphthosis have causes that remain idiopathic and are likely caused by multiple interrelated factors. It is postulated that cross-reaction occurs between the oral epithelium and microbial microorganisms, acting as
Table 2 Diagnosis of oral ulcers based on location Location Interdental Diagnosis ANUG AHGS Recurrent intraoral HSV Cyclic neutropenia HSV Zoster Trauma RAS Viral Syphilis Trauma EM Viral RAS EM ANUG AHGS
Masticatory mucosa (keratinized)
Nonattached mucosa
Posterior Diffuse
Fig. 6. Herpetiform ulcers. A clustered group of aphthous ulcers on the mucosal lip, described morphologically as herpetiform in arrangement.
Abbreviations: AHGS, acute herpes simplex virus gingivostomatitis; ANUG, acute necrotizing ulcerative gingivostomatitis; EM, erythema multiforme; HSV, herpes simplex virus; RAS, recurrent aphthous stomatitis.
an antigenic stimulus to humoral antibodies and cellmediated immune responses. These act jointly or independently, producing ulceration of the mucosal surface [9,19,20]. Clinically, the major differential of RAS is the recurrent herpetic ulcer caused by herpes simplex virus (HSV) infection. These two common forms of acute recurrent ulceration can be distinguished primarily on the basis of location (Table 2). RAS ulcers occur on loosely attached, nonkeratinized mucosa. This includes the buccal mucosa, labial mucosa, floor of the mouth, and ventral surface of the tongue. This contrasts with herpetic ulcers, which affect keratinized mucosa [21,22]. Keratinized areas are intimately part of the masticatory process, including the hard palate, attached gingivae, and dorsal tongue, and are subject to routine oral trauma. In general, RAS is more common than recurrent intraoral HSV infection. Lesions of RAS do not have a vesicular phase and are usually larger than the individual ulcers of HSV infection (Table 3) [21]. Recurrent intraoral HSV stomatitis Herpes simplex virus infection occurs uncommonly on intraoral locations. There are two distinct forms of herpetic infections that involve the oral cavity. Primary herpetic infection is known as acute herpetic gingivostomatitis and occurs following initial infection with the (HSV) virus. Patients usually have systemic manifestations accompanying infection, and are most often children because primary infection occurs typically before adulthood. Recurrent HSV infection manifests as one of two entities. The most common form of recurrent infec-
Fig. 7. Recurrent intraoral herpes simplex virus infection with grouped, small punched-out ulcers on the keratinized surface of the hard palate and attached gingivae.
Table 3 Discriminating features of RAS versus recurrent intraoral HSV infection RAS Location Loosely attached, nonkeratinized mucosa, including lateral and ventral tongue Frequency Common Pain Intensely painful Morphology Variable Size Typically larger than HSV Vesicular phase None HSV Keratinized mucosa adherent to underlying bone and dorsal tongue (masticatory mucosa) Uncommon Mild Usually grouped Usually small, discrete Initially
Abbreviations: HSV, herpes simplex virus; RAS, recurrent aphthous stomatitis.
tion is herpes simplex labialis, otherwise known as cold sores or fever blisters. These typically occur on the cutaneous lip and vermilion and do not form within the spectrum of intraoral ulceration. A more unusual form of recurrent herpetic infection, however, is intraoral herpesvirus infection [22,23]. It is likely that many patients with intraoral HSV infection are asymptomatic and unaware of infection. When lesions are evident, however, the appearance of the HSV ulcer may be clinically indistinguishable from RAS on morphology alone. Intraoral HSV infection, like RAS, may be precipitated by minor trauma. The major distinguishing feature of HSV infection from RAS is site of involvement. HSV infection typically affects keratinized surfaces where mucosa is tightly adherent to underlying bone (Fig. 7) [9,20,22,23]. Conversely, RAS, as indicated, rarely develops on keratinized mucosa and is usually on the loose mucosal surfaces. The difference in location of recurrent HSV versus RAS is well recognized as being the key clinical feature allowing diagnosis (see Table 2) [22,23]. It has also been suggested that the pain of herpes infection is usually mild in severity, contrasting with RAS, which is frequently intensely painful. Intraoral HSV lesions are often grouped (see Table 3). Confirmation of HSV infection can usually be achieved by cytology or viral cultures, which are both reliable diagnostic methods [24,25]. Exfoliative cytology (Tzanck smear) obtained from an ulcer base may demonstrate typical features of intracellular viral infection with a ground-glass appearance to the nuclear chromatin and multinucleated giant cells. The Tzanck smear is probably the best way to obtain rapid results at low cost. Culture is traditionally the gold standard. When performing a culture, the ulcer base should be swabbed vigorously because HSV is an
intracellular infection, and adequate cell sampling is required. More recently, however, DNA amplification techniques, such as polymerase chain reaction, are available in some institutions, which are able to demonstrate minute levels of DNA in infected tissue. This is more rapid and sensitive than viral culture [26 28]. Should culture or cytology fail to demonstrate HSV infection, a biopsy may be helpful in confirming diagnosis. This is particularly useful in the immunocompromised patient where ulcers may be atypical. In the immunocompromised patient, intraoral HSV infection can occur on any location, making differentiation from RAS almost impossible. This is not the case, however, in immunocompetent patients. Cyclic neutropenia Cyclic neutropenia is a rare cause of recurrent oral ulceration. Again, the lesions clinically resemble either recurrent intraoral HSV infection or RAS; however, differentiation is usually made on the basis of other features (see Fig. 1B). Patients usually present in childhood with recurrent ulceration in a very cyclic fashion, recurring with predictable periodicity. The rhythmicity is constant for each patient [29]. In addition, patients are systemically unwell at the time of oral ulceration, with accompanying fever, malaise, lymphadenopathy, and other constitutional symptoms. Cyclic neutropenia is thought to be the result of an arrest in the maturation of polymorphonuclear leukocyte, precipitating an eruption of oral ulcers at a predictable time. The diagnosis can be confirmed by the demonstration of neutropenia (may be less than 500/mm3) on a full blood count during
episodes of ulceration, and the association with other recurrent infections. Cyclic neutropenia is a rare disorder, and although it should be borne in mind when considering the differential of oral ulcers, it is not common in day-to-day practice. Systemic disease Ulcerations of the oral mucosa may be part of a multisystem disease where involvement of the oral mucosa is a manifestation of more widespread mucosal involvement. About 15% of patients with complex aphthosis have a systemic disorder, such as Behc ets syndrome, inflammatory bowel disease, gluten-sensitive enteropathy, or rarely Wegeners granulomatosis (Fig. 8) [15,19,30 35]. In this case, the oral ulcers are mucocutaneous markers of systemic disease [9,35]. The patient may give a history of ulceration affecting other mucosal sites or symptoms of gastrointestinal involvement, providing clues to diagnosis. Serologic screening including antinuclear antibody tests (ANA), endomysial and tissue transglutaminase antibody tests, and a multisystem evaluation, is important in patients with systemic symptoms. The HIV infection is another multisystem disorder, which can have oral ulceration as part of its protean manifestations. Patients with HIV infection may have very large, painful, or unusual oral ulcerations, which are refractory to standard therapy. Recurrent episodes of oral ulceration may be more severe and more prolonged than in immunocompromised patients, and diagnosis of HIV should be borne in mind when evaluating patients with an atypical presentation or unusually severe symptomatology.
Fig. 8. Large aphthous ulceration of both oral and genital regions in a patient with Behc ets syndrome. (A) Buccal mucosa. (B) Scrotum.
Nutritional deficiencies Nutritional deficiencies have been implicated as a cause of oral ulceration, and as many as 15% to 25% of patients with complex aphthosis may have an associated hematinic deficiency (see Fig. 1) [9,17,18]. These include iron deficiency anemia, folate, zinc, or vitamin B12 deficiency. These dietary deficiencies easily can be screened on basic laboratory testing and if present are easily correctable.
Box 1. List of drugs implicated in producing oral ulceration Antithyroid drugs Nicorandil [59] Hydroxyurea [39] Alendronate [38] Calcium channel blockers [37] Captopril Nonsteroidal anti-inflammatory drugs Piroxicam, indomethacin, ibuprofen Cytotoxic drugs Methotrexate, doxorubicin
Isolated oral ulceration There are multiple causes of an isolated episode of oral ulceration. Such episodes may not necessarily come to the attention of the clinician because they are short-lived, and many patients are cognizant of the cause of their oral discomfort, and do not seek medical consultation. It is, however, useful to have a working approach to the evaluation of an acute isolated episode of oral ulceration (see Fig. 1B). Trauma Traumatic ulcers may be inflicted by the patient, or iatrogenically during dental procedures. Thermal burns may be sustained during ingestion of hot retentive foods (such as cheese), which may adhere to the mucosal surface, particularly the palate. This is known as the pepperoni pizza burn. An ill-fitting denture, broken tooth, or dental appliance is more likely to cause recurrent or persistent oral ulceration, but dental procedures can result in inadvertent trauma. This may be the result of lip biting following an anesthetic procedure, or be directly caused by dental instrumentation or manipulation within the oral cavity. The patient usually identifies this with ease. Other factitial causes of ulceration include traumatic injuries frequently seen in children with ulceration sustained during a fall with a popsicle stick, pencils, or other sharp or pointed object. Drugs Drug-induced oral ulceration is rare but should be borne in mind when evaluating oral ulcers. Most often, a drug etiology is considered in the evaluation of a chronic oral ulcer, but all chronic ulcers start out as acute, and a detailed drug history is important when evaluating recent-onset oral ulceration without other apparent cause. Drugs that have been impli-
cated in the development of oral ulceration are listed in Box 1 [36]. The drugs most commonly associated with oral ulceration are the antineoplastic chemotherapeutic agents and the nonsteroidal anti-inflammatory drugs. As new drugs are developed, however, the list of medications that have the potential to create untoward reactions, such as oral ulceration, continues to expand [37 39]. Drug-induced ulceration may occur on the basis of either immunologic or nonimmunologic mechanisms. In the immunologic mechanism, the drug or a component triggers an immune response producing a reaction directed at the epithelial surface. Humoral immunity is predominantly involved in this type of reaction. The likelihood of such reaction depends on the innate immunogenicity of the drug, the frequency, the route of administration, and the inborn reactivity of the patients immune system. With cell-mediated immunity, T cells may be simulated by antigen-presenting cells, resulting in the release of cytokines and other immune inflammatory mediators. This brings about a local cytotoxic effect with ulceration. In a nonimmunologic reaction, a drug directly stimulates monocytes or lymphocytes to release cytotoxic chemical mediators. No immune response is involved in this situation, and these reactions are not antibody dependent. Drug-induced ulcers are often large, isolated, and are often formed along the lateral borders of the tongue. They may have a white halo and be extremely persistent, progressing to chronic ulcers, which persist for months or years [37]. Diagnosis is based on an appropriate drug history and the response to withdrawal of potential drug culprits. Stevens-Johnson syndrome (erythema multiforme major) represents the severe end of the spectrum of drug-induced ulceration and can be seen with numer-
Bacterial infection Several bacteria can be responsible for producing ulceration of the oral mucosa. Acute necrotizing ulcerative gingivitis (trench mouth) Acute necrotizing ulcerative gingivitis is an ulcerative disease of the gingiva typically of sudden onset. It is a destructive periodontal infection that primarily affects the gingiva, although other areas may be involved (see Table 2). It is encountered in susceptible individuals, who are usually either malnourished or immunocompromised. In developed countries it is more typical in young adults with risk factors, such as fatigue, smoking, and poor oral hygiene [4,43]. In less developed countries it occurs in malnourished children. The disease is associated with lymphadenopathy; fever and malaise may or may not be present. The gingiva are bright red and hemorrhagic, and painful (Fig. 10). Ulcerations first appear on the interdental papillae (the triangular tissue between adjacent teeth) and are not vesicular. The ulcers extend along the margin of the gingivae, ultimately being covered by a necrotic gray-white pseudomembrane. Invasive and anaerobic bacteria are causative, but impaired host resistance is usually a factor because the bacteria are opportunistic endogenous organisms [43]. It is not communicable. Treatment is aimed at local debridement, irrigation, and appropriate antibiotic therapy. Syphilis Syphilis is caused by the spirochete Treponema pallidum. All three stages of syphilis may be associated with mucosal ulceration. In primary syphilis, the
Fig. 9. Erythema multiforme with a large area of erosion and sloughing on the hard palate.
ous medications, although the sulfonamides are most frequently implicated (Fig. 9). Erythema multiforme has also been attributed to infective etiologies, most commonly HSV infection (see Fig. 9) [40]. Iatrogenic Chemotherapy Intensive anticancer therapy affects not only malignant cells but is also toxic to normal tissues. This can result in disruption of the mucosal barrier of the mouth, allowing subsequent infection by both acquired and endogenous organisms, which become pathogenic, perpetuating the mucositis and ulceration. Controlling infectious components by antiseptic mouthwashes until the mucosal barrier is allowed to regenerate can reduce the morbidity of chemotherapy-induced mucositis and ulceration. Mucosal protectants may also reduce the mucositis. Radiation injury Management of head and neck cancers with external beam radiation typically produces mucosal ulceration, with desquamation 2 to 3 weeks after the introduction of therapy. The severity of ulceration depends on the extent of treatment and on the preexisting condition of the oral mucosa. Typically, radiation mucositis resolves between 2 weeks and 2 months following the termination of treatment [4]. Radiation is not usually associated with increased outbreaks of recurrent HSV, but is associated with bacterial colonization by both fungi and gram-negative infections [41,42]. Patients wearing dentures or other dental appliances are particularly at risk for ulceration following radiotherapy, and may warrant a dental consult before initiation of therapy. Treatment should be aimed at reducing pain and inflammation, and managing the secondary colonization.
Fig. 10. Acute necrotizing ulcerative gingivostomatitis. Boggy erythematous and inflamed gingiva affecting in particular the interdental papillae.
lesions are known as chancres and occur at the site of penetration of the organism into the mucosa. This is a painless, indurated ulcer with a raised border, which may last several weeks. The lesions are not exudative and ultimately heal without scarring. In secondary syphilis, the oral lesions are diverse, including a nonspecific pharyngitis, glistening plaques, and oral ulcers (Fig. 11) [44]. The most characteristic oral manifestation is the mucous patch (Fig. 12). This is a shallow, irregular ulceration covered by a gray-white necrotic membrane, with surrounding erythema. Lesions are occasionally painful. Snail-track ulcers result when multiple mucous patches become confluent. Lesions of tertiary syphilis manifest as locally destructive granulomas (gummas), or as glossitis with mucosal atrophy; the latter tending to malignant transformation (Fig. 13). Oral lesions of syphilis are uncommonly encountered, but with the increasing incidence of HIV infection, it is important to consider lues in the evaluation of unusual oral lesions. Gonorrhea Gonorrhea is caused by the gram-negative bacteria Neisseria gonorrhea, and is transmitted sexually. The oral mucosa can be involved through orogenital contact. Although oral gonorrhea is rare, patients can present with multiple ulcers and a fiery red appearance to the mucosa with scattered white pseudomembranes [1]. Patients with this infection may be asymptomatic, or present with severe oral symptoms and complaints of a sore throat. Lymphadenopathy may be associated. The lesions of oral gonorrhea, however, are not specific and may mimic a wide variety of other diseases including HSV, erythema multiforme, and the immunobullous diseases.
Fig. 12. The mucous patch of secondary syphilis. An ill-defined slightly eroded erythematous plaque on the posterior pharynx.
Rhinoscleroma Rhinoscleroma is a rare disease caused by Klebsiella rhinoscleromatis. Infection produces proliferative granulomas within the oral mucosa, which may, on occasion, ulcerate. Tuberculosis Mycobacterium tuberculosis present in sputum can invade the oral mucosa producing nonhealing indurated ulcers. These ulcers are typically chronic in nature. A granulomatous inflammation is produced with associated caseous necrosis. These lesions are not distinctive, and diagnosis requires tissue culture. Histoplasmosis In patients with disseminated histoplasmosis, oral ulcers may occur [1]. There are usually multiple areas of involvement, affecting the larynx, posterior tongue, palate, and buccal mucosa with associated
Fig. 11. Extensive luetic leukoplakia in a patient with secondary syphilis.
Fig. 13. The rubbery, well-demarcated gumma of tertiary syphilis seen on the lateral and dorsal tongue.
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mucosa are reviewed by Hairston, Bruce, and Rogers in this issue. Herpes simplex virus Primary HSV infection refers to initial infection of the oral mucosa with the herpes virus. This is known as primary (acute) herpetic gingivostomatitis. Primary infection, unlike recurrent HSV, affects both the keratinized and nonkeratinized mucosal surfaces (Fig. 15). Acute herpetic gingivostomatitis infection typically occurs in childhood. It is currently thought that most primary HSV infections in children and young adults are asymptomatic or subclinical. Active disease produces widespread areas of vesiculation, which rapidly ulcerate. Pharyngitis, fever, and lymphadenopathy accompany infection (Fig. 16). Lesions can affect the lip, the labial commissures, or even the face and the intraoral mucosa. Infection usually resolves within 7 to 10 days in immunocompetent patients. Zoster Varicella zoster virus (VZV) may affect the oral mucosa with two distinct entities. The first is caused by primary VZV infection (chicken pox). In this setting, shallow, vesicular ulcers occur on the oral mucosa in association with cutaneous vesicles (Fig. 17). The infection is usually seen in childhood and early adolescence, although it is becoming rare in this age group since the introduction of the varicella zoster vaccine.
Fig. 14. Histoplasmosis infection of the tongue with diffuse involvement.
pain, weight loss, and hoarseness (Fig. 14). Biopsy and culture confirm the diagnosis. Viral infection There are several viral families capable of both direct infection of the oral mucosa and the production of characteristic enanthems. These can produce acute ulceration (see Fig. 1B). Viral infections of the oral
Fig. 15. Acute herpes simplex virus gingivostomatitis in a young adult, presenting with systemic symptoms and extensive areas of ulceration and sloughing affecting the labial mucosa and gingivae of the lower alveolar ridge.
Fig. 16. Acute herpes simplex virus gingivostomatitis producing ulceration of the posterior pharynx and soft palate. The posterior pharyngitis form of primary herpes simplex virus infection is seen more typically in young adults, rather than children.
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Table 4 Available therapies for managing oral ulcers Preventative Stop smoking Adjust diet Reduce oral trauma Correct nutritional deficiencies Correct poor oral hygiene and dental caries Supportive Fluids Antipyretics Acetaminophen Analgesics Acetaminophen Narcotics if needed Maintenance of oral hygiene Hydrogen peroxide 1% as a mouthwash Topical Topical analgesics therapies 2% viscous lidocaine directly to lesions 2.5 mL lidocaine diluted in 10 mL of water as gargle Benzocaine preparations (Anbesol, Orajel Mouth-Aid) Diphenhydramine elixir 12.5 mL/5 mL as a mouthwash (Benadryl) Coating agents Antacids (Maalox, Milk of Magnesia, Kaopectate) Dental pastes: Orabase, Zilactin (applied with a cotton swab) Antiseptics Chlorhexidine (with severe infection [eg, ANUG]) Cetylpyridium chloride solution (Cepacol) Tetracycline oral suspension concentration swished 1 2 min qid, then expectorated Anti-inflammatories Amlexanox (Aphthasol) Systemic Antiviral Acyclovir, Famciclovir, Valacyclovir Antibacterial Penicillin (syphilis, ANUG) Tetracycline Metronidazole (ANUG) Antineutrophilic Colchicine (RAS) Dapsone (RAS) Immunosuppressive Azathioprine Cyclosporin Thalidomide Miscellaneous Pentoxifylline Abbreviations: ANUG, acute necrotizing ulcerative gingivostomatitis; RAS, recurrent aphthous stomatitis.
Fig. 17. Papulovesicles occurring intraorally in a patient with chicken pox and simultaneous cutaneous lesions.
The course is usually uncomplicated in normal children, and the oral lesions resolve rapidly. Confirmatory testing is seldom necessary because the clinical features are characteristic [45]. Reactivation of VZV in adulthood (following childhood infection) produces lesions characteristically known as zoster (shingles). VZV remains dormant within neural tissue, and reactivation produces a cutaneous eruption in a dermatomal distribution, corresponding to the affected nerve root [46 48]. VZV involving branches of the trigeminal nerve may produce oral ulcers. These lesions are highly characteristic, because they are unilateral with preceding pain and dysesthesia. Oral vesicles rapidly erode into ulcers, which may involve the palate, buccal mucosa, tongue, or pharynx (Fig. 18). Therapy for
Fig. 18. Shingles. Unilateral clustered vesicles on the upper mucosal lip, associated with facial pain in a patient with recurrent zoster. Distribution follows the mandibular division of the trigeminal nerve.
12
varicella zoster consists of supportive measures, and the use of antiviral drugs as dictated by the patients immune status (Table 4). Coxsackie virus The Coxsackie virus produces an entity known as hand-foot-and-mouth disease , which accurately describes the cardinal clinical features. Hand-footand-mouth disease typically occurs in epidemics in young children [5,49]. There is a mild prodromal illness with a slight fever and flu-like symptoms. There is accompanied lymphadenopathy with the development of skin and oral lesions. The lesions develop as vesicles on a red base that may ulcerate. Lesions are seen not only on the oral mucosa of the soft palate, but also on the hands and feet as the name implies. Oral lesions may occur throughout the mouth but especially on the palate, tongue, and buccal mucosa. Herpangina is also caused by Coxsackie virus infection, but lesions are usually limited to the soft palate and are not found on other cutaneous surfaces. Children are typically affected, with epidemics occurring in the summer and fall [50]. Systemic symptoms are mild, and lesions are localized to the mouth where vesicles are seen on the pharynx and posterior region of the mouth. Oral pain may be secondary to the pharyngitis associated with the disease. The disease runs a benign course, is self-limiting, and treatment is supportive. Specific viral cultures or evaluation are not necessary. Rubeola Infection with this virus produces measles. The primary oral feature is the Kopliks spot, which presents as a small erythematous macule on the buccal mucosa. It may have a white necrotic center. The lesions usually appear 1 to 2 days before systemic symptoms begin, and the oral lesions resolve rapidly. They are followed by the typical cutaneous exemplum of measles beginning on the head, neck, and progressing caudally. Epstein-Barr virus Infection with Epstein-Barr virus is often subclinical but can produce a glandular fever syndrome, which may be associated with oral ulcers on the posterior oropharynx. Infectious mononucleosis typically has associated features of profound fatigue, lymphadenopathy, and disturbance of liver function. Oral lesions are usually trivial. Diagnosis is usually made on the basis of a positive Monospot Test, which demonstrates the pathognomonic heterophile antibody.
Cytomegalovirus infection may have a similar clinical presentation to Epstein-Barr virus infection. Although usually an asymptomatic disease, it may, on occasion, produce oral lesions.
Approach to diagnosis Accurate diagnosis of the cause of oral ulceration depends on an understanding and knowledge of the various patterns of oral ulcers as reviewed. There are several important features to be determined on history. These include differentiating acute from chronic oral ulcers based on the time frame and length of affliction. If an ulcer is acute in presentation, the clinician needs to determine whether this is an isolated episode or recurrent phenomenon. Determination of this allows differentiation into two differing subsets of etiology (see Fig. 1). The presence of systemic features must be sought on direct inquiry. These include constitutional symptoms, such as fever, malaise, and weight loss; symptoms of gastrointestinal disturbance; genital or ocular involvement; or other features suggestive of systemic disease. A dietary history must be obtained and a detailed review of other medical illnesses and a thorough drug history. Patients who have symptoms suggestive of bowel involvement require further evaluation. In the absence of associated systemic features, further evaluation of patients with oral ulcers includes a full blood count and differential, screen for hematinic deficiencies, routine serum chemistry, thyroid screen, and an endomysial antibody (Box 2). The need for further investigation
Box 2. Evaluation of oral ulcers Complete blood count and differential Hematinic screen (serum iron, ferritin, zinc, folate, B12) Liver function, routine chemistry Sedimentation rate Serum endomysial antibodies for gluten-sensitive enteropathy Cytology (Tzanck smear) Culture (bacteria, viral, fungal); swab and tissue if indicated Biopsy: hematoxylin and eosin (direct and indirect immunofluorescence if indicated) Gastrointestinal evaluation if relevant
13
including culture, biopsy, or serologic studies is dictated by clinical impression.
Maalox may be combined with a topical anesthetic, such as diphenhydramine (Benadryl), which provides additional relief (see Table 4). Specific therapy Corticosteroids Corticosteroids are frequently used to shorten the duration and pain of an individual ulcer [52]. It must be remembered, however, that topical or systemic corticosteroids are contraindicated if the ulcer is caused by an infective etiology, either bacterial or viral (HSV). When appropriate, 0.1% triamcinolone acetonide (Kenalog) in an emollient dental paste, such as Orabase, can be used, applying to the mucosa several times a day. This may be sufficient for many patients. Other authors have suggested that a corticosteroid solution, such as a 0.1% solution of mometasone furoate, is a practical strategy for management of oral ulcers (three drops applied to the ulcer, massaged in with the tongue and expectorated) [53]. Other more potent topical corticosteroids, such as fluocinonide gel (Lidex) or clobetasol ointment (Temovate), are also effective. The preference of a gel versus an ointment or cream depends on physician preference and patient desire, but in general the authors favor the use of topical gels, which adhere reasonable well to the oral mucosa. Numerous mouthwashes are available for symptomatic relief of ulcers. Most of these contain an antibacterial agent, which may have an anti-inflammatory and an analgesic property. Mouth rinses containing Triclosan (a lipid-soluble antimicrobial agent) have been shown to reduce the incidence of recurrent aphthous ulcers [54]. There are a variety of magic mouthwashes particular to various institutions, which usually contain a combination of tetracycline oral suspension and mycostatin, together with an anesthetic, such as diphenhydramine, and sometimes an additional corticosteroid component. Anti-infective In addition to control of oral microflora, systemic therapy with oral or occasionally intravenous antiviral or antibacterial antibiotic is sometimes necessary. Systemic acyclovir may be indicated for treatment of oral herpesvirus infection, particularly in severe disease or in immunocompromised individuals. Newer antiviral agents, such as famciclovir and valacyclovir, have more elegant and convenient dosing schedules, and are increasingly used in management of oral herpesvirus infections. Prophylactic antiviral therapy is helpful in managing recurrent episodes of intraoral HSV infection.
Management Management of oral ulcers often requires a comprehensive approach sometimes involving more than one subspecialty (see Table 4). Management of underlying disease Correction of causative factors needs to be addressed. Discontinuation of suspected medications may be necessary, and removal of potential irritant stimuli is indicated. The patient may need to be referred to dentistry to remove or repair ill-fitting dental appliances, correct rough-edged teeth, or attend to periodontal hygiene. If oral ulceration is part of a general multiorgan illness, this may need to be brought under control with immunosuppressive or other appropriate therapy. Primary nutritional deficiencies, or those secondary to inflammatory bowel disease, must be corrected (see Table 4). Supportive measures Irrespective of the cause of oral ulceration, attention must be given to immaculate oral hygiene. Patients should regularly cleanse their teeth using a soft-bristled toothbrush, fluoride toothpaste, and dental floss as necessary. Periodontal disease needs to be addressed. A dilute antiseptic or alkaline mouthwash is a useful adjuvant. Patients may need to adjust their diet, following a soft, bland diet eliminating sharpedged, hard, acidic, or irritating foods, such as popcorn, chips, pretzels, and other salty foods. A gluten-free diet is indicated in patients with RAS secondary to celiac disease. Symptomatic management is often adequate for many types of acute oral ulcers, particularly if shortlived. Topical anesthesia may be necessary to provide pain relief and allow patients to eat. This can be achieved by applying viscous lidocaine to the ulcer base with a cotton-tipped applicator. Alternatively, patients may gargle with viscous lidocaine (Xylocaine) diluted in water, swishing in the mouth for 2 to 3 minutes (half a teaspoon of Xylocaine to two teaspoons of water). Several other over-the-counter products are available to provide relief for oral ulcerations [51]. These include emollient dental pastes, such as Orabase. Cytoprotective or coating agents, such as Sucralfate (Carafate), or aluminum-magnesium antacids (Maalox) can be used as a gargle.
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A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115 [6] Fischman S. Oral ulcerations. Semin Dermatol 1994; 13:74 7. [7] Hale L, Wojnarowska F. Mouth ulcers: how can you help? Practitioner 1997;241:86 90. [8] Lake RIE, Thomas SJ, Martin NG. Genetic factors in the aetiology of mouth ulcers. Genet Epidemiol 1997; 14:17 33. [9] Rogers III RS. Recurrent aphthous stomatitis: clinical characteristics and associated systemic disorders. Semin Cutan Med Surg 1997;16:278 83. [10] Rovin S. On the etiology of recurring oral ulcers. Dent Clin North Am 1966:3 10. [11] Scully C, Shotts R. ABC of oral health: mouth ulcers and other causes of orofacial soreness and pain. BMJ 2000;321:162 5. [12] Cooke B. Recurrent oral ulcers. Br J Dermatol 1969; 81:159 61. [13] Chung JY, Ramos-Caro FA, Ford MJ, et al. Recurrent scarring ulcers of the oral mucosa. Arch Dermatol 1997;133:1162 3. [14] Redman RS. Recurrent oral ulcers. Northwest Dent 1972;51:232 4. [15] Rogers III RS. Recurrent aphthous stomatitis in the diagnosis of Behc ets disease. Yonsei Med J 1997; 38:370 9. [16] Ferguson MM, Wray D, Carmichael HA, et al. Coeliac disease associated with recurrent apthae. Gut 1980;21: 223 6. [17] Porter S, Flint S, Scully C. Recurrent aphthous stomatitis: the efficacy of replacement therapy in patients with underlying hematinic deficiencies. Ann Dent 1992;51:14 6. [18] Rogers III RS, Hutton K. Screening for haematinic deficiencies in patients with recurrent aphthous stomatitis. Aust J Dermatol 1986;27:98 103. [19] Ghate JR, Jorizzo JL. Behc ets disease and complex aphthosis. J Am Acad Dermatol 1999;40:1 18. [20] Rogers III RS. Recurrent aphthous stomatitis: clinical characteristics and evidence for an immunopathogenesis. J Invest Dermatol 1977;69:499 509. [21] Weathers DR, Griffin JW. Intraoral ulcerations of recurrent herpes simplex and recurrent aphthae: two distinct clinical entities. J Am Dent Assoc 1970;81: 81 8. [22] Schneider LC, Schneider AE. Diagnosis of oral ulcers. Mt Sinai J Med 1998;65:383 7. [23] Eisen D. The clinical characteristics of intraoral herpes simplex virus infection in 52 immunocompetent patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:432 7. [24] Nahass GT, Goldstein BA, Zhu WY, et al. Comparison of Tzanck smear, viral culture, and DNA diagnostic methods in detection of herpes simplex and varicellazoster infection. JAMA 1992;268:2541 4. [25] Solomon AR, Rasmussen JE, Weiss JS. A comparison of the Tzanck smear and viral isolation in varicella and herpes zoster. Arch Dermatol 1986;122:282 5. [26] Safrin S, Shaw H, Bolan G, et al. Comparison of virus culture and the polymerase chain reaction for diagnosis
Systemic antibiotic treatment is generally necessary to control oral ulcers resulting from bacterial infections, particularly with severe gingival disease as seen in acute necrotizing ulcerative gingivitis. Specific infective diseases, such as syphilis, gonorrhea, and so forth, naturally require appropriately directed antibiotics. Other agents Additional or other therapeutics targeted to manage oral ulcers depend on the etiology. In the case of RAS, a number of regimens have been found to be effective including the use of colchicine, dapsone, pentoxifylline, and even transdermal nicotine patches [55 58]. Ulcers related to systemic disease usually require immunosuppressive therapy to achieve remission of disease. Detailed discussion on management of specific ulcer subsets is beyond the scope of this article.
Summary In general, a detailed history and examination of the patient provides sufficient information for diagnosis. The pattern, frequency, and natural history of ulcer episodes are helpful. The presence or absence of associated features and the site of oral involvement guides most physicians accurately in the diagnosis. Additional investigations, including blood tests, and occasionally the use of oral cultures or biopsy, are needed to make a definitive diagnosis. A multispecialty approach is often necessary to evaluate patients with other systemic features. Most acute oral ulcers heal spontaneously without specific therapy being necessary, but an understanding of the cause of the ulcer is reassuring to the patient and guides the clinician in management to prevent recurrent episodes of oral ulceration, or chronicity of ulcers.
References
[1] Randle HW. Treatment of oral ulcers. Dermatol Clin 1993;11:801 8. [2] Budtz-Jorgensen E. Oral mucosal lesions associated with the wearing of removable dentures. J Oral Pathol 1981;10:65 80. [3] Reeve C, Van Roekel N. Denture sore mouth. Dermatol Clin 1987;5:681 6. [4] Salisbury III PL, Jorizzo JL. Oral ulcers and erosions. Adv Dermatol 1993;8:31 79. [5] Hebert AA, Lopez MD. Oral lesions in pediatric patients. Adv Dermatol 1997;12:169 93.
A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115 of mucocutaneous herpes simplex virus infection. Sex Transm Dis 1997;24:176 80. Coyle PV, Desai A, Wyatt D, et al. A comparison of virus isolation, indirect immunofluorescence and nested polymerase chain reaction for the diagnosis of primary and recurrent herpes simplex type 1 and type 2 infections. J Virol Methods 1999;83:75 82. Koropchak CM, Graham G, Palmer J, et al. Investigation of varicella-zoster virus infection by polymerase chain reaction in the immunocompetent host with acute varicella. J Infect Dis 1991;163:1016 22. Fink-Puches R, Kainz J, Kahr A, et al. Granulocytecolony stimulating-factor treatment of cyclic neutropenia with recurrent oral aphthae. Arch Dermatol 1996; 132:1399 400. International study group for Behc ets disease. Criteria for diagnosis of Behc ets disease. Lancet 1990;335: 1078 80. Jorizzo JL, Rogers III RS. Behc ets disease. J Am Acad Dermatol 1990;23:738 41. Lee S, Bang D, Lee E-S. Diagnosis of Behc ets disease. In: Lee S, Bang D, Lee E-S, John S, editors. Behc ets disease. Berlin: Springer; 2001. Matfin G, Durand D, DAgostino A, et al. An uncommon cause of oral ulcers. Hosp Pract (Off Ed) 1998;33: 11 4. Onder M, Gurer M. The multiple faces of Behc ets disease and its aetiological factors. JEADV 2001;15: 126 31. Schreiner D, Jorizzo J. Behc ets disease and complex aphthosis. Dermatol Clin 1987;5:769 78. Zelickson BD, Rogers III RS. Oral drug reactions. Dermatol Clin 1987;5:695 708. Cohen DM, Bhattacharyya I, Lydiatt WM. Recalcitrant oral ulcers caused by calcium channel blockers: diagnosis and treatment considerations. J Am Dent Assoc 1999;130:1611 8. Gonzalez-Moles MA, Bagan-Sebastian JV. Alendronate-related oral mucosa ulcerations. J Oral Pathol Med 2000;29:514 8. Paleri V, Lindsey L. Oral ulcers caused by hydroxyurea. J Laryngol Otol 2000;114:976 7. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of charactistics, diagnostic criteria, and causes. J Am Acad Dermatol 1983;8: 763 75. Makkonen T, Borthen L, Heimdahl A, et al. Oropharyngeal colonization with fungi and gram-negative rods in patients treated with radiotherapy of the head and neck. Br J Oral Maxillofac Surg 1989;27:334 40. Redding S, Luce E, Boren M. Oral herpes simplex virus infection in patients receiving head and neck
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Viral diseases of the oral mucosa

Bethany R. Hairston, MDa, Alison J. Bruce, MDb,c,*, Roy S. Rogers III, MDb,c
a
Department of Dermatology, Mayo Graduate School of Medicine, Rochester, MN 55905, USA b Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA c Department of Dermatology, Mayo Medical School, Rochester, MN 55905, USA
The oral mucosa is often involved in diseases caused by viral pathogens. Viruses isolated from the oral cavity may be direct causative agents, adjuncts in the disease process, or superinfection of a separate primary process. Viruses have variable mucosal processes and stages of evolution, and many viruses have similar clinical presentations. Often, the investigator must consider the oral lesions in the context of the general clinical presentation and use laboratory tests for diagnosis. Both DNA and RNA viral families have been implicated in oral mucosal diseases.
DNA viruses Human herpesvirus Multiple human herpesvirus (HHV) serotypes are associated with oral diseases (Table 1). All HHVs consist of double-stranded DNA. The viruses replicate in the host cell, causing both cytopathic and inflammatory-mediated cell damage. Human herpesvirus 1 and human herpesvirus 2 ( herpes simplex viruses) Herpes simplex virus (HSV)-1 and HSV-2 are associated with primary and recurrent mucocutaneous disease. The location of the disease depends on the site of inoculation. HSV-1 is responsible for more than 90% of the lesions caused by HSV in the oral mucosa
* Corresponding author. Department of Dermatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail address: bruce.alison@mayo.edu (A.J. Bruce).
[1]. More than 85% of the worlds population has serologic evidence of previous HSV-1 exposure [2]. Most persons are exposed to the virus during childhood by mucocutaneous contact with another infected person. A primary infection is the first infection with HSV in a seronegative patient; many people have asymptomatic primary infections and are unaware that they harbor the virus. Primary exposure to HSV-1 and, less commonly, HSV-2 results in the syndrome known as primary, or acute, herpetic gingivostomatitis. The disease is most common in children 1 to 5 years old or young adults, and the onset is approximately 5 to 10 days after intimate mucocutaneous exposure to HSV. The virus must come into contact with the mucosa or abraded skin for infection to occur [3]. Fever, sore throat, and painful vesicles that progress to erosions and ulcerations may be present. Most commonly, lesions are located on the buccal and gingival mucosa, hence, the term gingivostomatitis (Fig. 1). Both keratinized and nonkeratinized oral mucosa may be involved [4]. In severe cases, dysphagia and lymphadenopathy may be present. The episode usually lasts 10 to 14 days. Primary infections in adults are less likely to result in gingivostomatitis; however, HSV-associated pharyngitis may be a component of a mononucleosis-like syndrome (Fig. 2) [5]. Following primary infection, HSV migrates by retrograde axonal flow to the sensory ganglion innervating the primary lesion [6]. An eruption that occurs after latency is known as reactivated or recurrent infection and occurs in approximately 40% of those harboring HSV-1 [7,8]. HSV-2 recurrences in the oral mucosa are less common than HSV-1 recurrences [9]. Recurrences generally are milder and of shorter duration than primary episodes in immunocompetent hosts
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B.R. Hairston et al / Dermatol Clin 21 (2003) 1732
Table 1 Herpetic infections of the oral mucosa Oral disease Herpetic gingivostomatitis Herpes labialis Varicella Herpes zoster Mononucleosis Oral hairy leukoplakia Cytomegalovirus Exanthema subitum Kaposis sarcoma Etiology HSV-1, HSV-2 HSV-1, HSV-2 HHV-3 (varicella-zoster virus) HHV-3 (varicella-zoster virus) HHV-4 (Epstein-Barr virus) HHV-4 (Epstein-Barr virus) HHV-5 HHV-6 HHV-8
Abbreviations: HHV, human herpesvirus; HSV, herpes simplex virus. From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy 2002;15:271 87: with permission.
and typically occur three or four times per year. Activation of the virus with subsequent anterograde migration along the sensory nerve usually is heralded by a tingling, itching, or burning sensation at the vermilion border. Clustered lesions progress from
erythematous papules to vesicles and may ulcerate, producing the characteristic lesions of herpes labialis (Fig. 3). Recurrent intraoral HSV with vesicles and ulcers on the gingivae and hard palate may occur alone or in parallel with herpes labialis (Fig. 4). Healing generally occurs in 8 to 10 days. Recurrences may be spontaneous or associated with multiple factors, including emotional stress, fatigue, illness, dental trauma [10], neurosurgical axonal injury [11], orofacial fracture [12], and ultraviolet light [10,13,14]. Immune system compromise from malignancy or immunosuppressive therapy [15,16], radiation therapy [17], transplantation regimens [18 20], and HIV infection [21,22] may result in more frequent and more severe recurrences, with potential extension into the deep mucosal and cutaneous layers of the skin [23]. Recurrent erythema multiforme has been linked to preceding HSV infection and is known as herpesassociated erythema multiforme (Fig. 5) [24,25]. In a British study that reviewed recurrent erythema multiforme, approximately 71% of cases had previous HSV infection. Oral erosions or ulcerations were common
Fig. 1. Primary herpetic gingivostomatitis. (A) Vesicles and erosions of palate. (B) Well-circumscribed erosions of tongue. (C) Vesicles and erythema of gingivae and interdental papillae. (D) Labial mucosal vesicles and erosions. [(A) and (D) From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatol Ther 2002;15:271 87. By permission of Blackwell Publishing, Inc: with permission.]
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Fig. 2. Herpes pharyngitis, with erythema and erosions of posterior oropharynx.
(69%), especially of the buccal mucosa and palate [24]; targetoid lesions of the lips have also been described [25]. Diagnosis of primary and recurrent HSV is aided by the location and configuration of the lesions and associated clinical features. Differentiation of herpetic lesions from the herpetiform variant of recurrent aphthosis may be difficult [26]. Typically, aphthous ulcerations occur predominantly on the nonkeratinized mucosa, whereas recurrent HSV generally is found on keratinized mucosa overlying bony prominences (ie, alveolar ridges and the hard palate) [26,27]. Multiple laboratory tests are available to assist in the diagnosis of herpetic infection (Table 2). Under ideal conditions, the Tzanck smear is positive in approximately 50% of HSV infections [28]. Histologic
examination demonstrates a combination of direct cytopathic effect and inflammatory response [3]. Traditionally, the reference standard of diagnosis has been culture, with sensitivity increased in early vesicular lesions, primary disease, and immunosuppressed persons [23]. The polymerase chain reaction (PCR) detects specific DNA sequences in HSV infection and herpes-associated erythema multiforme [25,29] and is more sensitive than cell culture for detecting HSV [30 32]. Direct immunofluorescence [33] and in situ hybridization (ISH) [34] demonstrate HSV in cutaneous specimens. Serologic testing is useful in identifying past infection but has little value in diagnosing acute mucocutaneous HSV infection because titers are slow to rise [23]. Mouth rinses containing topical anesthetic agents (viscous lidocaine [Xylocaine]) or diphenhydramine (Benadryl) plus coating agents (magnesium-containing antacids) are helpful in relieving oral discomfort in severe herpetic gingivostomatitis [4]. Fluid and electrolyte balance should be maintained in infants and children. In a randomized, placebo-controlled clinical trial, oral acyclovir was effective for herpetic gingivostomatitis in children, but it has not been approved by the US Food and Drug Administration (FDA) for this indication [35]. Topical agents are often used to treat recurrent herpes labialis. In a recent double-blind, placebocontrolled study of recurrent herpes labialis, docosanol 10% cream, a 22-carbon, saturated, primary alcohol available as an over-the-counter medication (Abreva), was found to be clinically efficacious in decreasing the mean time to healing and the duration of symptoms [36]. Penciclovir (Denavir) is a topical nucleoside analogue superior to both placebo [37] and acyclovir for treatment of recurrent herpes labialis [38]; it has been approved by the FDA for recurrent disease. Topical
Fig. 3. (A) Recurrent herpes labialis of lower lip. (B) Well-circumscribed erosions of lateral tongue in association with lip lesions. [(A) From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy 2002;15:271 87: with permission.]
20
Fig. 4. Recurrent intraoral herpes simplex virus in patient with hairy cell leukemia.
acyclovir cream and ointment have been less effective for the treatment and suppression of recurrent HSV, likely because of poor absorption through perioral skin [14]. These three topical agents were compared recently in an animal model (guinea pig) of cutaneous HSV, and the efficacy of penciclovir was greater than that of acyclovir cream, which was greater than or equal to that of acyclovir ointment; the efficacy of all compared agents was superior to that of docosanol cream [39]. Protection of the lips from ultraviolet exposure with sunscreen is also beneficial [13]. Oral antiviral therapy has not been approved by the FDA for either the treatment or suppression of herpes labialis in immunocompetent persons; however, acyclovir has proved to be efficacious in decreasing lesion size and healing time without decreasing the number of lesions if treatment is started in the prodrome or erythema stage [14]. Famciclovir (Famvir), the well-absorbed oral prodrug of penciclovir, has been shown clinically to decrease lesion size and time to healing in herpes labialis induced by ultraviolet light [40]. Acyclovir prophylaxis against herpes labialis has been demonstrated to decrease the frequency
of recurrent episodes [41,42]. The effects from the therapy do not seem to be long-lasting, however, because the pretreatment recurrence rate returns after cessation of acyclovir treatment [41]. Acyclovir is the treatment of choice for immunosuppressed persons; oral, intravenous, and topical ointment formulations have been approved by the FDA [43]. Intravenous foscarnet (Foscavir) is recommended for acyclovir-resistant disease [44]. Suppressive therapy with acyclovir is commonly used in transplantation and chemotherapeutic regimens [45]. Famciclovir is indicated for the treatment of recurrent herpes labialis in HIV because it is as effective and well-tolerated as high-dose acyclovir [46]. Famciclovir also has been shown to decrease the frequency, duration, and severity of HSV recurrences in HIVinfected persons, but it has not been approved by the FDA for this indication [47]. Human herpesvirus 3 (varicella-zoster virus) Primary infection with varicella-zoster virus (VZV), resulting in varicella, occurs through direct contact with lesions or inhalation of infective respiratory droplets. Varicella is primarily a disease of childhood, with 90% of cases occurring in children younger than 10 years [48]. One study has demonstrated a nearly 99% rate of serologic immunity among adults [49]. The disease generally is more severe and prolonged in older persons [50]. After a 14- to 16-day incubation period following exposure to VZV, a generalized pruritic eruption with crops of erythematous maculae, papules, vesicles, pustules, and crusted lesions begins on the face and spreads rapidly to the trunk, with relative sparing of the extremities. Oral lesions may coincide in onset with the cutaneous eruption. Painful vesicles that may ulcerate are found most commonly on the palate or buccal or pharyngeal mucosa (Fig. 6) [51].
Fig. 5. Herpes-associated erythema multiforme. (A) Hemorrhagic crusting of lower lip. (B) Targetoid papules of palm.
B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 Table 2 Diagnostic tools for detection of herpetic infections Test Histopathology Method Hematoxylin and eosin stain Medium Tissue Comments Ballooning and reticular epidermal degeneration with multinucleated keratinocytes in HSV, VZV [3] Cytomegalic nuclear and cytoplasmic inclusions in CMV [94] Useful for HSV, VZV [33], and EBV [84]
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Direct immunofluorescence Culture Polymerase chain reaction In situ hybridization
Epifluorescence microscopy following monoclonal antibody application [33] Cell culture growth to detect cytopathic change [28] Identification of viral nucleic acid
Tissue
Tissue, vesicular fluid Tissue, vesicular fluid, paraffin-embedded tissue [65] Tissue, paraffinembedded tissue
Fluorescein-labeled DNA probe visualized with antifluorescein antibody [66] Detection of antibodies Characteristic viral cytopathic changes
Serology Tzancks smear
Serum Vesicle base scraping
Reference standard of detection for all herpesviruses Most sensitive means of detecting HSV [30 32] and VZV [28,64] Effective for all herpesviruses Demonstrates location of virus in tissue Useful for HSV [34], VZV [66], EBV [75,83], and CMV [94] Correlation with past infection Rapid, inexpensive Multinucleated keratinocytes in HSV and VZV [28,63]
Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; VZV, varicella-zoster virus. From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy 2002;15:271 87: with permission.
Fig. 6. Varicella infection with vesicles and surrounding palatal erythema. (From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy 2002;15:271 87: with permission.)
Similar to HSV, VZV establishes latency in sensory ganglia. Recurrent disease occurs in the dermatome innervated by the affected sensory ganglion. A recurrent episode is known as herpes zoster. Among multiple predisposing factors for herpes zoster are HIV [22,52 54], malignancy [55,56], iatrogenic immunosuppression with corticosteroids [57], transplantation regimens [50,58], and senescence of the cellular immune system related to aging [59]. The clinical features of herpes zoster include a dermatomal eruption heralded by segmental neuralgia and pruritus, followed by herpetiform vesicles and erythema with progression to pustules and crusting in 7 to 10 days. Cephalic zoster involves the second and third divisions of the trigeminal nerve and may present with oral cavity vesicles on an erythematous base, with erosions, ulceration, and crusting preceded by odontalgia (Fig. 7) [60]. Tooth exfoliation and mandibular necrosis are reported complications [54,61]. Ramsay Hunt syndrome, with neuritic involvement and inflammation of cranial nerves VII and VIII, may result in tinnitus, vertigo, otalgia, ageusia, hearing loss, and mucosal lesions on the palate and anterior two thirds of the tongue [62]. Facial palsy and deafness are potential complications.
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Fig. 7. Herpes zoster. (A) Unilateral erythema, erosions, and crusting of upper lip and cheek. (B) Erosion of palate. (C) Unilateral erosion and fissuring of tongue (arrow). [(A) and (B) From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy 2002;15:271 87: with permission.]
The diagnostic methods for VZV are similar to those for HSV. The Tzanck smear is positive in approximately 75% to 80% of cases of herpes zoster and viral cultures are positive in 44% to 60%, reflecting the difficulty with culturing VZV [28,63]. PCR is more sensitive than viral culture [28,64] and can detect VZV in formalin-fixed tissue specimens, vesicle fluid swabs, crusts, and Tzanck smear debris [65]. Neither PCR nor culture reliably demonstrate VZV from oral samples in primary varicella, however, because the virus is not harbored in the oropharynx after the incubation period [64]. Direct immunofluorescence [33] and ISH [66] also distinguish VZV from HSV. Positive serology correlates with immunity [67]. Acyclovir has been shown to decrease both the duration and severity of varicella in children [68]; however, it has not been approved by the FDA nor widely used in clinical practice because of the benign course of the disorder in immunocompetent hosts, financial considerations, and concern for emergence of acyclovir resistance. Painful oral lesions may respond to topical anesthetic mouth rinses [69]. Acyclovir is the drug of choice for adults and immunosup-
pressed persons. The live, attenuated OKA varicella vaccine has been approved by the FDA and is given to persons older than 12 months, those with chronic disease, and those who are immunosuppressed [48,70]. Intraoral herpes zoster generally is more severe and painful than oral varicella; oral analgesics administered in combination with topical anesthetic preparations may be needed. Acyclovir, famciclovir, and valacyclovir (Valtrex) have all received FDA approval for treatment of herpes zoster because the three agents have comparable efficacy and safety profiles [71 73]. Corticosteroids generally are not necessary for adjunctive treatment in herpes zoster except in Ramsay Hunt syndrome, for which the combination of acyclovir and prednisone has been shown to reduce facial nerve degeneration [74]. Human herpesvirus 4 (Epstein-Barr virus) Epstein-Barr virus (EBV) induced diseases with oral manifestations include infectious mononucleosis, oral hairy leukoplakia, and Burkitts and nasopharyngeal lymphomas. EBV infects multiple cell lines, including B and T lymphocytes and squamous epithe-
23
lial cells of the oropharyngeal and nasopharyngeal mucosa [75]. The virus establishes latency in B lymphocytes and may be reactivated in immunodeficiency. Infectious mononucleosis is associated with palatal petechiae, pharyngeal erythema, and tonsillar hypertrophy. These are nonspecific findings that may be seen in many infections of the upper respiratory tract. Fever, cervical lymphadenopathy, and a morbilliform, erythematous exanthem may be present. The cutaneous features are more common in childhood. In a severe case, infectious mononucleosis may be associated with necrotic gingival tissue [69]. The diagnosis is based on clinical symptoms, hematologic findings, and the presence of heterophil antibodies. Detection of EBV-specific antibody is confirmatory [76]. Because the disease is self-limited, treatment is usually symptomatic. Acyclovir is not effective [77]. Coinfection with b-hemolytic streptococci should be ruled out and, if present, treated with antibiotics; however, neither ampicillin (Omnipen, Principen) nor amoxicillin (Amoxil, Augmentin) should be used because of the potential for generalized morbilliform eruptions in patients with mononucleosis treated with these medications [78,79]. Oral hairy leukoplakia is a benign, asymptomatic white patch or plaque of hyperplasia most commonly located on the lateral border of the tongue (Fig. 8). Extension to the dorsal and ventral tongue, buccal mucosa, palate, and tonsillar region has been described [80]. It occurs most often in persons immunocompromised from HIV infection, but it has been reported in transplant recipients [81] and in patients with renal failure associated with Fabrys disease [82]. Oral hairy leukoplakia may be the first clinical sign of HIV
Fig. 9. Epstein-Barr virus demonstrated with in situ hybridization in the epidermis of patient with oral hairy leukoplakia.
infection in more than 5% of cases [22]. Diagnosis is aided by histopathologic examination; EBV may be identified with ISH (Fig. 9) [75,83], Southern blot hybridization, direct immunofluorescence, or electron microscopy [84]. Treatment with acyclovir is successful but has been associated with recurrence [85,86]. Other measures reported to improve the leukoplakia during treatment include antiretroviral therapy for HIV-associated disease [87], topical 0.1% vitamin A acid [86], and topical podophyllum resin [88]. EBV has been identified as an etiologic factor in Burkitts lymphoma by serologic tests [89] and ISH [83]; this disease is divided into African endemic [83] and nonendemic forms [89]. Nonendemic forms, however, are less likely to be associated with EBV [89,90]. Burkitts lymphoma is the most common childhood cancer in tropical Africa [75]. The characteristic features are palpable jaw masses, cervical lymphadenopathy, sore throat, loosened teeth, and odontalgia. The disease is responsive to chemotherapy. EBV is also associated with nasopharyngeal carcinoma, which most commonly presents with metastatic disease-containing lymphadenopathy. EBV-related nasopharyngeal carcinoma is the most common cancer in parts of southern Asia; 75% of nasopharyngeal carcinomas in the United States are induced by EBV [75]. Human herpesvirus 5 (cytomegalovirus) Primary infection with cytomegalovirus is usually subclinical and asymptomatic, although patients may have a mononucleosis-like syndrome with fever, lymphadenopathy, pharyngitis, and inflamed salivary glands. Cytomegalovirus persists in a latent phase, but reactivation rarely affects the skin and mucous membranes. Oropharyngeal ulcerations caused by cytomegalovirus have been described in iatrogenic
Fig. 8. Oral hairy leukoplakia with typical corrugated white plaque on lateral tongue. (From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy 2002;15:271 87: with permission.)
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immunosuppression [91], HIV infection [22,92], and bone marrow [93] and organ transplantation [92]. Cytomegalovirus may be cultured in fibroblast media. Characteristic histopathologic features include basophilic intranuclear inclusions and granular cytoplasmic inclusions, thus the name cytomegalic inclusion disease. Serologic testing, ISH, or PCR identifies the virus [94]. Ganciclovir has been effective in the treatment of cytomegalovirus-related oropharyngeal disease [92]. Human herpesvirus 6 HHV-6 is responsible for exanthema subitum (roseola infantum), the most common infectious exanthem during the first 2 years of life [95,96]. The virus remains latent in the salivary gland and can be transmitted by oropharyngeal secretions. The enanthem consists of erythematous maculae on the soft palate. It may precede cutaneous exanthem of discrete, 1- to 2-mm pink- to rose-colored maculae that originate on the trunk following defervescence [97]. Serologic testing may detect antibody to HHV-6 [96]. Treatment is supportive. Human herpesvirus 8 Kaposis sarcoma is a vascular neoplasm with several clinical variants: classic, African endemic, iatrogenic immunosuppression, and epidemic HIVassociated. HHV-8 has been isolated from all subtypes of Kaposis sarcoma, although its specific role in the pathogenesis of the disease is unknown [98,99]. Oral Kaposis sarcoma lesions are often the first indication of HIV infection [22]. Erythematous to violaceous maculae, patches, plaques, and nodules occur on the
Fig. 11. Violaceous exophytic and fungating plaque on hard palate, with violaceous macules and papules of lips in person with classic Kaposis sarcoma.
palate, gingiva, and tongue (Figs. 10 and 11). Generally, Kaposis sarcoma of the oral cavity is asymptomatic, although bleeding, pain, and ulceration may occur. Because HHV-8 is not exclusive to Kaposis sarcoma lesions, other pathogenic factors may contribute to the development of the sarcoma [98]. In conjunction with histologic examination, HHV-8 may be identified by PCR. Specific treatment options for oral Kaposis sarcoma include local excision [22], cryotherapy [100], injection of a sclerosing agent [101], intralesional interferon alfa-2b [102], intralesional vinblastine [103], or site-directed radiotherapy [104]. Radiotherapy must be used with caution to avoid secondary mucositis [105]. Systemic chemotherapy generally is reserved for patients with rapidly progressive or disseminated disease or a high tumor burden. Antiretroviral therapy in HIV-associated cases may interfere with immune deterioration and prevent or reverse Kaposis sarcoma [106]. No treatment has been approved specifically by the FDA for Kaposis sarcoma of the oral cavity. Human papillomavirus Human papillomavirus (HPV) is a nonenveloped, double-stranded DNA virus with at least 80 different genotypes [107]. Diseases of the oral cavity induced by HPV include squamous papilloma, oral verruca vulgaris, condyloma acuminatum, and focal epithelial hyperplasia (Table 3). Several subtypes of HPV have been linked to the induction of malignancy [107,108] but further study is needed to determine the role of HPV in the etiology of oral squamous cell carcinoma. Squamous papillomas and oral verrucae Squamous papillomas and oral verrucae are commonly referred to as oral warts. Both lesions are
Fig. 10. Violaceous plaques with erosion on hard palate, representing HIV-associated Kaposis sarcoma. (From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy 2002;15: 271 87: with permission.)
B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 Table 3 Benign HPV-associated oral diseases Oral manifestation Squamous papilloma Verruca vulgaris Condyloma acuminatum Focal epithelial hyperplasia Predominant HPV genotype HPV-6, HPV-11 [108,126] HPV-2, HPV-4 [108,125] HPV-6, HPV-11 [108,126] HPV-11, HPV-13, HPV-32 [108,113 115] Lesion
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Pedunculated, pink papule on palatine, buccal, labial mucosa Sessile, papillomatous, pink papule of lips, gingivae Multiple, soft, sessile, pink coalescing papules of palate, tongue Multiple, soft, pink papules of lips, buccal mucosa
Abbreviations: HPV, human papillomavirus.
typically exophytic, verrucous papules or plaques located on any oral mucosal surface, including the lips. A distinguishing feature between these two diseases is that squamous papillomas tend to be small and pedunculated, whereas the verrucae are more sessile [4]. Koilocytes are more common in oral verrucae than in squamous papillomas [108]. Condyloma acuminatum Condyloma acuminatum is predominantly an anogenital disease; however, lesions of the palate and tongue have been reported [109,110]. Oral lesions likely are acquired by sexual transmission, hematogenous spread, or autoinoculation by the hands from primary genital lesions. Oral condyloma acuminatum typically consists of multiple, small, white- to fleshcolored, soft exophytic papules that enlarge to plaques with a pebbled surface. Focal epithelial hyperplasia (Heck disease) Focal epithelial hyperplasia occurs most commonly in Native Americans and Eskimos of Greenland [111]. It also has been described in cases of HIV
infection [112]. Because the disease is relatively isolated to these subgroups of the population, a genetic predisposition and inheritance pattern are likely factors. The disease usually is located on the buccal mucosa or lips as asymptomatic solitary or multiple whitish papules; HPV DNA has been identified with ISH [113] and PCR in lesions of the oral mucosa [114]. Lesions often remit spontaneously. Mucosal involvement may be extensive and painful, however, and may be treated with surgical excision, cryotherapy, or laser ablation [22]. Topical interferon-b [115] and carbon dioxide laser [114] therapies have been described. Poxvirus Molluscum contagiosum Poxvirus, responsible for molluscum contagiosum, is a DNA virus that replicates in the cytoplasm of infected cells. Oral molluscum contagiosum presents as flesh-colored, dome-shaped, smooth-surfaced or umbilicated papules and is most commonly found in immunocompromised persons. Sites reported to be
Table 4 Oral infections caused by RNA viruses Oral infection Measles Mumps Rubella Hand-footand-mouth disease Herpangina Etiology Paramyxovirus Paramyxovirus Togavirus Picornavirus Picornavirus Transmission Infectious respiratory droplets, saliva Infectious respiratory droplets, saliva Infectious respiratory droplets, saliva Saliva, feces Saliva, feces Lesion Kopliks spots on buccal mucosa, Herrman spots on tonsils Edema and erythema of salivary gland orifices Forschheimer sign of palate Vesicles, erosions, or ulcerations of palate, buccal mucosa, tongue Vesicle or ulcerations with surrounding erythema of palate, tonsillar fauces, uvula
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RNA viruses All the RNA viruses that affect the oral mucosa consist of a single-stranded nucleic acid molecule. RNA viral enanthems may be associated with a cutaneous exanthem except for the paramyxovirus that causes mumps. Diseases caused by RNA viruses are listed in Table 4.
Paramyxovirus
Fig. 12. Measles infection with Kopliks spots having progressed to extensive necrosis, erosions, and ulceration of buccal mucosa. (From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy 2002;15:271 87: with permission.)
affected include the lips, buccal mucosa, and palate [116]. Large intracytoplasmic inclusion bodies (Henderson-Paterson bodies) are a characteristic histologic feature [117]. ISH demonstrates the poxvirus in clinical specimens [118]. Treatment of the oral lesions is with cryotherapy or excision [22].
Measles Paramyxoviridae-associated infections include measles (rubeola) and mumps [95]. A prodrome of fever, malaise, cough, coryza, and conjunctivitis may occur in measles, followed by a generalized erythematous morbilliform exanthem. Kopliks spots, pathognomonic for measles, are discrete, bluish white punctate mucosal maculae surrounded by a rim of erythema; they represent foci of epithelial necrosis (Fig. 12). The most common location of this enanthem is the buccal mucosa, where the lesions may resemble grains of salt sprinkled on an erythematous background [95]. Pharyngeal erythema and bluish gray to
Fig. 13. Hand-foot-and-mouth disease. (A) Pinpoint vesicle with surrounding erythema of buccal mucosa. (B) Discrete erythematous papules with vesiculation on both palms. (C) Similar erythematous papules and vesicles on dorsum of both feet.
27
white maculae (Herrman spots) may be present on the tonsils. Herrman spots are not specific for the measles virus [119]. Oropharyngeal disease may present 24 to 48 hours before the cutaneous exanthem. Measles is usually diagnosed clinically; serologic test results confirm the disease. Treatment generally is symptomatic, with analgesics, antipyretics, and maintenance of adequate hydration. Immune serum globulin treatment may be necessary for disease in children younger than 12 months, in pregnant women, and in immunosuppressed persons; it is best given within 6 days after exposure. The disease may be prevented with the measles-mumps-rubella (MMR) vaccine according to guidelines recommended by the Centers for Disease Control and Prevention [95,119]. Mumps Mumps is characterized by salivary gland swelling and tenderness, particularly of the parotid gland. Sublingual orifices, Stensens duct on the buccal
Fig. 15. Perioral and labial erosions and crusting of recurrent herpes simplex labialis associated with chronic lymphocytic leukemia.
mucosa, and Whartons duct at the base of the tongue may be edematous and erythematous. Serologic tests or culturing the orifice of Stensens duct confirms the diagnosis. Mumps may be prevented with the MMR vaccine [120]. Togavirus Rubella Togavirus is responsible for rubella, or German measles. Infection with togavirus during pregnancy may lead to serious fetal infection and congenital rubella syndrome. A prodrome is less common than in measles, but symptoms may occur in older children and adults. The fine, pale pink maculopapular exanthem spreads in a cephalocaudad pattern and may be followed by fine desquamation. The enanthem of erythematous, pinpoint, petechial-appearing maculae occurs on the soft palate and uvula. This nonpathognomonic enanthem is known as the Forschheimer sign [95]. It occurs in the prodrome or early rash in up to 20% of cases of rubella [69]. Marked lymphadenopathy, typically of the cervical and postauricular nodes, is often an accompanying feature. Diagnosis of rubella is more difficult than measles because it has no pathognomonic features and a low incidence with the widespread use of the MMR vaccine. Serologic testing is especially important in women of childbearing age and those who are pregnant to determine the status of immunity. In most persons, rubella is essentially benign, and treatment is symptomatic.
Fig. 14. Vesicles and erosions of hard palate and posterior oropharynx in herpangina. (From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy 2002;15:271 87: with permission.)
Picornavirus Hand-foot-and-mouth disease and herpangina are picornavirus-associated diseases with characteristic
28
Table 5 Viral diseases of the oral mucosa in HIV infection Viral disease Herpes labialis [21,22] Herpes zoster [22,52 54] Oral hairy leukoplakia [21,22,80,84] Cytomegalovirus [22,92] Kaposi sarcoma [22,98,99] Oral verrucae [127] Condyloma acuminatum [22] Molluscum contagiosum [22] Etiology HSV-1, HSV-2 HHV-3 HHV-4 HHV-5 HHV-8 HPV-7, HPV-32 HPV-6, HPV-11 Poxvirus
onset of fever without a prodrome. Pain and dysphagia are associated with small erythematous papules, vesicles, or ulcerations covered by a pseudomembrane. Typical locations of these lesions are the tonsils and tonsillar fauces, palate, and uvula (Fig. 14) [4]. The virus may be isolated from vesicles of the throat or fecal culture [123]. Because herpangina may be associated with high fever, febrile seizure is a rare potential complication. Otherwise, therapy is usually supportive, with hydration, analgesics, antipyretics, and topical oral anesthetics. HIV HIV is an RNA retrovirus with the reverse transcriptase enzyme responsible for conversion of RNA to DNA. Oral lesions often are the indication for initial HIV testing, and oral diseases are more common as the CD4 + count decreases [21]. The acute seroconversion syndrome following HIV infection is associated with oral erythema and ulcerations in up to 30% of patients [124]. Similar to the more severe and frequent herpetic viral infections in malignancy and during immunosuppressive therapy (Fig. 15) [3], viral pathogens often display a more aggressive and protracted course in HIV-infected persons (Table 5).
Abbreviations: HHV, human herpesvirus; HIV, human immunodeficiency virus; HPV, human papillomavirus; HSV, herpes simplex virus.
features that allow a specific diagnosis. Type-specific immunity is established in both herpangina and handfoot-and-mouth disease; however, recurrences of the clinical syndromes are possible because both diseases may be caused by various members of the Picornavirus family. Hand-foot-and-mouth disease Hand-foot-and-mouth disease is most commonly caused by coxsackievirus serotype A16 or enterovirus 71 [121,122]. The disease usually occurs in small epidemics among groups of children and is quite contagious. Typical features include a short prodrome of upper respiratory symptoms and low-grade fever, followed by mucosal and cutaneous lesions. Shallow erosions and ulcerations with surrounding erythema are most common on the palate, tongue, and buccal mucosa (Fig. 13A). Erythematous papules, vesicles, or ulcers occur on the dorsal and palmoplantar surfaces of the hands and feet either concomitantly with the mucosal lesions or shortly thereafter (Fig. 13B and C). Picornaviridae may be cultured from the saliva or feces. PCR detects viral DNA in vesicles and defines the specific serotype [121]. Serologic testing also detects antibodies to the specific coxsackievirus [122]. Symptomatic therapy for hand-foot-and-mouth disease is usually sufficient. Oral analgesics and anesthetic mouth rinses alleviate stomatodynia. Complications of hand-foot-and-mouth disease are rare; however, enterovirus 71 was associated with central nervous system disease, including meningitis, encephalitis, and flaccid monoparesis, in 24% and 8% of afflicted patients in the 1973 and 1978 hand-foot-andmouth disease outbreaks, respectively, in Japan [122]. Herpangina Herpangina is induced most commonly by coxsackievirus [123] and is characterized by the sudden
Summary A wide variety of both DNA and RNA viruses affect the oral cavity. When considered in conjunction with cutaneous features, careful examination of the oral mucosa and oropharynx aids the clinician in making a diagnosis. Examination of the oral cavity should be incorporated as a regular component of the dermatologic examination because diagnostic clues are readily available to assist in the evaluation of infectious processes.
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Recurrent aphthous stomatitis

Susan L. Zunt, DDS, MS
Department of Oral Pathology, Medicine, and Radiology, Indiana University School of Dentistry, 1121 West Michigan Street, Indianapolis, IN 46202 5186, USA
Recurrent aphthous stomatitis (RAS), also known as canker sores or simple or complex aphthosis, is the most common form of painful oral ulcers [1]. RAS affects more than 30% of adults and up to 37% of school-age children [2]. Outbreaks of RAS may take weeks to months to heal, with 50% of individuals having a recurrence within the next 3 months [3]. RAS has been associated with a variety of clinical features, local factors, and systemic associations. The chief complaint of RAS typically is pain. The painful ulcerations usually develop on freely movable oral mucosa, often the buccal mucosa, vestibules, inner lips, tongue, and soft palate. The ulcers develop after prodromal symptoms of altered sensation or focal erythema or swelling, but without antecedent vesicles or bulla.
Etiology The cause of RAS is unknown and thought to be multifactorial with many triggers or precipitating factors [4]. Patients with RAS demonstrate increased antibody-dependent cell-mediated cytotoxicity [5]. Neutrophils phagocytize and eliminate antigenic material or damaged tissue in RAS [6]. Neither cellmediated hypersensitivity nor cross-reactivity to streptococcal or viral antigens has been established. Natural killer T-lymphocyte cell counts and activity levels are lower in patients with RAS than in controls [7]. Patient factors include familial tendencies or genetic predisposition, allergy, medications, hormones,
E-mail address: Szunt@iupui.edu
stress or anxiety, and immunologic abnormalities. A tendency for RAS to occur in families has been observed in approximately 40% [8]. The likelihood of a child developing RAS is influenced by the parents RAS status [9]. Associations between RAS and specific HLA subtypes suggest a genetic basis for susceptibility for RAS [10]. HIV-associated immunosuppression is associated with RAS or atypical ulcerations as they are also known. Lesions develop because of immunologically cell-mediated cell toxicity of the epithelium [4]. Helicobacter pylori have not been shown to have a direct association with oral RAS [11]. Allergens have been reported to play a significant role in the precipitation of new lesions in approximately 35% of RAS patients [12]. It is well recognized that RAS may be associated with sensitivity to gluten. Gluten intolerance with intestinal lesions is known as celiac disease. Gluten intolerance with RAS and in the absence of intestinal lesions also occurs [13]. Gluten is a protein found in wheat, barley, oats, and rye. Other allergens reported to be associated with RAS include benzoic acid, cinnamaldehyde, nickel, parabens, dichromate, mercury, fragrance mix, methyl methacrylate, sorbic acid, phosphorus, colophony, and balsam of Peru. An allergist or dermatologist may be able to conduct skin patch tests or radioallergosorbent tests on blood to identify specific allergens. Alternatively, an elimination diet may be of benefit in identifying food or food additives that precipitate RAS. The elimination diet should be cereal and fruit free and avoid chocolate, nuts, tomatoes, and citrus fruits. Cosmetics and toothpastes also should be eliminated. If there is no improvement of the RAS in 6 to 8 weeks the diet can be stopped. If improvement has occurred, one new food item may be introduced
0733-8635/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 2 ) 0 0 0 7 5 - X
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S.L. Zunt / Dermatol Clin 21 (2003) 3339
every 4 days. If allergens that trigger RAS are identified and the allergens can be avoided, approximately 40% become asymptomatic, 50% demonstrate marked improvement, and 10% remain unchanged [14]. Medications, such the cyclooxygenase-2 inhibitors celecoxib and rofecoxib, nonsteroidal anti-inflammatory agents used for arthritis, have been associated with the rare occurrence of aphthous-like ulcerations and may contribute to oral dryness, which in turn may promote the development of RAS. The antidepressant sertraline (Zoloft) has been associated with the development of dry mouth and aphthous stomatitis [15].
Fig. 2. A large, crateriform, painful aphthous ulcer of several weeks duration is present on the soft palate of a 54-year-old male. He has not been free of ulcers for the past 3 months.
Clinical features The painful aphthous ulcers are usually round to oval and covered with a white-yellow fibrinous pseudomembranous cap. An erythematous halo reflecting the mucosal inflammatory reaction surrounds the ulcer [16]. Rogers [17] separates the clinical types of RAS into simple and complex. Simple RAS includes the most common presentation of solitary to few ulcers that heal in 1 to 2 weeks and recur infrequently. Complex aphthosis includes deep, multiple, large ulcers with marked pain and disability, and episodes may even be accompanied by the occasional genital or perianal lesion. Recurrent aphthous stomatitis is often divided into three distinct morphologic subtypes: (1) minor, (2) major, and (3) herpetiform. Minor RAS is the most common type affecting approximately 80% of individuals with recurrent oral ulcers. Minor RAS exhibits typically solitary ulcers or less than 10 ulcers at one
time, each less than 1 cm in greatest dimension. These minor RAS ulcers are located usually on freely movable lining mucosa or on the tongue (Fig. 1) The ulcer is usually oval with a white-yellow-gray fibrinous covering surrounded by an erythematous halo on the mucosa. Prodromal tingling or pain may precede ulcer development. Healing occurs within 4 to 14 days without scarring. Major RAS, representing 5% to 10% of all cases of RAS, exhibits large, deep, crateriform ulcers. The outline of the ulcers may be irregular. These ulcers are found on freely movable lining mucosa or the dorsal tongue (Figs. 2 4). The lesion of major RAS may take weeks to months to heal, and healing may be accompanied by scarring (Fig. 5). Herpetiform RAS represents 5% to 10% of all cases of RAS [18]. The herpetiform ulcerations are
Fig. 1. This 16-year-old female suffered from frequent simple (minor) aphthous ulcers for 10 years. She reports hypersensitivity to metals. Results of hematologic testing were normal.
Fig. 3. Same patient as in Fig. 2. Lesion healed after treatment with prednisone, topical fluocinonide and chlorhexidine rinses in addition to increasing water intake due to dry mouth. See Figure 4.
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Fig. 4. Same patient as in Figs. 2 and 3. Salivary flow rate measurement using Modified Schirmer test is zero/31 mm in three minutes, consistent with profound dry mouth. Salivary pH was 5.0, normal 7.0 7.4.
Fig. 6. A 46-year-old female experienced multiple crops of exquisitely painful shallow cluster of ulcerations in a bilateral distribution for the past 5 months. This cluster of herpetiform ulcerations is present on the right side of the lower lip.
characterized by successive crops of dozens of exquisitely painful ulcerations usually 1 to 3 mm in diameter. The ulcers typically develop in a bilateral distribution on nonkeratinized mucosa, although the dorsal tongue may be involved. Like minor and major RAS, vesicles do not precede the development of ulcerations. There is no known relationship of herpetiform RAS to herpes simplex virus infection (Figs. 6 and 7).
cial pemphigoid, pemphigus vulgaris, Behc ets disease, Wegeners granulomatosis, and pyostomatitis vegetans [17,19]. In most instances, a careful history and clinical examination result in the establishment of a definitive diagnosis. Viral infections, acute oral ulcers, pseudo-Behc ets disease, and complex aphthosis and Behc ets disease are discussed elsewhere in this issue.
Differential diagnosis The differential diagnosis of RAS includes recurrent intraoral herpes simplex virus, herpes varicella zoster virus, herpangina, hand-foot-and-mouth disease, erythema multiforme, oral lichen planus, cicatri-
Diagnosis The diagnosis of RAS may be accomplished by careful history and clinical evaluation, with adjunctive procedures of biopsy, cytology [20], and culture if necessary for lesions that fail to heal or respond to treatment. Although the microscopic features of RAS ulcerations are nonspecific, biopsy may help
Fig. 5. This 19-year-old male has had severe aphthous ulcerations for 12 years. Mucosal scarring is present. Results of hematologic testing were normal. Low levels of gliadin antibody IgA were detected.
Fig. 7. Same patient as in Fig. 6. A cluster of shallow painful ulcerations on the left ventral tongue.
36
to eliminate other specific disease from the differential diagnosis. Culture may rule out specific viral infections that may also cause oral ulcerations, such as herpes simplex, herpes varicella zoster, or cytomegalovirus. The clinical evaluation and history includes attention to complicating local and systemic factors that must be considered in developing treatment recommendations.
Local factors Local factors influencing the frequency of RAS include chemical and mechanical injury, such as the use of sodium lauryl sulfate contained in dental health care products; traumatic injury; inadequate saliva; and cessation of tobacco use. Sodium lauryl sulfate is an anionic detergent, desirable in oral health care products for its foaming properties, but which decreases mucin and increases oral mucosal antigen exposure. Avoidance of sodium lauryl sulfate containing mouthwash and dentifrices has been shown to decrease aphthous ulcers by 64% [21,22]. Interestingly, the antibacterial, anti-inflammatory chemical triclosan has been demonstrated to prevent the chemotoxicity of sodium lauryl sulfate and reduce aphthous ulcers by 96% [23,24]. Colgate Total, (Colgate-Palmolive, New York, NY) is a commercially available dentifrice containing triclosan. Mechanical injury, such as with a toothbrush or sharp, dry food, may precipitate the development of RAS. Lack of adequate saliva to lubricate and protect the oral mucosa from injury and antigenic exposure may contribute to the development of RAS (see Figs. 2 and 3) [19]. Cessation of tobacco use may be accompanied by the onset of frequent RAS. Tobacco use induces a mild hyperkeratosis that reduces antigen exposure [25]. As the hyperkeratosis resolves with tobacco use cessation, painful mouth ulcers may develop within a week or more. Although it is likely that the hyperkeratosis associated with tobacco use is responsible for reduction in RAS for most patients, nicotine has been demonstrated to be protective against the development of oral aphthae for a few patients [25].
Treatment The goals of treatment of RAS include control of pain, promotion of healing, and decreased numbers of future ulcers [26]. Many cases of RAS can be managed with the careful control of local factors and the judicious use of over-the-counter preparations or
prescription topical medications, such as amlexanox, corticosteroids, or chlorhexidine. Over-the-counter preparations include covering agents, such as Orabase (Colgate Pharmaceuticals Canton, MA); Zilactin (Zila Pharmaceuticals Phoenix, AZ); local anesthetics; oxygenating agents; antiseptics; and chemical cautery agents [27]. Prescription options include the nonsteroidal antiinflammatory agent topical amlexanox 5% paste applied four times a day to the ulcers to enhance healing and reduce pain with minimum side affects [28 30], and topical glucocorticoids. Topical triamcinolone, fluocinonide [31], and clobesterol have demonstrated efficacy in the treatment of RAS. The topical corticosteroids may be used alone or mixed with Orabase mucosal adherent, although the dilution may affect the strength. In general, for topical corticosteroid use, the patient should dry the area gently and apply a thin film of the corticosteroid up to four times daily until the ulcer has healed [32]. Tetracycline rinses may be helpful in the patient with RAS. Tetracycline is antimicrobial and reduces collagenase activity [26]. The use of topical medications, such as glucocorticoids or tetracycline, can be problematic in the patient with diminished salivary flow. Corticosteroids and tetracycline may promote the growth of endogenous fungal Candida albicans, resulting in an opportunistic infection. Additionally, tetracycline is extremely acidic and may cause tooth erosion and mucosal soreness if used topically, especially in patients with diminished salivary flow characteristic of salivary gland hypofunction. Chlorhexidine mouthwash 0.12%, 0.5 oz, for 30 seconds twice daily (after brushing and flossing in dentate patients) may help to decrease the duration of the ulcer and pain with RAS [33] in addition to reducing the chance of oral candidiasis [34,35]. The treatment of simple aphthosis includes attention to the role of local factors to reduce recurrences and topical medication to minimize the discomfort and to promote healing of painful ulcers. Patients with complex aphthosis, major RAS, or herpetiform RAS should have evaluation of local and systemic associations. Hematologic testing for folate, iron, serum ferritin, and vitamin B12 is recommended [4,36,53]. Remission or marked improvement of RAS is seen in 70% of patients with replacement therapy for nutritional-hematologic abnormalities. Debridement with the removal of the fibrinous pseudomembrane and necrotic plug from the ulcer base has been reported to stimulate healing and decrease discomfort [37], perhaps by allowing endogenous protein secretory leukocyte inhibitor to reach
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the base of the ulcer [38]. The debridement can be accomplished more easily and with greater patient comfort after the application of a topical anesthetic. Bioadhesive 2-octyl cyanoacrylate has been recommended as a topical, nonprescription treatment for RAS to reduce pain [39]. Oral corticosteroids may be used for the management of severe RAS [40]. Burst therapy of 20 to 40 mg daily may be given for 5 to 10 days, or an initial higher dose may be followed by a taper over 2 weeks [3]. Other systemic treatments for RAS include thalidomide [41], levamisole [42], colchicine [43], cyclosporine [44], axelastine [45], dapsone [46], and pentoxifylline [47]. The uncommon albeit clinically distinctive RAS variant seen in some children is known as periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome [48,49]. It has been shown to respond within 2 to 4 hours to a single oral dose of prednisone, 2 mg/kg [50], or cimetidine therapy [51]. Rebound phenomenon has been observed following the single oral dose of prednisone.
Summary Recurrent aphthous stomatitis remains a commonly occurring cause of oral pain and ulceration. Although the ulcerations of RAS are multifactorial and of unknown cause, recognition of the role of patient and environmental factors may be helpful in developing recommendations for treatment and prevention of future ulcers.
References
[1] Zunt SL. Recurrent Aphthous Ulceration An Update. J Ind Dent Assn 1985;64(5):27 33. [2] Kleinman DV, Swango PA, Pindborg JJ. Epidemiology of oral mucosal lesions in United States schoolchildren: 1986 87. Community Dent Oral Epidemiol 1994;22:243 53. [3] Ship JA. Recurrent aphthous stomatitis. An update. Oral Surg Oral Med Oral Pathol Oral Radiol Endo 1996;81:141 7. [4] Porter SR, Scully C. Recurrent aphthous stomatitis. Crit Rev Oral Biol Med 1998;9(3):306 21. [5] Mills MP, Mackler BF, Nelms DC, Peavy DL. Quantitative distribution of inflammatory cells in recurrent aphthous stomatitis. J Dent Res 1980;59:562 6. [6] Degalis P, Bagg J, Walker DM. Spontaneous migration and chemotactic activity of neutrophil polymorphonuclear leukocytes in recurrent aphthous ulceration. Oral Surg Oral Med Oral Pathol 1987;64:298 301. [7] Sistig S, Cekic-Arambasis A, Rabatic S, VucicevicBoras V, Kleinheinz J, Piffko J. Natural immunity in recurrent aphthous ulceration. J Oral Pathol Med 2001; 30:275 80. [8] Ship II. Inheritance of aphthous ulcers of the mouth. J Dent Res 1965;44:837 44. [9] Ship II. Epidemiologic aspects of recurrent aphthous ulcerations. Oral Surg Oral Med Oral Pathol 1972;33: 400 6. [10] Scully C, Porter SR. Recurrent aphthous stomatitis: Current concepts of etiology, pathogenesis and management. J Oral Pathol Med 1989;18:21 7. [11] Shimoyama T, Horie N, Kato T, Kaneko T, Komiyama K. Helicobacter pylori in oral ulcerations. J Oral Sci 2000;42(4):225 9. [12] Nolan A, Lamey P-J, Milligan KA, Forsyth A. Recurrent aphthous ulceration and food sensitivity. J Oral Pathol Med 1991;20:473 5. [13] OFarrelly C, OMahony C, Graeme-Cook F, Feighery C, McCartan B, Weir D. Gliadin antibodies identify gluten sensitive oral ulceration in the absence of villous atrophy. J Oral Pathol Med 1991;20:476 8. [14] Hay KD, Reade PC. The use of an elimination diet in the treatment of recurrent aphthous ulceration of the oral cavity. Oral Surg Oral Med Oral Pathol 1984; 57(5):504 7.
Control of local factors The clinician should identify and control local factors influencing recurrences of aphthae: 1. Consider an empirical clinical trial of sodium lauryl sulfate-free toothpaste and mouthwash. Commercially available products include Biotene toothpaste (Laclede, Rancho Dominguez, CA) and Rembrandts Canker Sore toothpaste (DenMat, Santa Maria, CA). 2. Measure the salivary flow rate using objective volumetric, gravimetric, or calibrated paper [52] methodology to determine adequacy of saliva objectively and accurately. In patients with a low salivary flow rate, management with palliative and therapeutic options including adequate water ingestion daily and sialogogue medications, such as pilocarpine (Salagen, MGI Pharma Bloomington, MN; 5 mg, three to four times daily) and cevimeline (Evoxac, Daiichi, Montvale, NJ; 30 mg, three times daily), may be indicated. 3. Avoid or minimize mechanical injury to oral mucosa. Soft toothbrushes are desirable to minimize injury. 4. If the patient has onset with smoking cessation the clinician may consider a trial of nicotine gum or a nicotine patch.
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S.L. Zunt / Dermatol Clin 21 (2003) 3339 [32] Woo S-B, Sonis ST. Recurrent aphthous ulcers: A review of diagnosis and treatment. J Am Dent Assoc 1996;127:1202 13. [33] Meiller TF, Kutcher MJ, Overholser CD, Niehaus C, DePaola LG, Siegel MA. Effect of an antimicrobial mouthrinse on recurrent aphthous ulcerations. Oral Surg Oral Med Oral Pathol 1991;72:425 9. [34] Matthews RW, Scully GM, Levers BGH, Hislop WS. Clinical evaluation of benzydamine, chlorhexidine and placebo mouthwashes in the management of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol 1987;63:189 91. [35] Zunt SL. Oral Candidiasis: Diagnosis and Treatment. The Journal of Practical Hygiene 2000;9(5):31 6. [36] Rogers III RS, Hutton KP. Screening for hematinic deficiencies in otherwise healthy patients with recurrent aphthous stomatitis. Austral J Dermatol 1986;27: 95 103. [37] Hartsfield Jr. CE. Recurrent aphthous ulcer: An effective method of self-treatment. Gen Dent 1990;38(3): 194 5. [38] Hartsfield Jr. CE. Aphthous ulcer revisited. J Am Dent Assoc 2001;132(6):728. [39] Krutcher MJ, Ludlow JB, Samuelson AD, Campbell T, Pusek SN. Evaluation of a bioadhesive device for the management of aphthous ulcers. J Am Dent Assoc 2001;132(3):368 76. [40] Siegel MA, Silverman Jr S, Sollecito TP, editors. Clinicians Guide to Treatment of Common Oral Conditions. 5th ed. Baltimore: The American Academy of Oral Medicine; 2001. p. 12 4. [41] Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB, et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 1997;336:1487 93. [42] Lu S-Y, Chen W-J, Hock-Liew E. Response to levamisole and low-dose prednisolone in 41 patients with chronic oral ulcers. A 3-year open clinical trial and follow-up study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:438 45. [43] Katz J, Langevitz P, Shemer J, Barak S, Livneh A. Prevention of recurrent aphthous stomatitis with colchicines: An open clinical trial. J Am Acad Derm 1994;31(3 Pt 1):459 61. [44] Masuda K, Nakajima A, Urayama A, Kakae K, Kogure M, Inaba G. Double-masked trial of cyclosporin versus colchicines and long-term open study of cyclosporin in Behc ets disease. Lancet 1 (8647): 1093 96, 1989. [45] Utea E, Osaka T, Yoneda K, Yamamoto T, Kato I. A clinical trial of Axelastine in recurrent aphthous ulceration, with an analysis of its actions on leukocytes. J Oral Pathol Med 1994;23:123 9. [46] Muzyka BC, Glick M. Major aphthous ulcers in patients with HIV disease. Oral Surg Oral Pathol Oral Med 1994;77:116 20. [47] Chandrasekhar J, Liem AA, Cox NH, Paterson AW. Oxypentifylline in the management of recurrent aphthous oral ulcers. An open clinical trial. Oral Surg
[15] Gage TW, Pickett FA. Mosbys Dental Drug Reference, 5th edition. Mosby: St. Louis; 2001. [16] Vincent SD, Lilly GE. Clinical, historic, and therapeutic features of aphthous stomatitis. Literature review and open clinical trial employing steroids. Oral Surg Oral Med Oral Pathol 1992;74:79 86. [17] Rogers III RS. Recurrent aphthous stomatitis: Clinical characteristics and associated systemic disorders. Semin Cutan Med Surg 1997;16(4):278 83. [18] Brooke RI, Sapp JP. Herpetiform ulceration. Oral Surg Oral Med Oral Pathol 1976;42:182 8. [19] Ship JA, Chavez EM, Doerr PA, Henson BS, Sarmadi M. Recurrent aphthous stomatitis. Quintessence Int 2001;31:95 112. [20] Wood Jr. TA, DeWitt SH, Chu EW, Rabson AS, Graykowski EA. Anitschkow nuclear changes observed in oral smears. Acta Cytol 1975;19:434 7. [21] Herlofson BB, Karkvoll P. Sodium lauryl sulfate and recurrent aphthous ulcersa preliminary study. Acta Odontol Scand 1994;52:257 9. [22] Herlofson BB, Karkvoll P. The effect of two toothpaste detergents on the frequency of recurrent aphthous ulcers. Acta Odontol Scand 1996;54:150 3. [23] Skaare AB, Herlofson BB, Barkvoll P. Mouthrinses containing triclosan reduce the incidence of recurrent aphthous ulcers (RAU). J Clin Periodontol 1996;23(8): 778 81. [24] Skaare AB, Rolla G, Barkvoll P. The influence of triclosan, zinc or propylene glycol on oral mucosa exposed to sodium lauryl sulfate. Eur J Oral Sci 1997;105:527 33. [25] Grady D, Ernster VL, Stillman L, Greenspan J. Smokeless tobacco use prevents aphthous stomatitis. Oral Surg Oral Med Oral Pathol 1992;74(4):463 5. [26] Barrons RW. Treatment strategies for recurrent aphthous ulcers. Am J Health-System Pharmacy 2001; 58(1):41 53. [27] Carpenter WM, Silverman Jr. S. Over-the-counter products for oral ulcerations. California Dental Assoc J 1998;26(3):199 201. [28] Binnie WH, Curro FA, Khandwala A, Van Inwegan RG. Amlexanox oral paste: a novel treatment that accelerates the healing of aphthous ulcers. Compendium of Continuing Education in Dentistry 1997;18(11): 1116 8, 1120 2. [29] Khandwala A, Van Inwegen RG, Alfano MC. 5% Amlexanox oral paste: a new treatment of recurrent minor aphthous ulcers. I. Clinical demonstration of acceleration of healing and resolution of pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:222 30. [30] Khandwala A, Van Inwegen RG, Charney MR, Alfano MC. 5% amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers: II. Pharmacokinetics and demonstration of clinical safety. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83(2): 231 8. [31] Pimlott SJ, Walker DM. A controlled clinical trial of the efficacy of topical applied fluocinonide gel in the treatment of recurrent aphthous ulceration. Br Dent J 1983;154:174 7.
S.L. Zunt / Dermatol Clin 21 (2003) 3339 Oral Med Oral Pathol Oral Radiol Endod 1999;87: 564 7. [48] Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis and aphthous stomatitis. J Pediatr 1987;110:43 6. [49] Thomas KT, Edwards KM. Periodic fever syndrome. Pediatr Infect Dis J 1999;18(1):68 9. [50] Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, et al. Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: Clinical characteristics and outcome. J Pediatr 1999;135(1):98 101.
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[51] Feder HM. Cimetidine treatment for periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis. Pediatr Infect Dis J 1992;11: 318 21. [52] Woo S, Wai Y. The modified Schirmer test as a screening instrument to measure saliva wetness. J Dent Res 1995;74(special issue):546 (abstr #1162). [53] Olson JA, Feinberg I, Silverman Jr S, Abrams D, Greenspan JS. Serum vitamin B12, folate, and iron levels in recurrent aphthous ulceration. Oral Surg Oral Med Oral Pathol 1982;54(5):517 20.
Complex aphthosis and Behc ets disease

Martha Ann McCarty, MS, PA-C, Rachel A. Garton, MD, Joseph L. Jorizzo, MD*
Department of Dermatology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA
Complex aphthosis is a term introduced in 1984 by Jorizzo et al [1] to describe the patient presentation of recurrent oral and genital aphthous ulcers or almost constant, multiple ( ! 3) oral aphthae, without manifestations of systemic disease. Behc ets disease is a systemic inflammatory disease characterized by recurrent oral and genital aphthae, and possibly arthritis, cutaneous lesions, ocular, or neurologic manifestations [2]. Differentiation of complex aphthosis from Behc ets disease at baseline may be difficult because the initial clinical presentation of Behc ets disease is often confined to mucocutaneous lesions.
patients per 100,000 inhabitants [7]. The lowest reported prevalence in the world is 0.1 to 7.5 patients per 100,000 inhabitants in Europe and the United Stares [7]. Familial occurrence has been reported, although there is no known specific mode of mendelian transmission [8]. Onset of Behc ets disease is usually in the third decade of life [9], but Behc ets disease has been reported to start in the first months of life and as late as 72 years. Pediatric cases are not uncommonly reported, and boys and girls seem to be equally affected [10]. Current epidemiologic studies of adults show an approximately equal male-tofemale ratio in several populations [7].
Epidemiology Diagnosis and differential diagnosis Complex aphthosis can be viewed as an extreme manifestation of oral ulcerations called recurrent aphthous stomatitis. Recurrent aphthous stomatitis is the most common inflammatory ulcerative condition of the oral mucosa in North American patients, with a prevalence ranging from 5% to 66% [3]. Recurrent aphthae usually begin in childhood or adolescence, with decreasing frequency and severity with age [4,5]. Complex aphthosis likely makes up a small subset of recurrent aphthous stomatitis [6]. The prevalence of Behc ets disease is variable, depending not only on the patients ethnic origin but also on the geographic area in which the patient currently lives. The highest prevalence in the world is in Northeastern Turkey (Anatolia) with 370 Although simple aphthosis represents the common presentation of a few, infrequently recurring lesions that heal in 1 to 2 weeks, complex aphthosis is characterized by a more complicated clinical picture of severe disease with numerous new lesions developing as older lesions heal (continuous ulcerations). The patient experiences marked pain or disability, and occasionally associated genital or perianal lesions [11]. The criteria of almost constant, multiple ( > 3) oral or recurrent oral and genital aphthosis has been the clinical standard for diagnosis [1]. The diagnosis of Behc ets disease is based on clinical criteria and various sets of criteria have been published [12 14]. Preferred criteria are those of ODuffy and Goldstein [15], which require the presence of recurrent oral aphthae plus at least two of the following: genital aphthae, synovitis, posterior uveitis, cutaneous pustular vasculitis, or meningoencephalitis.
* Corresponding author. E-mail address: jjorizzo@wfubmc.edu (J.L. Jorizzo).
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Inflammatory bowel disease, systemic lupus erythematosus, Reiters disease, and herpetic infections must be excluded (Table 1). The International Study Group for Behc ets disease also published criteria in 1990 that require the presence of oral aphthae plus two of the following: recurrent genital aphthae, eye lesions, skin lesions, or a positive pathergy test (Fig. 1) [13]. Explanation of these criteria is given in Table 2. The omission of synovitis and meningoencephalitis, however, makes four of the five criteria variations of a similar mucocutaneous lesion. The authors require histologic confirmation that the cutaneous pustular lesions are vessel-based and neutrophilic and the exclusion of inflammatory bowel disease. Nearly 20% of normal young adults have oral aphthae and almost all adolescents have at least one papulopustular lesion, which together almost meet criteria if acneiform skin lesions are not excluded. Oral aphthae can be seen in other conditions, such as familial idiopathic recurrent aphthosis, ulcerative colitis, Crohns disease, systemic lupus erythematosus, HIV-associated disease, drug eruptions, hematologic and other disorders [16]. Oral aphthae persisting for more than 3 weeks may require biopsy to exclude diseases of the oral cavity, such as herpes simplex; herpangina; and causes of clinically different appearing erosions, such as lichen planus, erythema multiforme, bullous pemphigoid, and pemphigus vulgaris. Reiters disease and the HLA-B27 positive spectrum of diseases are characterized by an axial erosive arthritis and by psoriasiform mucocutaneous lesions, but there are no aphthae and no pustular vasculitis in these patients unless they have enteropathic (ie, inflammatory bowel disease associated) arthritis. The genital lesions of Reiters disease are psoriasi-
Fig. 1. Pathergy lesions induced by intradermal injection of sterile saline at 24 hours.
Table 1 ODuffy criteria for diagnosis of Behc ets disease Criteria Aphthous stomatitis Aphthous genital ulceration Uveitis Cutaneous pustular vasculitis Synovitis Meningoencephalitis Diagnosis At least three criteria present, one being recurrent aphthous ulceration Incomplete form Two criteria present, one being recurrent aphthous ulceration Exclusions Inflammatory bowel disease, systemic lupus erythematosus, Reiters disease, and herpetic infections
form and are localized to the penis, whereas those of Behc ets disease are aphthae seen on the scrotum or penis. Patients with inflammatory bowel disease have an increased incidence of oral aphthae [17]. These patients or those who have had bowel bypass or Billroth II surgery can have a dermatosis-arthritis syndrome that mimics Behc ets disease, including an indistinguishable pustular vasculitis [18]. The enteropathic arthritis, however, is erosive, axial, and patients are generally HLA-B27 positive. Patients with complex aphthosis have recurrent oral and genital aphthae or almost constant, multiple (>3) oral aphthae, but no other features of Behc ets disease [1,6]. Patients with pustular vasculitis without aphthae may have gonococcal or even chronic meningococcal sepsis, or the pustular vasculitis may occur as an idiopathic syndrome [19]. Initial evaluation of a patient presenting with complex aphthosis and Behc ets disease should include a thorough review of systems to evaluate for arthralgias and ocular, gastrointestinal, or neurologic symptoms. Positive findings may suggest a need for referral for further evaluation by an ophthalmologist, rheumatologist, gastroenterologist, or neurologist. Additional laboratory studies are guided by the differential diagnosis. Herpes simplex viral cultures or polymerase chain reaction are necessary to exclude this common cause of oral lesions and genital ulcerations. In patients with complex aphthosis, blood tests should include serum vitamin B12, folate, and iron profile, and complete blood count to rule out hematologic abnormalities caused by nutritional deficiencies, cyclic neutropenia, or lymphopenia. Although renal dysfunction is uncommon in Behc ets disease [20], routine urinalysis may detect proteinuria and microscopic hematuria. If dapsone therapy is planned then a glucose-6-phosphate dehydrogenase level determination is needed to identify those at risk for severe drug-induced hemolysis. Radiologic exam-
M.A. McCarty et al / Dermatol Clin 21 (2003) 4148 Table 2 International criteria for Behc ets disease * Criteria Oral Plus two of the following: Genital Eye Skin Pathergy Description
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Minor aphthae, major aphthae, or herpetiform ulcers observed by physicians or reported reliably by patient. Recurrent at least three times in one 12-month period. Recurrent genital aphthae or scarring, especially scrotal in males, observed by physician or reliably reported by patient. Anterior uveitis, posterior uveitis, cells in vitreous on slit-lamp examination, or retinal vasculitis, observed by qualified physician. Erythema nodosum-like lesions observed by physician, or papulopustular lesions consistent with Behc ets disease, observed by a physician. Positive pathergy test (neutrophilic vascular reaction or leukocytoclastic vasculitis) read by a physician at 24 or 48 h, performed with oblique insertion of a 20-gauge or smaller needle under sterile conditions.
* Findings are applicable if no other clinical explanation is present.
ination may be useful to exclude erosive arthritis or sacroiliitis in patients with specific joint complaints. Patients with a suggestive history need HLA-B27 testing and additional evaluation for Reiters syndrome or inflammatory bowel disease. Complete dermatologic examination should be performed on all patients and biopsy of appropriate lesions is required to confirm the clinicopathologic diagnosis of cutaneous manifestations of Behc ets disease. Pathergy testing may be useful to assist in the diagnosis [6].
Immunogenetics and pathogenesis The intermittent nature of both complex aphthosis and Behc ets disease and the lack of consistent response to therapy make the underlying etiologies difficult to define. The pathogenesis of Behc ets disease may relate to a combination of factors involving genetic predisposition; immune dysregulation; inflammatory mediators; and possibly immune response to infectious triggers, such as herpes simplex virus or Streptococcal species [21]. The cause of simple or complex aphthosis is most likely multifactorial and influenced by predisposing factors. Precipitants include genetics, trauma, nonsmoking, emotional stress, hormonal factors, viruses, bacteria, food hypersensitivity, and immune dysregulation [6]. Systemic diseases, such as inflammatory bowel disease, Sweets syndrome, and HIV disease, may have aphthae as associations. Recurrent aphthosis is also frequently seen as a complication of AIDS, and may be caused by a combination of factors including impaired cell-mediated immunity [6].
Genetic predisposition is likely a component in the pathogenesis of Behc ets disease. In the Middle East, Japan, and Mediterranean countries, a significant association has been shown to exist between HLA-B51 and Behc ets disease, although this relationship is not as strong in the Unites States and the United Kingdom [22]. The allele does seem to be associated with a more severe prognosis [7]. Familial clustering of Behc ets disease has been reported, but is not common [7,23]. Infectious precipitants may also play a role in Behc ets disease and complex aphthosis. Studies have been performed that suggest a role for Streptococcus species [24]. In terms of a viral etiology, there have been conflicting data concerning the molecular detection of herpes simplex virus from ulcers in patients with Behc ets disease [25 27]. Furthermore, heat shock proteins of microorganisms may trigger cross-reactive autoimmune responses in patients [28]. Although a specific infectious agent has not been reproducibly isolated, it is likely that infectious agents trigger an immunoregulatory defect in genetically predisposed individuals. Circulating immune complexes and neutrophils have been investigated for their possible role in the pathogenesis of Behc ets disease. Studies support a neutrophilic vascular reaction or even a fully developed leukocytoclastic vasculitis as the earliest finding in mucocutaneous lesions [18,29]. Circulating immune complexes may elicit the neutrophilic vascular reaction that characterizes the mucocutaneous pustular and systemic lesions of Behc ets disease [6,18]. Neutrophil adhesion to endothelial cells and neutrophil migration in response to chemoattractants have also been areas of investigation [30,31]. Lastly,
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various immunologic mediators, including tumor necrosis factor, interleukin-1, interleukin-2 receptor, and soluble CD8 antigen, may play a role in the pathogenesis of Behc ets disease and complex aphthosis [6].
Clinical manifestations Aphthae are localized, painful, shallow, round-tooval ulcers covered by a yellowish pseudomembrane, with a sharp, red border. The lesions most often occur on nonmasticatory surfaces including the buccal mucosa, tongue, gingiva, and soft palate, although they can occur anywhere on the oral mucosa (Fig. 2) [16]. Patients with simple aphthosis usually show spontaneous healing in 1 to 2 weeks without treatment. The lesions can be recurrent, with the intensity and diameter of the lesions varying from one episode to the next. Patients with complex aphthosis have similar lesions, but they are more extensive and can involve oral or genital mucosa. Aphthae major are larger, deeper, and usually heal with some scarring. Virtually all patients with Behc ets disease have oral aphthae [16,32]. These ulcers represent the initial manifestation of Behc ets disease in most patients worldwide and usually heal without scarring [28,33]. Genital aphthae may occur together with or after the development of oral aphthae and usually persist over 10 to 30 days (Figs. 3 and 4). Aphthae major or pyoderma gangrenosum like genital aphthae (Fig. 5) produce scarring and are an important finding to support a suspicion of more severe mucocutaneous disease. Other cutaneous findings of Behc ets disease include cutaneous pustular vasculitis (including pathergy lesions); erythema nodosum like lesions; Sweets-like lesions; and palpable purpuric lesions of necrotizing venulitis [21]. All of these mucocutaneous findings of Behc ets disease are associated with
Fig. 3. Vulvar aphthous ulcer. Vulvar lesions tend to be larger than most oral lesions and heal more slowly.
vessel-based neutrophilic inflammation with leukocytoclasis (ie, either a neutrophilic vascular reaction or frank leukocytoclastic vasculitis) [34]. In addition to mucocutaneous lesions, the clinical findings of Behc ets disease include systemic manifestations, such as ocular, musculoskeletal, vascular, and central nervous system involvement. Ocular involvement is the major cause of morbidity. Posterior uveitis (also called retinal vasculitis) can lead to blindness and is the most diagnostically relevant lesion. Anterior uveitis, hypopyon (a now uncommon condition caused by pus in the anterior chamber of the eye), and secondary complications including cataracts, glaucoma, and neovascular lesions also occur [35]. A nonerosive, asymmetric oligoarthritis is characteristic and should not be confused with the erosive sacroiliitis seen in HLA-B27 positive patients with Reiters disease [21]. Central nervous system involvement is uncommon, although meningoencephalitis, cerebral venous sinus thrombosis, cranial nerve palsies, benign intracranial hyperten-
Fig. 2. Aphthous ulcer on tongue. Note the small round-tooval ulcers with a fibromembranous slough in the center.
Fig. 4. Penile aphthous ulcer. Penile lesions have the same morphologic characteristics as oral or vulvar lesions.
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Fig. 5. Vulvar pyoderma gangrenosum-like major aphthous ulcer.
Fig. 7. High-power (200x) lesional specimen showing endothelial swelling with leukocytoclasia and extravasated erythrocytes without fibrinoid necrosis of vessel walls (H and E).
sion, brainstem lesions, and pyramidal or extrapyramidal lesions have all been described [36,37]. Vascular involvement includes aneurysms, arterial or venous occlusions, and varices, which can lead to death [6,38]. Cardiac, renal, and gastrointestinal systems can also be affected [20,39].
ings in Behc ets disease are not diagnostic in the absence of clinical presentation. Clinical course and prognosis Prognosis of patients with complex aphthosis is dependent on the underlying cause. Patients with idiopathic disease often experience a diminution of signs and symptoms as they age, with the syndrome being uncommon in the elderly [4]. Fifty-two percent of 67 prospectively evaluated patients with recurrent oral aphthosis (average 10 recurrences per year) in Korea developed Behc ets disease within 8 years after the onset of oral aphthous ulcers [42]. This percentage is far lower in patients who live outside areas of high prevalence (ie, the United States and Europe). There are subsets of patients who present with complex aphthosis who never progress into Behc ets disease. The course and prognosis of Behc ets disease is variable, depending on the extent of systemic involvement. Diagnosis of Behc ets disease may be delayed by several years after onset of disease, which can directly influence prognosis. Ophthalmic disease is the leading cause of morbidity. A delay in the diagnosis of the ocular component is of significance, because early treatment is especially important in preventing blindness [43]. Skin lesions may be a predictive factor in vision loss, as is posterior as opposed to anterior uveitis [44]. Central nervous system, pulmonary, and large vessel involvement, and bowel perforation are the major life-threatening complications [7]. Immunosuppressive therapy can also contribute to complications and death. Early development of systemic features, male gender, and HLA-B51 positivity are markers of severe prognosis; however, onset in childhood does not necessarily predict a poor prognosis [7]. Spontaneous remissions of certain or all manifesta-
Laboratory findings and histopathology There are no pathognomonic laboratory findings in Behc ets disease or complex aphthosis. The characteristic histopathologic feature of Behc ets disease is a neutrophilic vascular reaction (Fig. 6) [6,21]. Biopsy specimens from early mucocutaneous lesions show a neutrophilic vascular reaction with endothelial swelling, extravasated erythrocytes and leukocytoclasia, or a fully developed leukocytoclastic vasculitis (Fig. 7) [29,40]. Older lesions show a lymphocytic perivasculitis [41]; however, the neutrophilic vasculitis is the predominant histopathologic finding. It can be concluded that the histologic find-
Fig. 6. Low-power (40x) biopsy specimen from a cutaneous pustular vasculitis lesion (H and E).
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tions of Behc ets disease have been observed [7], but periodic remissions and exacerbations typically characterize the course of the disease.
Overview of treatment Treatment of Behc ets disease is challenging, and must be tailored to the site and severity of the clinical manifestations of the disease. The variable course of the disease, age, and sex differences all must be taken into consideration in assessing any agent for therapeutic use. Drug management is directed at suppression of inflammation, especially during the early phases, with the aim of preventing irreversible organ damage. Treatment often requires a combination of therapies. It is important to use a therapeutic ladder, because patients with primarily mucocutaneous lesions should not be treated as aggressively as those with ocular or other systemic manifestations (Table 3).
Therapeutic approaches Initial treatment for aphthae includes local anesthetics, counterirritant agents, potent topical corticosteroids or topical tacrolimus, and intralesional corticosteroids [6]. Aerosolized corticosteroids can also be used for posterior oropharyngeal lesions, but the corticosteroid should not be inhaled. Patients
Table 3 Therapeutic ladder for Behc ets disease Mucocutaneous disease Local anesthetics or counterirritants (3) Topical, intralesional, or aerosolized corticosteroids (3) Topical tacrolimus (3) Colchicine (1) Dapsone (3) Combination of the above (3) Severe mucocutaneous disease Thalidomide (1) Low-dose weekly pulse methotrexate (3) Prednisone with intermittent tapers (2) Interferon alpha (2) Severe ocular and systemic disease Prednisone (1) Azathioprine (1) Cyclophosphamide (3) Chlorambucil (2) Cyclosporin (1) Tumor necrosis factor-a inhibitors (eg, etanercept or infliximab) (3) Other experimental therapies (1) double-blind studies, (2) case series, (3) anecdote.
who do not achieve adequate control with these methods may respond to the addition of colchicine, 0.6 mg orally two to three times daily, as tolerated by the gastrointestinal tract [29,45]. Patients should be monitored for the infrequent neutropenia that can complicate therapy, especially in the older patient. In addition, dapsone, either alone or with colchicine, can be effective [46]. Pentoxifylline is also therapeutic for some patients [47]. Patients experiencing more severe mucocutaneous lesions have been shown to benefit from thalidomide therapy, although teratogenicity and peripheral neuropathy complicate use of this agent [30,48]. Low-dose weekly methotrexate, intermittent slow tapering courses of prednisone, and interferon-a have also been effective in treating more severe mucocutaneous disease [6,49,50]. Patients on methotrexate need periodic monitoring for liver abnormalities and renal insufficiency. Anecdotally, the anti tumor necrosis factor-a antibody infliximab has been used successfully to treat recalcitrant mucocutaneous ulcerations [51]. For severe ocular and systemic disease, immunosuppressive agents, such as prednisone, azathioprine, cyclophosphamide, chlorambucil, and cyclosporin, can be used [6,49,52 54]. More recently, infliximab has been used successfully to treat gastrointestinal disease and uveitis [55,56]. Combination therapy with the aforementioned immunosuppressive medications can be used for the most severe systemic disease. Patients on these agents should be monitored closely for side effects, including myelosuppression with azathioprine, hematologic disturbances and hemorrhagic cystitis with cyclophosphamide, and nephrotoxicity with cyclosporin. Complex aphthosis is a disorder in which patients develop recurrent oral and genital aphthous ulcers or almost constant, multiple ( ! 3) oral aphthae, without manifestations of systemic disease. Behc ets disease is a multisystem disease characterized clinically by oral and genital aphthae; arthritis; cutaneous lesions; and ocular, gastrointestinal, and neurologic manifestations. The exact etiology of both complex aphthosis and Behc ets disease is unknown and no pathognomonic laboratory tests exist. This article reviews both disorders, including their clinical and histologic presentations, factors in pathogenesis, and an overview of therapeutic modalities.
References
[1] Jorizzo JL, Taylor RS, Schmalstieg FC, et al. Complex aphthosis: a forme fruste of Behc ets syndrome? J Am Acad Dermatol 1985;13:80 4.
M.A. McCarty et al / Dermatol Clin 21 (2003) 4148 [2] Schreiner DT, Jorizzo JL. Behc ets disease and complex aphthosis. Dermatol Clin 1987;5:769 78. [3] Embil JA, Stephens RG, Manuel FR. Prevalence of recurrent herpes labialis and aphthous ulcers among young adults on six continents. Can Med Assoc J 1975;113:627 30. [4] Rees TD, Binnie WH. Recurrent aphthous stomatitis. Dermatol Clin 1996;14:243 56. [5] Woo SB, Sonis ST. Recurrent aphthous ulcers: a review of diagnosis and treatment. J Am Dental Assoc 1996;127:1202 13. [6] Ghate J, Jorizzo JL. Behc ets disease and complex aphthosis. J Am Acad Dermatol 1999;40:1 18. [7] Zouboulis C. Epidemiology of adamantiades-Behc ets disease. In: Bang D, Lee ES, Lee S, editors. Behc ets disease: proceedings of the 8th and 9th International Conference on Behc ets disease. Seoul: Design Mecca; 2000. p. 43 7. [8] Stewart JAB. Genetic analysis of families with Behc ets syndrome: data incompatible with autosomal recessive inheritance. Ann Rheum Dis 1986;45:265 8. [9] Gurler A, Boyvat A, Tursen U. Clinical manifestations of Behc ets disease: an analysis of 2147 patients. Yonsei Med J 1997;38:423 35. [10] Kone-Paut I, Yurdakul S, Bahabri SA, et al. Clinical features of Behc ets disease in children: an international collaborative study of 86 cases. J Pediatr 1998;132: 721 5. [11] Rogers RS. Recurrent aphthous stomatitis in the diagnosis of Behc ets disease. Yonsei Med J 1997;38:370 9. [12] Ferraz MB, Walter SD, Heymann R, et al. Sensitivity and specificity of different diagnostic criteria for Behc ets disease according to the latent class approach. Br J Rheumatol 1995;34:932 5. [13] International Study Group for Behc ets Disease. Criteria for diagnosis of Behc ets disease. Lancet 1990;335: 1078 178. [14] Wechsler B, Davatchi F, Mizushima Y. Evaluation of diagnostic (classification) criteria in Behc ets disease: toward internationally agreed criteria. In: ODuffy JD, Kokmen E, editors. Behc ets Disease: Basic and Clinical Aspects. New York: Marcel Dekker, Inc.; 1991. p. 11 39. [15] ODuffy JD, Goldstein NP. Neurologic involvement in seven patients with Behc ets disease. Am J Med 1976; 61:170 8. [16] Chams-Davatchi C, Davatchi F, Shahram F, et al. Classification of muco-cutaneous lesions of Behc ets disease. In: Bang D, Lee ES, Lee S, editors. Behc ets disease: proceedings of the 8th and 9th international conference on Behc ets disease. Seoul: Design Mecca; 2000. p. 283 5. [17] Hutton KP, Rogers RS. Recurrent aphthous stomatitis. Dermatol Clin 1987;5:761 8. [18] Jorizzo JL, Hudson RD, Schmalstieg FC, et al. Behc ets syndrome: immune regulation, circulating immune complexes, neutrophil migration and colchicine therapy. J Am Acad Dermatol 1984;10:205 14. [19] McNeely MC, Jorizzo JL, Solomon AR, et al. Primary
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M.A. McCarty et al / Dermatol Clin 21 (2003) 4148 complications in Behc ets syndrome. Brain 1999;122: 2183 94. Siva A, Kantarci OH, Saip S, et al. Behc ets disease: diagnostic and prognostic aspects of neurological involvement. J Neurol 2001;248:95 103. Sagdic K, Ozer ZG, Saba D, et al. Venous lesions in Behc ets disease. Eur J Vasc Endovasc Surg 1996;11: 437 40. James DG, Thomson A. Recognition of the diverse cardiovascular manifestations of Behc ets disease. Am Heart J 1982;103:457 8. Jorizzo JL, Abernethy JL, White WL, et al. Mucocutaneous criteria for the diagnosis of Behc ets disease: an analysis of clinicopathologic data from multiple international centers. J Am Acad Dermatol 1995;32: 968 76. Lakhanpal S, Tani K, Lie JT, et al. Pathologic features of Behc ets syndrome: a review of Japanese autopsy registry data. Hum Pathol 1985;16:790 5. Bang D, Hur W, Lee ES, et al. Prognosis and clinical relevance of recurrent oral ulceration in Behc ets disease. J Dermatol 1995;22:926 9. Abdollahi A, Hallaji Z, Jamshidi A, et al. Visual outcome of the early and late treatment in ocular Behc ets disease. In: Bang D, Lee ES, Lee E, editors. Behc ets disease: proceedings of the 8th and 9th international conference on Behc ets disease. Seoul: Design Mecca; 2000. p. 394 8. Sakamoto M, Akazawa K, Nishioka Y, et al. Prognostic factors of vision in patients with Behc ets disease. Ophthalmology 1995;102:317 21. Miyachi Y, Taniguchi S, Ozaki M, et al. Colchicine in the treatment of cutaneous manifestations of Behc ets disease. Br J Dermatol 1981;104:67 9. [46] Sharquie KE. Suppression of Behc ets disease with dapsone. Br J Dermatol 1984;110:493 4. [47] Yasui K, Ohta K, Kobayashi M, et al. Successful treatment of Behc ets disease with pentoxifylline. Ann Intern Med 1996;124:891 3. [48] Hamuryudan V, Mat C, Saip S, et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behc ets syndrome: a randomized double-blinded, placebo controlled trial. Ann Intern Med 1998;128:443 50. [49] Kaklamani V, Kaklamanis P. Treatment of Behc ets disease: an update. Semin Arthritis Rheum 2001;30: 299 312. [50] ODuffy JD, Calamia K, Cohen S, et al. Interferonalpha treatment of Behc ets disease. J Rheumatol 1998;25:1938 44. [51] Goossens PH, Verburg RJ, Breedveld FC. Remission of Behc ets syndrome with tumour necrosis factor a blocking therapy. Ann Rheum Dis 2001;60:637. [52] Nussenblatt RB, Palestine AG, Chan CC, et al. Effectiveness of cyclosporine therapy for Behc ets disease. Arthritis Rheum 1985;28:671 9. [53] ODuffy JD, Robertson DM, Goldstein NP. Chlorambucil in the treatment of uveitis and meningoencephalitis of Behc ets disease. Am J Med 1984;76:75 84. [54] Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behc ets syndrome. N Engl J Med 1990;322:281 5. [55] Hassard PV, Binder SW, Nelson V, et al. Anti-tumor necrosis factor monoclonal antibody therapy for gastrointestinal Behc ets disease: a case report. Gastroenterology 2001;120:995 9. [56] Sfikakis PP, Theodossiadis PG, Katsiari CG, et al. Effect of infliximab in sight threatening panuveitis in Behc ets disease. Lancet 2001;358:295 6.
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Pseudo-Behc ets disease

Roy S. Rogers III, MD
Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905-0001, USA
Behc ets disease (BD) is a complex multisystem disease characterized by oral, ocular, and genital lesions with a variety of cutaneous or systemic manifestations [1 8]. This multisystem disease was first described by the Turkish dermatologist Behc et in 1937 [1]. BD can afflict virtually any organ system and is included in the differential diagnosis of many diseases. Mucocutaneous manifestations are the hallmarks of BD [2 5,7]. Oral and genital aphthae, ocular inflammation ranging from conjunctivitis to uveitis, and skin lesions ranging from a papulopustular eruption to erythema nodosum or cutaneous vasculitis are characteristic. Oral aphthae occur in virtually every patient with BD. Because of the complex and multisystem nature of BD, the presence of chronic oral and genital lesions or oral, ocular, and genital lesions may lead the clinician to consider BD in the differential diagnosis of ill-defined mucocutaneous diseases. BD is a potentially devastating disease with severe central nervous system, ocular, and vascular complications. Firm confirmatory evidence should be identified before a diagnosis of BD is made. Some patients do not have BD but have other diseases. Those patients whose signs and symptoms involve (1) oral and genital manifestations, (2) oral, ocular, and genital manifestations, or (3) oral, ocular, genital, and cutaneous manifestations may have pseudo-BD. Pseudo-BD is a term used to describe patients referred for consultation with a diagnosis of BD who do not have BD [9,10]. The presence of oral and genital or ocular lesions can occur in several mucocutaneous conditions as follows: Complex aphthosis Herpes simplex virus infections
E-mail address: rogers.roy@mayo.edu
Crohns disease Chronic ulcerative colitis Reiters syndrome Lichen planus Erythema multiforme Paraneoplastic pemphigus Pemphigus vulgaris Mucous membrane pemphigoid Linear IgA bullous dermatosis Clinicians who care for severely ill patients are aware of the diagnostic dilemmas posed by severe, recurrent herpes simplex virus infections, which may become chronic or disseminated in immunocompromised hosts. Likewise, the overlap of inflammatory bowel diseases (IBD), such as Crohns disease and chronic ulcerative colitis, and BD is well recognized, particularly in light of the extracolonic manifestations of IBD, such as aphthosis, iritis, erythema nodosum, and nonerosive arthropathy [9,11 13]. Other mucocutaneous diseases present a similar diagnostic dilemma. Patients with complex aphthosis, erythema multiforme (EM), mucous membrane pemphigoid (MMP), and the vulvovaginal-gingival (VVG) form of erosive oral lichen planus (LP) have been referred to the author as patients with BD.
Behc ets disease The diagnosis of BD is based on clinical criteria [3,5,12]. There are no pathognomonic laboratory tests. The pathergic skin test, the development of a pustule 24 hours after cutaneous trauma by a needle prick or the intradermal injection of saline, has been advocated as important diagnostic criteria [5,14]. The positive pathergic skin test is positive much more
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R.S. Rogers III / Dermatol Clin 21 (2003) 4961
Table 1 International study group on Behc ets disease criteria (1990) Recurrent oral ulceration Plus 2 of: Recurrent genital ulceration Eye lesions Skin lesions Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient, which occurred at least three times in one 12-mo period. Aphthous ulceration or scarring observed by physician or patient. Anterior uveitis, posterior uveitis, or cells in vitreous on slit lamp examination; or retinal vasculitis observed by ophthalmologist. Erythema nodosum observed by physician or patient, pseudofolliculitis, or papulopustular lesions; or acneiform nodules observed by physician in postadolescent patients not on corticosteroid treatment. Read by physician at 24 48 h.
Positive pathergy test
often in Mediterranean and Middle-Eastern countries than in Europe and North America. Several sets of criteria for the diagnosis of BD have been proposed [15 18]. Some are more useful in defined geographic areas. The various criteria are carefully reviewed by Lee et al [5]. The most recent criteria were promulgated by the International Study Group on Behc ets Disease and published in 1990 (Table 1) [15]. Dermatologists recognize the vagaries of the pustular skin reactions or papulopustular skin lesions, because BD occurs in young persons who may also have folliculitis, acne vulgaris, or corticosteroidinduced acne or folliculitis as secondary or incidental findings [3 5,19,20]. Nevertheless, the papulopustular skin lesions are important cutaneous manifestations of BD. The mucocutaneous manifestations of BD are the hallmarks of the disease [2 4,7,14,21,22]. They are quite common in populations with BD (Table 2). The cutaneous lesions are variable. One classification divides the skin findings into papulopustular lesions, reactive erythema, and vascular-based lesions (Table 3). Obvious overlap between categories is recognized. Behc ets disease evolves over time; months to years may elapse before the complete picture is recognized. The patient with complex aphthosis or uveitis may develop other criteria for BD during the
Table 2 Mucocutaneous manifestations of Behc ets disease Frequency of symptoms (%) Symptom Oral aphthae Genital aphthae Ocular lesions Cutaneous lesions Number of patients Japan, 1991 [21] 98 73 69 87 3316
evolution of the full-blown disease. The diagnosis should not be made until the patients disease conforms to the diagnostic criteria. The prognosis of BD, although variable and often benign, is a potentially devastating one. The patient with pseudo-BD should be identified by the disease from which they suffer for both prognostic and therapeutic reasons.
Complex aphthosis Virtually all patients with BD suffer from recurrent aphthous stomatitis (RAS) [3,7,23 25]. RAS can be classified as simple versus complex aphthosis [3,7,24,25]. RAS has been reviewed by several authors and is discussed by Zunt elsewhere in this issue. BD is also discussed elsewhere in this issue by MacCarthy, Garton, and Jorizzo. Recurrent aphthous stomatitis has many synonyms: canker sores, aphthosis, aphthous ulcers, or recurrent oral ulcers. The word aphthae means ulcers. The author prefers the term recurrent aphthous stomatitis [7,24,25]. The lesions of RAS are discrete, round-to-oval erosions or shallow ulcers of the nonmasticatory oral mucosa. They typically have a perilesional erythematous halo and are covered by a grayish fibromembranous slough (Fig. 1). Sites of predilection include the buccal and labial mucosae, the lateral and ventral tongue, the floor of
Turkey, 1985 [14] 100 77 47 78 496
Germany, 1996 [22] 98 79 47 78 130
United States, 1999 [2] 99 83 57 100 108
R.S. Rogers III / Dermatol Clin 21 (2003) 4961 Table 3 Cutaneous manifestations of Behc ets disease Papulopustular lesions Pathergic skin hyperreactivity Pseudofolliculitis Acneiform nodules Reactive erythemas Erythema nodosum Erythema multiforme Sweets syndrome-like lesions Vascular-based lesions
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Superficial thrombophlebitis Pyoderma gangrenosum-like lesions Palpable purpura and lesions of cutaneous small vessel vasculitis Pathergic skin hyperactivity
the mouth, and the soft palate and fauces. Lesions of the masticatory mucosa of the hard palate and maxillary and mandibular attached gingivae and dorsal tongue are unusual. Patients usually develop RAS during childhood or adolescence. Recurrences are less frequent and milder with increasing age. The prevalence of RAS varies with the population studied. Some populations, such as medical and dental students, have a prevalence rate of 50%. It is estimated that 20% of the general population has RAS during their childhood or early adult life. The presence of the lesions of RAS is critical to the diagnosis of BD [5,7]. The diagnosis is rarely made in the absence of oral aphthosis (Table 2). Aphthosis can be classified as simple aphthosis or complex aphthosis (Table 4). Patients with BD typically have complex aphthosis. Simple aphthosis is a common, episodic, short-lived type of RAS affecting 20% to 50% of the population in their youth [7,24,25]. Complex aphthosis is an uncommon, persistent, chronic type of RAS that may be associated with systemic diseases [7,25 27]. Complex aphthosis patients may have anogenital aphthae. The presence of oral plus anogenital aphthae does not constitute a diagnosis of BD. The condition might be considered a forme fruste of BD [26], but the
diagnosis of complex aphthosis is preferable to making an inaccurate diagnosis of BD. The recurrent aphthae of both simple and complex aphthosis are classified morphologically as minor aphthous ulcers, major aphthous ulcers, and herpetiform ulcers (Table 5; Figs. 1 4 [23,24]. Some authors note an increased prevalence of major aphthous ulcers in patients with BD when compared with all patients with RAS [29,30]. Successful management of patients with complex aphthosis requires an accurate diagnosis, classification of the disease, and recognition of causal or associated conditions, such as the following: Ulcus vulvae acutum Behc ets disease Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome Fever, aphthosis, pharyngitis, and adenitis (FAPA) syndrome Cyclic neutropenia Aphthous-like ulcerations of HIV disease Hematinic deficiencies Celiac disease (sprue, gluten-sensitive enteropathy) Inflammatory bowel disease It is incumbent on the clinician to evaluate the patient with complex aphthosis for these conditions. Correction of the underlying condition, such as gluten-sensitive enteropathy by a gluten-free diet,
Table 4 Classification of recurrent aphthous stomatitis Simple aphthosis Common Episodic Short-lived lesions Few lesions 3 6 episodes/y Heal quickly Minimal pain Little disability Limited to oral cavity Complex aphthosis Uncommon Episodic or continuous Persistent Few to many lesions Continuous ulcerations Slow healing Marked pain Disabling May have genital lesions
Fig. 1. Recurrent aphthous stomatitis. Minor aphthous ulcers involve the labial mucosae but spare the lip vermilion and the keratinized gingivae of the masticatory mucosa.
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Table 5 Classification of recurrent aphthous stomatitis Type MiAU MjAU HU %F 56 44 73 Age (onset) 10 19 10 19 20 29 Size (mm) < 10 ! 10 12 Number Few Few Many Location Anterior Ant > posterior Both Prevalence (%) 85 10 5
Abbreviations: HU, herpetiform ulcers; MiAU, minor aphthous ulcers; MjAU, major aphthous ulcers.
can result in a substantial diminution of disease activity or a remission [31]. Ulcus vulvae acutum represents an acute severe episode of oral and vulvar aphthae (Fig. 5) often associated with an infectious gastroenteritis, such as tuberculous enterocolitis, typhoid fever, or Yersinia enterocolitis. On recovery, simple aphthosis may remain as the only remnant of the disease. Patients with rare combinations of signs and symptoms in the context of complex aphthosis have been reported as the MAGIC syndrome (mouth and genital ulcers with inflamed cartilage); the FAPA syndrome (fever, aphthosis, pharyngitis, and adenitis); and cyclic neutropenia. Aphthous-like oral ulcerations have been reported in HIV-positive patients. Lesions tend to be large and disabling. These lesions of complex aphthosis tend to occur in individuals with CD4 + counts less than 100 cells/mL. The differential diagnosis of this profound immunosuppressive state includes infectious or drug-induced oral ulcers. The diagnosis of HIV-associated aphthous-like oral ulcers is one of exclusion. Anemia and hematinic deficiencies have been associated with lesions of RAS for many years. Several studies have confirmed the presence of a subset of patients who may be deficient in iron; folic acid; zinc; vitamins B1, B2, B6, and B12; and whose disease remits or improves dramatically with replace-
ment of their deficiencies [28,32 35]. Hematologic screening should be considered for all patients with complex aphthosis, those patients with persistently troublesome signs and symptoms, and any patients with signs or symptoms of malabsorption or nutritional deficiency. Screening includes a complete blood count with red blood cell indices; serum levels of iron, zinc, and vitamin B12; red blood cell or serum folate; and antiendomysial, antigliadin or tissue transglutaminase antibody studies. Gastrointestinal diseases have been associated with lesions of RAS for many years. Indeed, according to DuBois and van den Berghe [36], the word sprue, signifying the gastrointestinal disease, is derived from the Dutch word spruw, which means aphthosis. The association of lesions of RAS with gluten-sensitive enteropathy (sprue) has been recognized previously [31]. The malabsorption associated with gluten-sensitive enteropathy can lead to deficiencies of B vitamins and folate. Some authors report that both oral and gut lesions resolve with a gluten-free diet. Furthermore, some patients with lesions of RAS may not have symptoms of glutensensitive enteropathy, but yet the oral lesions improve with a gluten-free diet [37]. Patients with RAS may have symptomatic or asymptomatic gluten-sensitive
Fig. 2. Recurrent aphthous stomatitis. Minor aphthous ulcers are the most common form. They are less than 1 cm in diameter and heal without scarring.
Fig. 3. Recurrent aphthous stomatitis. Major aphthous ulcers (periadenitis mucosa necrotica recurrens) are larger than 1 cm in diameter. They are particularly painful and heal with scarring.
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Fig. 4. Recurrent aphthous stomatitis. Herpetiform ulcers are grouped tiny papulovesicles, which become confluent shallow ulcers. Herpetiform ulcers tend to be numerous and painful. This is the least common form of recurrent aphthous stomatitis.
distinction between multisystem IBD and BD may be difficult [9,11 13]. Clearly, complex aphthosis alone does not constitute BD. Furthermore, the patient with complex aphthosis should be evaluated for associated conditions or diseases, some of which are correctable causes of RAS. The oral lesions of BD are aphthous in nature and are classified best as complex aphthosis. Although some patients with complex aphthosis develop BD, some remain as sufferers of complex aphthosis for years until a cause is identified or the disease enters a spontaneous or therapeutically induced remission. Complex aphthosis is the major pseudo-BD encountered in a referral practice [10].
Erythema multiforme Erythema multiforme is a mucocutaneous reaction pattern to a variety of antigenic stimuli. The mucocutaneous nature of EM may lead the clinician to consider BD, particularly when the disease process is recurrent. EM is an immunologically mediated mucocutaneous disease. EM has a wide range of clinical expressions characterized by cutaneous, exanthematic papules and plaques that develop an iris or target pattern of concentric zones of inflammation. These skin lesions may develop severe edema producing a subepithelial blister (Fig. 6). These are the lesions termed erythema in many forms or erythema multiforme. The skin lesions may be limited in distribution or widespread.
enteropathy with gluten hypersensitivity or nutritional deficiencies, either or both of which may be related to the development of the lesions of RAS. Hunter et al [38] report, however, that in the absence of documented gluten-sensitive enteropathy, a double-blind controlled study of patients with RAS did not confirm that a gluten-free diet or a gluten-supplemented diet consistently yielded benefit or worsening for patients, but did show a large placebo effect. The lesions of RAS may be associated with IBD, such as ulcerative colitis and Crohns disease. Simple or complex aphthosis may antedate, coexist, or serve as a marker for increasing intestinal disease activity. Patients with IBD not only have lesions of RAS but may also have erythema nodosum; papulopustular lesions or lesions of pustular vasculitis; and inflammatory ocular disease, such as iritis and uveitis. The
Fig. 5. Ulcus vulvae acutum. A large major aphthous ulcer is present on the vulva of this patient who had oral and genital aphthae in association with a severe viral gastroenteritis. All lesions healed when she recovered from the gastroenteritis.
Fig. 6. Cutaneous target lesions of erythema multiforme. These vesiculobullous lesions are typical for the target or iris lesions of erythema multiforme. The center is the site of greatest damage with concentric rings of lesser damage noted by color and morphologic changes. These lesions are believed by some authors to represent the sine qua non lesion of erythema multiforme.
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In addition to skin lesions, the mucosae may be involved. The oral lesions of EM are discussed by Ayangco and Rogers elsewhere in this issue. Oral, ocular, and genital mucosae may be affected. Oral lesions are erythematous plaques (Fig. 7), which may develop a subepithelial blistering process producing erosion covered by a hemorrhagic or fibromembranous crust. The vermilion of the lips is characteristically affected by oral EM (Fig. 8). This is a site not typically involved by aphthous lesions. The spectrum of disease diagnosed as EM is broad and includes (1) EM minor, (2) EM major, (3) Stevens-Johnson syndrome (SJS), (4) toxic epidermal necrolysis (TEN), and (5) oral EM (Tables 6 and 7). Erythema multiforme was first described by Hebra [39] in 1886 as a relatively benign condition characterized by skin lesions with concentric color changes, which were symmetrically distributed. Lesions of EM are located primarily on the extremities and have a tendency to recur. The disease tends to have an episodic course with duration of 1 to 4 weeks. It usually occurs in young, healthy individuals. The entity described by Hebra [39] did not mention mucosal involvement, but most authors have accepted occasional erythematous or erosive oral lesions as part of EM. Stevens and Johnson [40] reported two children who had fever, conjunctivitis, stomatitis, and a generalized exanthem with skin lesions of purplish cutaneous maculae and necrotic centers, which were distinct from EM. In 1950, Thomas [41] suggested that EM and SJS were variants of the same pathologic process. He proposed that the mild cutaneous form of Hebra [39] be called EM minor, and the more severe
Fig. 8. Oral lesions of erythema multiforme major. Lesions of the vermilion of the lip are characteristic of erythema multiforme. Vesiculobullous lesions erode; are covered by a fibromembranous slough; and may become hemorrhagic with deeper, more necrotic involvement.
mucocutaneous varieties, as described by Stevens and Johnson [40] and others, be called EM major. In 1956, Lyell [42] reported a series of patients with a life-threatening, rapidly evolving mucocutaneous reaction characterized by widespread erythema, necrosis, and bullous detachment of the epidermis resembling scalding, a condition currently known as toxic epidermal necrolysis. In 1968, Kennett [43] described an inflammatory stomatitis with lesions typical of the oral lesions of EM as EM affecting the oral cavity. In 1978, Lozada and Silverman [44] reported 50 patients with oral EM lesions dominating the clinical picture. Similar patients were reported by Bean and Quezada [45] in 1983. Some authors including Huff et al [46] aver that . . .diagnosis of EM of illnesses characterized by only acute mucosal inflammation without skin lesions is unjustified: the typical skin lesion is sine qua non for the diagnosis of EM. Significant differences exist among EM minor, EM major, SJS, and TEN with regard to severity and clinical expression. All variants, however, share two common features: typical or less typical cutaneous target lesions and satellite cell or more widespread necrosis of the epithelium. These features are consid-
Table 6 The spectrum of erythema multiforme Disorder Fig. 7. Oral lesions of erythema multiforme major. Oral lesions may be diffuse, causing a generalized stomatitis. The gingivae and buccal mucosae are involved by a confluent inflammatory reaction with erosions and a covering fibromembranous slough. Erythema multiforme minor Erythema multiforme major Stevens-Johnson syndrome Toxic epidermal necrolysis Oral erythema multiforme Original author Hebra [39] Thomas [41] Stevens and Johnson [40] Lyell [42] Kennett [43]
Table 7 Spectrum of erythema multiforme Course Erythema multiforme Acute, self limited, minor occasionally recurrent Cutaneous involvement Mucous membrane involvement Absent or limited to one mucosal site, usually oral Duration 1 3 wk Prognosis Recovery; may be episodic R.S. Rogers III / Dermatol Clin 21 (2003) 4961
Typical symmetric target lesions/raised atypical targets acrally distributed. Blisters, when present, involve < 10% of BSA. () Nikolskys sign Erythema multiforme Acute, self limited Typical symmetric target lesions/raised major atypical targets acrally distributed. Blisters, when present, involve < 10% of BSA. () Nikolskys sign Stevens-Johnson Acute, progressive Widespread small blisters, purple macules syndrome systemic illness or flat atypical target lesions predominantly occurring on the torso. (+) Nikolskys sign. Epidermal detachment < 10% of BSA Toxic epidermal Prodromal mucosal Widespread small blisters, purple macules necrolysis inflammation followed or flat atypical target lesions predominantly by acute systemic illness occurring on the torso. (+) Nikolskys sign. Epidermal detachment 30% or more of BSA. Nails may be shed. Oral erythema Acute, self-limited, Typical symmetric target lesions acrally multiforme occasionally recurrent distributed in 25% of patients or chronic
Involvement almost exclusively limited 1 6 wk to the oral cavity; may be the most prominent element of the disease Involvement of one or more mucous membrane with possibility of scarring; extensive mucosal involvement is characteristic Involvement of one or more mucous membrane with possibility of scarring; extensive mucosal involvement. 2 6 wk
Mortality may occur; may be episodic 10% mortality
2 6 wk
30% mortality
Limited to the oral cavity and the lips
Cyclic episodes last from 10 days to 6 wk. Frequency of episodes occur from every 3 wk to annually.
Chronic with recurrent episodes over protracted period of time.
Abbreviations: BSA, body surface area.
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ered to be sequelae of a cytotoxic immunologic attack on keratinocytes expressing non self-antigens. These antigens are primarily microbial (viruses) or drugs and in rare instances histocompatibility antigens [47]. Although the precise pathogenesis is unknown, there is currently a tendency to consider EM, both minor and major, as part of one spectrum that is most often triggered by viral infections, and SJS and TEN as a separate one most often elicited by drugs with EM major and SJS representing a bridge in the continuum of EM [48,49]. The oral lesions of EM begin as erythematous maculae, which evolve by a vesiculobullous process to superficial erosions covered by a yellow fibropurulent membrane or a hemorrhagic crust (see Figs. 7 and 8). Lesions affect both nonkeratinized and keratinized mucosal surfaces and the vermilion of the lips, whereas aphthae affect only the nonkeratinized mucosa. The lesions are less discrete than aphthae and become confluent as the reactive process evolves. The genital lesions have a similar morphology and progression. The oral lesions are painful. Patients suffer eating, drinking, and swallowing difficulties. In severe episodes, mucosal lesions of EM may extend from the anterior oral cavity to involve the oropharynx, hypopharynx, larynx, esophagus, and upper respiratory tree. Lesions may also involve the nasopharynx and nose. Ocular lesions involve the bulbar and palpebral conjunctivae with severe external eye involvement (Fig. 9). Scarring in the form of cicatrizing conjunctivitis and symblephara may occur. Approximately 40% of patients with the SJS-TEN forms of EM develop ocular or anogenital lesions [47]. Oral and lip lesions usually heal without
scarring, but scarring sequelae can occur with throat, esophageal, bronchial, or anogenital involvement. The rapid onset of the clinical picture, the characteristic nature of the cutaneous lesions of EM, and the diffuse nature and distribution of the mucosal lesions permit a diagnosis of the EM spectrum of disease in most circumstances. Few clinicians include BD in this exanthematic mucocutaneous presentation. Some patients, however, have recurrent episodes of EM with oral, ocular, anogenital, and skin involvement. When recurrent disease is present with mucocutaneous manifestations, BD is included in the differential diagnosis. Other EM patients have a recurrent or chronic mucosal disease, which is centered on oral lesions (oral EM) [43 45,50]. The most commonly recognized cause for recurrent EM is recurrent herpes simplex virus infections. The eruption of the lesions of recurrent herpes simplex virus labialis (or other sites) is followed by the reactive efflorescence of EM. Despite important clinical differences, these patients may be considered to have BD. Oral EM patients often have lesions of the vermilion of the lip [44,45,50]. Such lesions are quite unusual for BD. In addition, the oral lesions are not discrete aphthae but are more diffuse vesiculoulcerative lesions (see Fig. 8). About 25% of oral EM patients have typical EM target lesions of the skin or anogenital lesions of EM (see Fig. 6). This clinical pattern may be confused with BD. Ocular involvement with oral EM is rare. The clinician must be aware of the diagnostic dilemma of recurrent EM or recurrent oral EM in the differential diagnosis of BD. Recognition of morphologic and other clinical differences permits the careful clinician to recognize EM and recurrent oral EM as pseudo-BD.
Mucous membrane pemphigoid Mucous membrane pemphigoid is an immunologically mediated subepithelial blistering disease with a predilection for oral, ocular, and, occasionally, anogenital and cutaneous lesions [51 53]. MMP is part of the spectrum of pemphigoid diseases, which include bullous pemphigoid; pemphigoid gestationis; oral pemphigoid; ocular pemphigoid; Brunsting-Perry pemphigoid; and several other variants of bullous pemphigoid, such as pruritic pemphigoid and pemphigoid nodularis [51,54]. Scarring can occur resulting in permanent sequelae (cicatricial pemphigoid). Lesions of pemphigoid
Fig. 9. Ocular lesions of Stevens-Johnson syndrome. The bulbar and palpebral conjunctivae are involved. Symblephara or scar bands between the conjunctival surfaces may follow such severe involvement.
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Fig. 10. Oral lesions of mucous membrane pemphigoid. Erosive, ulcerative lesions develop from erythematous plaques by the subepithelial vesiculobullous pathogenic mechanism. Note the large lesion of the hard palate.
Fig. 12. Ocular lesions of mucous membrane pemphigoid. Ocular lesions begin as conjunctivitis and progress to symblephara and entropion in advanced disease. Scarring forms in the conjunctival tissues.
result from an immunologic attack on components of the basement membrane zone resulting in a subepithelial blister. The mucosal lesions are characterized by erythema, edema, blisters, and erosions. Lesions tend to be diffuse affecting the nonkeratinized and the keratinized oral mucosa, similar to the mucosal lesions of EM (Fig. 10). Gingival involvement is typical of MMP [55,56]. It presents as a desquamative gingivitis (Fig. 11). Individual lesions are vesiculoerosive patches, which do not resemble the discrete aphthae of complex aphthosis or BD. Genital lesions also tend to be diffuse and vesiculoerosive rather than discrete. Ocular lesions of MMP begin as conjunctivitis, as can the ocular lesions of BD. The inflammatory process of MMP, however, leads to symblepharon
formation with scar bands developing between the palpebral and bulbar conjunctivae (Fig. 12). The ocular manifestations of MMP are chronic and usually slowly progressive, whereas the ocular manifestations of EM, SJS, and TEN tend to be acute and progressive. The ocular findings of BD include iritis and uveitis, which are uncommon in EM, SJS, TEN, or MMP. The cutaneous lesions of MMP are vesiculobullous with large, diffuse, inflammatory patches and plaques, which may develop a subepidermal blister. Again, the lesions differ from the cutaneous lesions of BD by being bullous and diffuse. The diffuse blistering and erosive nature of MMP separates it from BD. Nevertheless, some clinicians, when faced with a patient suffering oral, ocular, and anogenital lesions, implicate BD in the differential diagnosis. Recognition of morphologic and clinical manifestations of MMP permits the careful clinician to recognize MMP as pseudo-BD.
VVG variant of erosive oral LP The VVG variant of erosive oral LP is an immunologically mediated mucocutaneous disease with oral, genital, and cutaneous manifestations [57 60]. Lesions result from inflammatory destruction of epithelial basal cell keratinocytes resulting in an interface inflammatory reaction pattern (lichenoid tissue reaction). Clinically, the cutaneous lesions of LP are papulosquamous. These scaly papules are purple, polygonal, and pruritic. They are not reminiscent of any skin lesions of BD but are discrete.
Fig. 11. Desquamative gingivitis lesions of mucous membrane pemphigoid. Desquamative gingivitis begins as erythema and edema of the attached gingivae. It progresses to desquamation of the epithelium as the subepithelial vesiculobullous process continues. Blisters are noted on the left lower alveolar gingivae.
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Fig. 13. Erosive oral lesions of lichen planus. A large erosive lesion present in the deep left buccal mucosa. It is surrounded by reticular white hyperkeratosis.
Fig. 15. Gingival lesions of the vulvovaginal-gingival variant of erosive oral lichen planus. The gingivae are involved by a desquamative gingivitis form of erosive oral lichen planus. This patient has unilateral involvement.
The mucosal lesions may be discrete or diffuse (Fig. 13). Oral lesions of LP are discussed by Eisen and oral and genital manifestations of LP are discussed by Rogers and Eisen elsewhere in this issue. Oral lesions of LP may be reticular, white, lacy or lattice-like, hyperkeratotic, raised lesions (Fig. 14). Some may be erythematous, diffuse patches and plaques. A third type of lesion is erosive patches. The gingivae are typically involved in the VVG variant (Fig. 15). The lesions are similar to the desquamative gingivitis of MMP but tend to be less erosive and more firm and infiltrated with a white hyperkeratotic element at times. Genital lesions are also discrete or desquamative and erosive (Fig. 16). Ocular lesions are rare. The papulosquamous cutaneous and reticular, erythematous, or erosive mucosal lesions are distinct. They may affect the nonkeratinized or keratinized oral mucosa. Neither the oral lesions nor the cutaneous lesions resemble the mucocutaneous manifestations of BD. Neverthe-
less, some clinicians, when faced with a mucocutaneous disorder, particularly with active genital lesions, may implicate BD in the differential diagnosis. Recognition of the clinical and morphologic manifestations of the VVG variant of erosive oral LP
Fig. 14. Hyperkeratotic lesions of oral lichen planus. The hyperkeratotic reticular lesions may be asymptomatic until they become erosive. These are the best lesions for biopsy material.
Fig. 16. Vulvar lesions of the vulvovaginal-gingival variant of erosive oral lichen planus. The introitus is erythematous, eroded, and very tender. The erosive disease can extend into the vagina. Vaginal stenosis may develop.
Table 8 Differential diagnosis of pseudo-Behc ets disease Behcets disease Age Oral lesions Genital lesions Ocular lesions Cutaneous lesions Histopathology 15 30 y Typical discrete aphthae Aphthae Conjunctivitis, iritis, uveitis Variable, papulopustular, erythema nodosum Vascular-based inflammation, lymphocytic inflammation Nonspecific Complex aphthosis 15 30 y Typical discrete aphthae Occasional aphthae Nil Nil Lymphocytic inflammation Nonspecific Erythema multiforme 20 35 y Red patches, erosions, crusts Red patches, erosions, crusts Conjunctivitis Red patches, target lesions, bullous lesions Perivascular round cell inflammation with epithelial damage Nonspecific Mucous membrane pemphigoid 50 75 y Desquamative gingivitis, erosions Erosions Conjunctivitis, symblephara Bullous lesions Subepithelial blister VVG variant of erosive oral LP 40 70 y Desquamative gingivitis, hyperkeratotic plaques, erosions Hyperkeratotic papules, erosions Rare Purple polygonal pruritic papules Lichenoid tissue reaction
Immunopathology
Linear deposition of IgG, C3 along the basement membrane zone
Shaggy deposition of fibrinogen +/ cytoid bodies IgM, IgA
Abbreviations: LP, lichen planus; VVG, vulvovaginal-gingival.
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R.S. Rogers III / Dermatol Clin 21 (2003) 4961 In: Lee S, Bang D, Lee E-S, et al, editors. Behc ets disease. Berlin: Springer; 2001. p. 19 50. Rogers III RS, ODuffy JD. Behc ets syndrome and treatment with colchicine. J Am Acad Dermatol 1984;4:483 4. Dilsen H, Konice M, Aral O. Our diagnostic criteria of Behc ets disease: an overview. In: Lehner T, Barnes CG, editors. Recent advances in Behc ets disease. Proceedings of the Fourth International Conference on Behc ets Disease, London, 5 6 September, 1985. London: Royal Society of Medicine Services; 1985. p. 177 80. International Study Group for Behc ets Disease. Criteria for diagnosis of Behc ets disease. Lancet 1990;335: 1078 80. Mason RM, Barnes CG. Behc ets syndrome with arthritis. Ann Rheum Dis 1969;28:95 103. Misushima Y, Inaba G, Mimura Y, et al. Diagnostic criteria for Behc ets disease in 1987, and guideline for treating Behc ets disease. Saishin Igaku 1988;43: 391 3. ODuffy JD. Criteres proposes pour le diagnostic de la maladie Behc ets et notes therapeutiques. Rev Med 1974;36:2371 9. Jorizzo JL, Abernethy JL, White WL, et al. Mucocutaneous criteria for the diagnosis of Behc ets disease: an analysis of clinicopathologic data from multiple international centers. J Am Acad Dermatol 1995;32: 968 76. Jorizzo JL, Rogers III RS. Behc ets disease. J Am Acad Dermatol 1990;23:738 41. Nakane K, Masaki F, Hashimoto T, et al. In: Weshsler B, Godeau P, editors. Behc ets disease. Proceedings of the 6th International Conference on Behc ets Disease. Paris: Exerpta Medica International Congress Series; 1993;1037:145 51. Zouboulis CC, Kotter I, Djawari D, et al. Epidemiological features of Adamantiades-Behc ets disease in Germany and in Europe. Yonsei Med J 1997;38: 411 22. Lehner T. Autoimmunity in oral diseases, with special reference to recurrent oral ulcerations. Proc R Soc Med 1968;61:515 24. Rogers III RS. Recurrent aphthous stomatitis: clinical characteristics and evidence for an immunopathogenesis. J Invest Dermatol 1977;69:499 509. Rogers III RS. Recurrent aphthous stomatitis: clinical characteristics and associated systemic disorders. Semin Cutan Med Surg 1998;16:278 83. Jorizzo JL, Taylor RS, Schmalstieg FC, et al. Complex aphthosis: a forme fruste of Behc ets syndrome? J Am Acad Dermatol 1985;113:80 4. Schreiner DT, Jorizzo JL. Behc ets disease and complex aphthosis. Dermatol Clin 1987;5:760 78. Rogers III RS, Hutton KP. Screening for hematinic deficiencies in otherwise healthy patients with recurrent aphthous stomatitis. Aust J Dermatol 1986;27: 98 103. Bang D, Hur W, Lee E-S, et al. Prognosis and clinical
permits the careful clinician to recognize this condition as pseudo-BD.

[13]
Summary The conditions of complex aphthosis, EM, MMP, and the VVG variant of erosive oral LP may be confused by clinicians who refer patients for diagnosis and management of BD (Table 8). The mucocutaneous presentations or the presence of complex aphthosis, the hallmark of BD, can be confusing and lead to the referral of the patient for a diagnosis of BD. The astute clinician evaluating patients for BD considers pseudo-BD in the differential diagnosis of the mucocutaneous manifestations of BD.
[14]
[15]
[16] [17]
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[1] Behc et III H. Uber rezidivivierende aphthose, durch ein virus verursachte geschwure am mund, am auge und an den genitalien. Dermatol Wochenschr 1937;105: 1152 7. [2] Balabanova M, Calamia KT, Perniciaro C, et al. A study of the cutaneous manifestations of Behc ets disease in patients from the United States. J Am Acad Dermatol 1999;41:540 5. [3] Ghate JV, Jorizzo JL. Behc ets disease and complex aphthosis. J Am Acad Dermatol 1999;40:1 18. [4] Lee E-S, Bang D, Lee S. Dermatologic manifestations of Behc ets disease. Yonsei Med J 1997;38:380 9. [5] Lee S, Bang D, Lee E-S, et al. Diagnosis of Behc ets disease. In: Lee S, Bang D, Lee E-S, et al, editors. Behc ets disease. Berlin: Springer; 2001. p. 51 7. [6] Onder M, Gurer MA. The multiple faces of Behc ets disease and its aetiological factors. JEADV 2001;15: 126 36. [7] Rogers III RS. Recurrent aphthous stomatitis in the diagnosis of Behc ets disease. Yonsei Med J 1997;38: 370 9. [8] Sakane T, Takeno M, Suzuki N, et al. Current concepts: Behc ets disease. N Engl J Med 1999;341: 1284 91. [9] Levine JA, ODuffy JD. Pseudo-Behc ets syndrome. In: Weshsler B, Godeau P, editors. Behc ets Disease. Paris: Excerpta Medica International Congress Series; 1993;1037:295 8. [10] Rogers III RS. Pseudo-Behc ets disease. Programs and Abstracts of the 9th International Congress on Behc ets Disease, Seoul, 2000. Yonsei Med J 2000;41:11. [11] Jorizzo JL, Hudson RD, Schmalstieg FC, et al. Behc ets syndrome: immune regulation, circulating immune complexes, neutrophil migration, and colchicine therapy. J Am Acad Dermatol 1984;10:205 14. [12] Lee S, Bang D, Lee E-S, et al. Clinical manifestations.
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R.S. Rogers III / Dermatol Clin 21 (2003) 4961 relevance of recurrent oral ulceration in Behc ets disease. J Dermatol 1995;22:926 9. Krause I, Rosen Y, Kaplan I, et al. Recurrent aphthous stomatitis in Behc ets disease: clinical features and correlation with systemic disease expression and severity. J Oral Pathol Med 1999;28:193 6. Ferguson MM, Wray D, Carmichael HA, et al. Coeliac disease associated with recurrent aphthae. Gut 1980; 21:223 6. Nolan A, McIntosh WB, Allam BF, Lamey P-J. Recurrent aphthous ulceration: vitamin B1, B2 and B6 status and response to replacement therapy. J Oral Pathol Med 1991;20:389 91. Porter S, Flint S, Scully C. Recurrent aphthous stomatitis: the efficacy of replacement therapy in patients with underlying hematinic deficiencies. Ann Dent 1992;51:14 6. Tyldesley WR. Stomatitis and recurrent oral ulceration: is a full blood screen necessary? Br J Oral Surg 1983;21:26 30. Wray D, Ferguson MM, Hutcheon AW, et al. Nutritional deficiencies in recurrent aphthae. J Oral Pathol Med 1978;7:418 23. DuBois A, van den Berghe L. Diseases of the warm climates: their clinical features, diagnosis, and treatment. New York: Grune & Stratton; 1948. Wray D. Gluten-sensitive recurrent aphthous stomatitis. Dig Dis Sci 1981;26:737 40. Hunter IP, Ferguson MM, Scully C, et al. Effects of dietary gluten elimination in patients with recurrent minor aphthous stomatitis and no detectable gluten enteropathy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1993;75:595 8. von Hebra F. Atlas der hautkrankheiten. Vienna: Kaiserliche Akademie der Wissenchaftgen Wien; 1866. Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia. Am J Dis Child 1922;24:526 33. Thomas BA. The so-called Stevens-Johnson syndrome. BMJ 1950;1:1393 7. Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol 1956; 68:355 61. Kennett S. Erythema multiforme affecting the oral cavity. Oral Surg 1968;25:366 73. Lozada F, Silverman S. Erythema multiforme: clinical and natural history in fifty patients. Oral Surg 1978;25: 366 73. Bean SF, Quezada RK. Recurrent oral erythema multiforme: clinical experience with 11 patients. JAMA 1983;249:2810 2. Huff JC, Weston WL, Tonnesen MG. Erythema multi-
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forme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol 1983;8: 763 75. Fritsch PO, Maldonado RR. Erythema multiforme. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al, editors. Dermatology in General Medicine, vol. 2. 4th edition. New York: McGraw-Hill; 1993. p. 636 43. Assier H, Bastuji-Garin S, Revuz J, et al. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol 1995;131: 539 43. Cote B, Wechsler J, Bastuji-Garin S, et al. Clinicopathologic correlation in erythema multiforme and Stevens-Johnson syndrome. Arch Dermatol 1995; 131:1268 72. Bean SF. Diagnosis and management of chronic oral mucosal bullous diseases. Dermatol Clin 1987;5: 751 60. Person JR, Rogers III RS. Bullous and cicatricial pemphigoid: clinical, histopathologic, and immunopathologic correlations. Mayo Clin Proc 1977;52:54 66. Rogers III RS. Mucous membrane pemphigoid: dermatology at the millennium. In: Dyall-Smith D, Marks R, editors. Proceedings of the 19th World Congress of Dermatology. London: Parthenon Publishing; 1997. p. 654 8. Scully C, Carrozzo M, Gandolfo S, et al. Update on mucous membrane pemphigoid. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;8:56 8. Liu HN, Su WPD, Rogers III RS. Clinical variants of pemphigoid. Int J Dermatol 1986;25:17 27. Rogers III RS, Sheridan PJ, Jordon RE. Desquamative gingivitis: clinical, histopathologic, immunopathologic investigations. Oral Surg 1976;42:316 27. Rogers III RS, Sheridan PJ, Nightingale SH. Desquamative gingivitis: clinical, histopathologic, immunopathologic and treatment observations. J Am Acad Dermatol 1982;7:729 35. Eisen D. The vulvovaginal-gingival syndrome of lichen planus. Arch Dermatol 1994;130:1379 82. Pelisse M, Leibowitch M, Sedel D, Hewitt J. Un noveau syndrome vulvo-vagino-gingival. Lichen plan erosif plurimuqueux. Ann Dermatol Venereol 1982; 109:797 8. Pelisse M. The vulvo-vaginal-gingival syndrome: a new form of erosive lichen planus. Int J Dermatol 1989;28:381 4. Rogers III RS. Erosive orogenital lichen planus in women (vulvovaginal-gingival syndrome) [abstract]. J Oral Pathol Med 1998;27:362.
[46]
White lesions of the oral cavity

Diana V. Messadi, DDS, MMSc, DMSca, Jill S. Waibel, MDb, Ginat W. Mirowski, DMD, MDc,d,*
a
Section of Oral Medicine, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Box 951668, Los Angeles, CA 90095 1668, USA b Section of Dermatology, Wright Stat School of Medicine, PO Box 927, Dayton, OH 45401 0927, USA c Department of Oral Pathology, Medicine, Radiology, Indiana University School of Dentistry, Indianapolis, IN, USA d Department of Dermatology, Suite 3240, Indiana University School of Medicine, 550 North University Boulevard, Indianapolis, IN 46202, USA
White lesions are frequently found during the examination of the oral cavity. Although some benign physiologic entities may present as white lesions, systemic conditions, infections, and malignancies may also present as white oral lesions. An appreciation of the many clinical entities that white lesions may represent is necessary if a differential diagnosis of white lesions is to be elucidated. The appreciation of subtle clinical findings associated with white lesions of the oral cavity permits clinicians better to care for their patients.
lence indicates that it is a variant of normal versus a pathologic process. Some reports have suggested, however, that leukoedema is more severe in smokers and lessens with cessation. Histopathology Oral lesions of leukoedema show parakeratosis and an increase in thickness of the oral mucosa epithelium with intracellular edema of the spinous layer. The cells of the spinous layer are large with pyknotic nuclei. Rete ridges may be elongated. No dysplasia or hypergranulosis is evident. Diagnostic tests
Leukoedema Leukoedema is a common oral condition of unknown cause. The oral mucosa appears to have an asymptomatic, symmetric, opalescent milky-white film with accentuation of edematous folds or streaks (Fig. 1). Leukoedema most commonly occurs bilaterally on the buccal mucosa; it may also be noted on the floor of the mouth and palatopharyngeal tissues. The white opaque character of the lesion diminishes or disappears with the stretching and eversion of the oral mucosa. Leukoedema has a greater prevalence in the black population; its prevalence has been reported to be as high as 90% in black adults. This high preva-
The white lesions of leukoedema do not rub off. Stretching of the oral mucosa and the resultant disappearance of the opalescence in the mucosa is diagnostic. Any diffuse white lesions of the oral mucosa should always be stretched out to rule out any other underlying lesions. Treatment No treatment is necessary. Leukoedema has no malignant potential.
* Corresponding author. Department of Dermatology, Suite 3240, Indiana University School of Medicine, 550 North University Boulevard, Indianapolis, IN 46202, USA. E-mail address: gmirowsk@iupui.edu (G.W. Mirowski).
Linea alba Linea alba (horizontal bite line) is a very common benign alteration of the buccal mucosa. Linea alba
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D.V. Messadi et al. / Dermatol Clin 21 (2003) 6378
Morsicatio buccarum et labiorum Morsicatio buccarum (chronic cheek and lip biting) is a physical reaction to chronic trauma to the oral mucosa caused by chronic nibbling. Morsicatio buccarum is frequently found bilaterally on the buccal mucosa, or combined with labial and tongue lesions. Clinically morsicatio presents as thickened, shredded white areas that can be peeled off by the patient [1]. Intervening zones of erythema, erosions, or focal traumatic ulcerations can be seen. The affected areas are more pronounced along the occlusal plane and in the anterior one third of the buccal mucosa. When the lips are affected, it is the lower lip that is typically more severely affected than the upper lip. Most patients are aware of their habit but many deny the self-inflicted injury or perform the act subconsciously. It occurs more often in women and over the age of 35. Pathophysiology presents as a distinct white line that is usually bilateral on the buccal mucosa at the level of the occlusal plane of the adjacent teeth. The line varies in prominence from barely visible to highly prominent. The horizontal line becomes more pronounced distally toward the posterior teeth. Pathophysiology The horizontal alignment of this finding, and its presence only in patients who are dentulous, suggests that the linea alba is caused by a combination of frictional irritation and mild sucking trauma along the facial surfaces of the teeth and along the opposing occlusal surfaces. Histologic picture Hyperkeratosis overlying normal mucosa is demonstrated. Sometimes a mild chronic inflammatory cells infiltrate may be seen. Diagnostic tests The clinical picture is pathognomonic to establish a diagnosis. No biopsy is required. Treatment Bite splints worn at night may protect the cheek mucosa from involuntary biting. Morsicatio comes from the Latin word morsus, meaning bite. Chronic nibbling of the cheek produces lesions that are located more frequently on the buccal mucosa but sometimes the lingual mucosa (morsicatio labiorum) and lateral border of tongue (morsicatio linguarum) can also be affected. Histopathology Hyperparakeratosis with numerous keratin projections lined by and colonization by bacterial organisms are characteristic of morsicatio. Clusters of vacuolated keratinocytes may be present in the superficial layers of the spinous cell layer. Similar findings in linea alba and leukoedema also may be noted. The clinical findings on the lateral border of the tongue and the histologic findings may resemble oral hairy leukoplakia, a lesion most frequently found in HIV patients. The bacterial colonization, however, is diagnostic. Diagnostic tests The clinical presentation and location are characteristic. Treatment Instructing the patient to avoid cheek biting is important. If the habit is uncontrollable, an acrylic shield that covers the facial surfaces of the teeth may be beneficial. Medications to control the habit may be used as adjunct therapy.
Fig. 1. Leukoedema. Opalescent, whitish gray, ill-defined patches on buccal mucosa. They are usually bilateral and present in dark-skinned individuals. Lesions disappear when mucosa is stretched.
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White sponge nevus White sponge nevus (WSN) is an autosomaldominant disorder characterized by asymptomatic white, thickened, and folded spongy plaques occurring symmetrically on the buccal mucosa. The tongue, labial mucosa, alveolar ridges, and floor of the mouth are also commonly affected. WSN presents at birth or early in childhood; rarely, the condition may appear during adulthood. Once they appear, they remain unchanged throughout the patients life, except sometimes they become more pronounced during pregnancy. Extraoral mucous sites are less commonly affected; 15% to 30% can be found on the nose, esophagus, vagina, anus, and penis. Pathophysiology Recent genetic linkage analysis demonstrated a novel mutation in a vital domain of the K13 protein caused WSN in a large Scottish family, confirming a mutation hotspot in the mucosal keratins [2]. It seems that mutations in both keratin 4 and 13 may be present in WSN [3]. Some authors suggest that oral microflora could contribute to the stimulation of the lesion, because it has been demonstrated that WSN improved after tetracycline treatment. Histopathology The histologic findings are characteristic but not pathognomonic. These findings include prominent hyperparakeratosis and acanthosis with clearing of the cytoplasm in the spinous layer. Sometimes eosinophilic condensation, presented as aggregates of keratin intermediate filaments, is seen in the superficial layers of the epithelium. Diagnostic tests Exfoliative cytology of the epithelial cells stained with Papanicolaous method show the characteristic eosinophilic perinuclear condensation better than histopathologic sections. Treatment No treatment is necessary.
metric waxy, dirty keratotic papules involving the scalp, face, trunk, and flexures of the extremities (seborrheic distribution). As the disease progresses, the neck, shoulders, extremities, trunk, buttocks, genitals, and oral cavity may be affected. The lips may ulcerate or crust, fissure, and become edematous. Intraoral involvement occurs on the dorsal surface of the tongue. Small pebbly keratotic white papules are present on keratinized mucosa of the gingiva and hard palate. Pathophysiology Keratosis follicularis is an autosomal-dominant genodermatosis [4]. Defects in the tonofilament-desmosomal complex are reported. In some families, a linkage to the Duffy blood group locus at 1q21-q22 [5] has been made. Others have demonstrated linkage to markers in the 12q23-q24.1 region [6,7]. The site on chromosome 12 of this disorder of keratinization is distal to that of the type II keratin gene cluster at 12q11-q13 [8]. A defect in the gene encoding the SERCA2 (Ca (2+)-ATPase (ATP2A2) has been found as the causative mutation in keratosis follicularis. Histopathology Perivascular infiltration in the dermis and submucosa is typically seen on histologic evaluation. Dermal villi protrude into the epidermis, with suprabasal detachment of the spinous layer forming lacunae and containing acantholytic cells. Dyskeratotic round epidermal cells and grains of parakeratotic cells are seen within a hyperkeratotic horny layer of the stratum corneum. Diagnostic tests A complete physical evaluation permits differentiation from other syndromes. The palmar surface may also have punctate keratoses, raising the differential diagnostic possibility of nevoid basal cell carcinoma syndrome (Gorlins syndrome). Nail involvement shows subungual hyperkeratosis, fragility, and red streaks. The free edge may show triangular nicking. Involvement of the oropharynx, esophagus, hypopharynx, larynx, and the anorectal mucosa in keratosis follicularis has been reported.
Keratosis follicularis Keratosis follicularis (Dariers disease or DarierWhite disease) is a condition characterized by sym-
Dyskeratosis congenita Dyskeratosis congenita is an inherited disorder with x-linked, autosomal-recessive and autosomal-
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Oral leukokeratosis is similar in its appearance to that observed in dyskeratosis congenita. Dysplasia, however, does not develop. Pathophysiology The genetic defect associated with pachyonychia congenita is localized to chromosome 17q12-q21 and chromosome 12q13. Both of these result in keratin defects. Treatment Topical retinoids and topical podophyllin, although not approved by the Food and Drug Administration, have been used.
Fig. 2. Dyskeratosis congenita. Diffuse white striae along the buccal mucosa. These areas are premalignant. (Courtesy of R.S. Rogers III, MD, Rochester, MN.)
Focal epithelial hyperplasia Focal epithelial hyperplasia (Hecks disease) is a benign, proliferative, wart-like disease of the oral mucosa that shows an unusual racial and geographic distribution. The lesions predominantly affect children and young adults, with girls more than boys. The lesions are asymptomatic, soft, fleshy papules and plaques ranging in color from pink to white, most frequently occurring on the lips, buccal mucosa, and lateral borders of the tongue. The anal-genital mucosa may be affected, whereas skin involvement is rare. The lesions range from 2 to 4 mm and mostly appear multiple and confluent. A cobblestone or fissured
dominant pedigrees. Dyskeratosis congenita is characterized by skin pigmentation, leukoplakia, and nail dystrophy associated with a progressive bone marrow failure (Fig. 2). Clinical manifestations in dyskeratosis congenita often appear during childhood. The skin pigmentation and nail changes typically appear first, usually by the age of 10 years [9 11]. Mucosal leukoplakia and epiphora appear later and by the midteens the serious complications of bone marrow failure and malignancy begin to develop. Rarely, marrow abnormalities may appear before the skin manifestations. Pathophysiology An RNA component of telomerase is mutated [12]. Treatment Treatment for this fatal disease remains unsatisfactory.
Pachyonychia congenita Pachyonychia congenita (Jackson-Lawler syndrome or Jadassohn-Lewandowsky syndrome) are a group of ectodermal dysplasias. The autosomal-dominantly inherited disorder is characterized by onychogryphosis; hyperkeratosis of the palms, soles, knees, and elbows; extensive tiny cutaneous horns; and leukokeratosis of the oral mucous membranes (Fig. 3). Hyperhidrosis of the hands and feet is present frequently. Autosomal-recessive and late-onset pedigrees have been described.
Fig. 3. Pachyonychia congenita. Diffuse white plaques along the lingual aspect of the palate. (Courtesy of R.S. Rogers III, MD, Rochester, MN.)
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pattern is observed with coalescing sheets of the lesions. The surface may be smooth or papillary [13]. Pathophysiology Focal epithelial hyperplasia is frequently seen in Inuits and Indians from North, Central, and South America [14,15]. Focal epithelial hyperplasia was first described by Archard et al [16] in 1965 in 15 Navajo children suffering from verruciform papules and nodules in the oral cavity. The causative organism is human papilloma virus (HPV) types 13 and 32; additional HPV types 6, 11, and 26 have also been identified. Histopathology Acanthosis and elongation with prominent clubbing and lateral anastomosing of the rete pegs is characteristic. Keratinocytes show typical HPV transformed cells characterized by pyknotic nuclei and perinuclear vacuoles [13]. Treatment Usually therapy includes surgery, cryosurgery, and laser excision. Recently, Steinhoff et al [17] showed successful elimination of these lesions using a topical interferon-b gel after 12 weeks of daily application.
peripheral hyperpigmented plaques are common. Overlying scale forming carpet tack follicular plugs is noted. Less commonly, other sites may be affected. Distinctive oral plaques of DLE appear as sunburst with erythematous plaques surrounded by white, radiating striations. Telangiectasias at the peripheral border may be noted (Fig. 4). Scale is not found in the oral cavity [19]. Although any mucosal surface may be involved, the buccal mucosa, the vermilion borders, the gingiva, and the labial mucosa are affected in decreasing order of frequency. The oral lesions may become secondarily infected with Candida. Discoid LE lesions may be painful, particularly when acidic or salty foods are ingested. Oral DLE plaques may resemble erosive lichen planus or a lichenoid mucositis. Oral DLE plaques, however, are less likely to be symmetric and more frequently are associated with lesions on the vermilion or facial skin. A small subset of patients may have only oral DLE lesions. Histopathology Oral DLE lesions reveal hyperkeratosis, vacuolar degeneration of the basal cell layer, and a thickened basement membrane. An interface mucositis with a mild to moderate perivascular infiltrate can be seen. Diagnostic tests Patchy deposits of periodic acid Schiff positive material in the basement membrane are noted. Direct immunofluorescence testing of oral tissue may reveal a granular band of immunoreactants (IgG, IgM, and IgA), complement (C3), and fibrinogen along the basement membrane of long-standing lesions (Fig. 5). The
Discoid lupus erythematosus Lupus erythematosus (LE) is an autoimmune condition with a broad spectrum of disease manifestations. LE may present in chronic form or it may present acutely. Occasionally, subacute lesions can be seen. Skin and oral lesions characterize chronic mucocutaneous LE. Subacute cutaneous LE is characterized by recurring superficial nonscarring annular skin lesions that are more disseminated and present more acute features both clinically and histologically than those seen in the chronic discoid type. Acute systemic LE lesions present as erythematous edematous plaques on the skin and erosions of the mucous membranes. Chronic cutaneous LE primarily affects the skin but the oral mucosa can also be affected [18]. Patients with discoid lupus erythematosus (DLE) lesions typically have cutaneous findings and, rarely, they may also present with oral findings. DLE is used to describe both the skin and oral findings. Cutaneous DLE lesions are common on the scalp, face, and in the ears. In the skin, central atrophic hypopigmented and
Fig. 4. Discoid lupus. Erythematous and white plaques on the buccal mucosa with a rim or erythema secondary to telangiectasias
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Fig. 5. Discoid lupus. Granular deposition of IgG along the basement membrane zone confirming the diagnosis of lupus erythematosus. (Courtesy of R.S. Rogers III, MD, Rochester, MN.)
finding of granular C3 deposits along the basement membrane zone or fibrinogen is not diagnostic. The presence of anti-ssDNA occurs with widespread active disease. Treatment Topical corticosteroids may expedite the resolution of oral LE lesions. If patients have painful discoid lesions, intralesional corticosteroids are recommended and, if these treatments are unsuccessful, patients may require systemic medications.
Pyostomatitis vegetans Pyostomatitis vegetans is a rare inflammatory pustular disorder of the oral mucosa. This rare finding is a specific marker of inflammatory bowel disease [50]. Most patients have ulcerative colitis. Pyostomatitis vegetans has also been reported, however, in Crohns disease, sclerosing cholangitis, and other liver diseases. Clinically, yellowish, elevated pustules are found on an erythematous mucosa. These pustules quickly rupture leading to erosions and ulcerations. The ruptured pustules form a snail track (Fig. 6).
Fig. 6. Pyostomatitis vegetans. Extensive discrete superficial pustules along the gingivae and vestibule. (Courtesy of R.S. Rogers III, MD, Rochester, MN.)
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Vegetative plaques may also be found on the buccal mucosa. Patients may have mild to moderate pain particularly when the erosions and ulcers appear. The most commonly affected areas of the oral cavity include the buccal mucosa, labial mucosa, and attached gingivae. The oral lesions may either precede or be concurrent with intestinal findings [17,20,21]. Histopathology Microscopically pyostomatitis vegetans shows marked edema that may have a hyperkeratotic and acantholytic appearance. In the spinous layer an accumulation of eosinophils and neutrophils forms intraepithelial abscesses. An infiltrate of eosinophils, neutrophils, and lymphocytes is noted in the submucosa. Perivascular inflammation has also been reported. Diagnostic tests Direct immunofluorescence testing is usually negative. This helps differentiate pyostomatitis vegetans from other autoimmune disorders, such as pemphigus and pemphigoid. A peripheral eosinophilia may be found in up to 90% of patients. Treatment Topical and systemic corticosteroids may be effective to treat oral lesions. When oral disease activity correlates with the gastrointestinal disease, management of the underlying inflammatory bowel disease with systemic corticosteroids, sulfasalazine, dapsone, diet, or surgery may clear the oral lesions. Recurrences are frequent if therapy is stopped. Pyostomatitis vegetans may be refractory to therapy [22].
lesion site in a follow-up time of up to 20 years. When compared with other oral sites, the tongue and gingiva have a higher tendency for malignant transformation. The authors suggest that if mortality data from both reports were combined, the PVL-associated deaths would be 50%. Pathophysiology Smoking [25] has not been associated in most individuals. Ultimately, PVL is associated with considerable morbidity and a strong potential for malignant transformation. HPV seems to be a possible etiologic factor for PVL. Palefsky et al [26] found that 89% of their patients were HPV positive. Histopathology Individual lesions progress from benign-appearing hyperkeratosis to verrucous hyperplasia, to different degrees of dysplasia to verrucous or squamous cell carcinoma. The inflammatory cell infiltrate in the connective tissue is quite variable ranging from mild and diffuse to dense subepithelial clustering [25,27]. Diagnostic tests Polymerase chain reaction testing for HPV 16 on DNA samples from tissue samples can be performed to confirm the presence of HPV in these specimens [26]. Treatment The treatment for PVL continues to be unsatisfactory with a very high rate of recurrence after surgical excision. Still, the treatment of choice is surgical or laser excision.
Proliferative verrucous leukoplakia Florid oral papillomatosis Proliferative verrucous leukoplakia (PVL) was first described by Hansen et al in 1985 [23]. PVL is characterized by progressive expanding exophyticverrucous white plaques. Early lesions appear as a solitary, homogeneous leukoplakia. Women are affected four times as frequently as men. The most common sites for women are the buccal mucosa and gingiva, and for men, the tongue. Early biopsies show only hyperkeratosis without dysplasia [24]. These innocuous lesions recur and spread to involve several sites resulting in a diffuse, multifocal, exophytic, or warty-type presentation. Hansen et al [23] reported that 86.7% of the patients developed carcinoma at the Florid oral papillomatosis is a rare condition considered to be premalignant by some authors and is usually associated with a marked capacity for progression and recurrence [28]. Florid oral papillomatosis is characterized by multiple papillomas involving the whole oral mucosal including the palate, tongue, and lips (Fig. 7). Pathophysiology Some authors suggested a viral etiology but the role of HPV in these lesions remains unclear [28].
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Histopathology Histologic evaluation of syphilis mucous patches is nonspecific. The epithelium may be either ulcerated or hyperplastic. The lamina propria may have increased vascular channels and chronic inflammatory reaction. This inflammatory perivascular infiltrate is principally comprised of lymphocytes and plasma cells. Diagnostic tests Special stains, such as Warthin-Starry or Steiner, may be used and often show the spirochetes. The most specific tests are the demonstration of the spirochete in skin biopsy or darkfield examination. False-positive results are possible in the oral cavity because of morphologically similar bacteria T. microdentium, T macrodentium, and T. mucosum. Confirmation of syphilis should be performed with serology following biopsy or darkfield examination. The serologic tests in secondary syphilis are usually positive. Serologic tests, which are nonspecific and highly sensitive, include the Venereal Disease Research Laboratory and the rapid plasma reagin. Specific and highly sensitive serologic tests for syphilis include the fluorescent treponemal antibody absorption test. This test becomes positive at the development of the initial lesion and is positive for life. It is less effective in diagnosis of second infection of syphilis. Treatment The treatment of choice for syphilis is benzathine penicillin G, 2.4 million units in a single intramuscular dose. Patients should have follow-up serologic titers at 3 and 6 months to ensure a fourfold decline in titers. In addition, patient reporting to proper public health
Fig. 7. Florid oral papillomatosis. Diffuse confluent and adherent papillated white hyperkeratosis along the attached and free gingivae. (Courtesy of R.S. Rogers III, MD, Rochester, MN.)
Histopathology Hyperplasia with parakeratosis and acanthosis is observed. Dysplastic changes are rare. Treatment Various modes of therapy have been proposed including surgery, bleomycin chemotherapy, radiotherapy, interferon alfa-2a injections, and laser surgery [28].
Syphilis mucous patches Mucous patches are an oral manifestation of secondary syphilis. The plaques are usually oval and covered with white or gray membrane that is removed easily to reveal underlying raw connective tissue. Roughly 30% of patients with secondary syphilis present with superficial painless oral lesions with irregular, grayish mucosal necrosis. These patches are found on the tongue, lips, buccal mucosa, and palate. Mucous patches may heal spontaneously, but have a high incidence of recurrence (Fig. 8). Other findings associated with secondary syphilis include a papulosquamous eruption with prominent copper-colored scaly plaques involving the palms and soles; a moth-eaten alopecia; and genital condylomata lata lesions, which may be associated with a mild lymphadenopathy, hepatosplenomegaly, and a residual chancre. Pathophysiology Syphilis is caused by the spirochete Treponema pallidum.
Fig. 8. Syphilis mucous patch. Well-demarcated erythroleukoplakia on the palate of a patient with secondary syphilis. (Courtesy of R.S. Rogers III, MD, Rochester, MN.)
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agencies ensures tracking and management of known sexual partners.
Candidosis (candidiasis) Candidosis, synonymously called candidiasis, is caused by Candida organisms, fungi that inhabit the oral cavity, gastrointestinal tract, other mucous membranes, and the skin [29]. Moniliasis is an old and inaccurate term that should be abandoned. Candidosis is the most common infection of the oral cavity with the exception of dental caries and periodontal diseases. Oral candidosis manifests in six specific clinical forms [30]: 1. 2. 3. 4. 5. Pseudomembranous candidiasis Acute atrophic-erythematous candidiasis Chronic atrophic candidiasis ` che) Angular cheilitis (perle Chronic hypertrophic-hyperplastic candidiasis (Candida leukoplakia) 6. Median rhomboid glossitis
Pseudomembranous candidiasis presents with superficial curdlike white patches that wipe off, leaving an erythematous base (Fig. 9). Any mucosal surface may be affected. The elderly, infants, and AIDS patients are frequently affected, as are patients with a history of broad-spectrum antibiotics or corticosteroid treatment, nutritional deficiency, and diabetes mellitus. Patients may complain of stomatodynia and dysgeusia.
Fig. 9. Pseudomembranous candidiasis. Localized removable white plaques on the dorsal aspect of the tongue. (Courtesy of R.S. Rogers III, MD, Rochester, MN.)
Erythematous candidiasis is a generalized category of candidiasis that appears as focal or diffuse areas of erythema with variable causes and symptoms. These include items 2 through 6 on the previous list, as discussed next. Acute atrophic candidiasis is most often seen on the tongue and palate, and is a frequent complication of broad-spectrum antibiotic, corticosteroid, and corticosteroid aerosol therapy. These lesions present as small or generalized large red patches of inflammation and edema of the surrounding tissues. Chronic atrophic candidiasis presents as red diffuse areas with a slightly pebbly or velvet surface located on the palate and upper and lower edentulous ridges. This entity is frequently found under ill-fitting dentures or poorly cleaned dentures (denture stomatitis). Angular cheilitis presents as fissures, erosions, and crusting with underlying erythema developing at the commissures (corners of the mouth). Predisposing factors include ill-fitting dentures with overclosure, drooling at the corners of the mouth, lip-licking habits, and thumb sucking habits. Chronic hyperplastic candidiasis (candidal leukoplakia) appears as well-demarcated, white, thick, or verrucous white plaques that cannot rub off. These develop most frequently on the anterior buccal mucosa and palate. Median rhomboid glossitis was previously thought to be a congenital anomaly from faulty involution of the tuberculum impar at the junction of the anterior two thirds and posterior one third of the tongue. It appears as a diamond- or oval-shaped erythematous depapillated area of the posterior dorsum of the tongue (Fig. 10). The surface could be smooth or lobulated, and it is asymptomatic. It occurs more frequently in AIDS patients. There is a generalized mucocutaneous form of candidosis that presents as chronic infection of the oral mucosa, nails, skin, and vaginal mucosa. It usually starts as pseudomembranous candidiasis, and then proceeds to become chronic hyperplastic candidiasis. Several types are familial and can present during early childhood. Another familial form exists in association with endocrinopathy, such as hypoparathyroidism, Addisons disease, hypothyroidism, or diabetes mellitus. When changes occur in the host environment that results in an imbalance of the flora or a decrease in resistance, Candida becomes an opportunistic pathogen. Most cases of oral candidiasis are caused by Candida albicans, although a large number of other yeast species maybe found intraorally. These include C. tropicalis, C. krusei, C. parapsilosis, and C. guilliermondii. These different species can be differenti-
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Diagnostic tests The most common laboratory test is the digestion of an exfoliative cytology smear of the oral sites affected with 10% potassium hydroxide, demonstrating the pseudohyphae or budding cells that are consistent with the Candida morphology. A cytologic smear or biopsy can be stained with periodic acid Schiff. This method stains the abundant carbohydrates in the fungal cell walls. The organisms are identified easily by their bright magenta color. Definitive identification of the fungi is performed by culture growing on Sabourauds dextrose agar.
Fig. 10. Median rhomboid glossitis. In chronic candidiasis, localized asymptomatic erythematous patch on the middorsal surface of the tongue. Long-standing lesions may become nodular.
Treatment Several antifungal medications have been developed for managing oral candidiasis. There are three main categories [29]. The polyenes, which include amphotericin B and nystatin, destroy the protein gradient in the cell because of leakage of cellular components. Amphotericin B is highly effective when given intravenously, but could cause toxicity and renal dysfunction. The second group is the azoles, including clotrimazole, ketoconazole, fluconazole, and itraconazole. These inhibit ergosterol biosynthesis. The third category is 5-flucytosine. This drug disrupts the DNA and protein synthesis of the cell. It is usually used in combination with amphotericin B, fluconazole, or itraconazole (Table 1).
ated from one another by polymerase chain reaction techniques that are being developed to aid in the diagnosis [31]. Candida albicans exists in several forms from yeast to hyphae. The yeast form is commensal and harmless; the hyphae form is invasive, pathogenic, and causes clinical candidiasis. Recently, it has been shown [32] that adherence of hyphae to the oral keratinocyte may be caused by a protein called Hwp1. This protein forms a covalent bond to epithelial cells with the aid of the enzyme transglutaminase. The authors state that without Hwp1, adherence of the hyphae to human oral mucosal cells is reduced 80%. There are several predisposing factors to Candida infection, such as diabetes; congenital or acquired immunodeficiency, such as AIDS; xerostomia or decreased salivary flow; and patients undergoing radiotherapy or chemotherapy for cancer treatments. Patients on long-term therapy with antibiotics or corticosteroids are all susceptible to develop candidosis. Leukemia, organ, or bone marrow transplant patients and denture-wearing patients are all prone to candidal infection.
Warts There are two main categories of warts: common warts (verruca vulgaris) and venereal warts (condyloma acuminatum). Verruca vulgaris (common warts) are the result of epithelial hyperplasia, which appear as solitary or multiple, asymptomatic, exophytic growths with roughened or verrucous surface identical to cutaneous
Table 1 Most common antifungal drugs for treatment of oral candidiasis Drugs Nystatin Amphotericin B Clotrimazole Ketoconazole (Nizoral) Fluconazole (Diflucan) Itraconazole (Sporanox) Route Oral (suspension, troches), topical IV, oral suspension Oral (troches), topical Oral, topical Oral (tablet, suspension) Oral (capsules, suspension) Dosage 200,000 400,000 U, 4 5 times/d IV: 1 3 mg/kg/d, oral: 100 mg, 4 6 times/d 10 mg, 5 times/d 200 400 mg/d 100 200 mg/d 200 400 mg/d
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warts. Lesions are either pedunculated or sessile and range in color from pink to white. Individual lesions usually achieve an average size of about 0.5 to 1 cm. Oral verruca vulgaris arise more frequently in children than in adults. The lesions develop in sites of inoculation, mainly the labial mucosa, tongue, and gingiva. Although warts are more common in the skin, they are present in the oral mucosa mostly because of autoinoculation from hands and fingers. Common warts are caused by viral infection with HPV types 2, 4, 40, and 57 [13]. Condyloma acuminatum (venereal warts or genital warts) is the most common sexually transmitted disease and arises in the oral mucosa because of autoinoculation or more commonly by orogenital sexual transmission. The incubation period for a condyloma is 1 to 3 months from the time of sexual contact. It is associated more frequently with HPV types 6, 11, 16, and 18. It is also very common in HIV patients. Recently, Greenspan et al [33] demonstrated that in AIDS patients using the highly active antiretroviral therapy, there is a striking increase in oral warts. Lesions are frequently present in the labial mucosa, followed by lingual frenum, soft palate, and gingiva. They present as asymptomatic, pink, sessile, less frequently pedunculated, exophytic cauliflowerlike growths. They are multiple rather than single. They are usually larger than verruca vulgaris, ranging from 1 to 3 cm. Histopathology Warts are characterized by a proliferation of hyperkeratotic stratified squamous epithelium arranged into finger-like projections with connective tissue cores [34]. The converging or cupping arrangement of the peripheral rete ridges and a prominent granular cell layer demonstrate coarse, clumped keratohyaline granules. Numerous koilocytes that are virally transformed cells characterized by pyknotic nuclei and perinuclear vacuoles are present. Diagnostic tests Electron microscopy, immunoperoxidase staining, or in situ hybridization can detect HPV viral particles in the biopsy samples. Treatment Both oral and cutaneous lesions are treated by surgical excision, cryosurgery, electrosurgery, and laser. Recently, the use of podophyllin as a 20% solution of tincture of benzoin has been used with
some success. Because the agent is teratogenic and toxic to the kidneys, brain, and myocardium it has to be applied to the areas by the dentist or physician.
Leukoplakia Leukoplakia is a nonspecific clinical descriptive term for a white patch or plaque in the oral cavity that cannot be characterized clinically or pathologically as any other disease. Although leukoplakia may be a premalignant lesion, it does not imply that dysplasia is always present. Leukoplakia usually occurs after the age of 40 and the incidence increases with age, with the highest incidence in men. The main predisposing factors for the development of oral leukoplakia are smoking and alcohol consumption. Physical irritants, chronic trauma, and poor oral hygiene have also been implicated. Leukoplakia can appear in several clinical forms. Leukoplakia may range in size from a few millimeters to several centimeters; the surface can be smooth or verrucous and range from slightly elevated white, hyperkeratotic plaque to thick corrugated lesions. Long-term clinical studies suggest that 5% to 50% of the lesions turn malignant; this depends on the histologic grading, length of follow-up, and the presence of risk factors [35,36]. Histopathology The microscopic picture consists of a wide spectrum of findings ranging from hyperkeratosis to dysplasia, carcinoma in situ, and squamous cell carcinoma. Treatment The standard treatment is surgical resection or laser ablation.
Frictional keratosis Chronic irritation to the oral mucosa causes morphologic changes that appear as white areas called frictional keratoses. Trauma is the most common etiologic factor in the development of these lesions; examples are chronic cheek or lip biting, poor-fitting dentures, sharp teeth cusps, and broken dental restorations [37]. These white plaques vary in size, shape, and thickness depending on the degree and duration of trauma. The tongue is frequently affected followed by
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the labial mucosa, alveolar ridge, and buccal mucosa. Single or multiple areas may be involved. Histopathology The most common histopathologic features are hyperkeratosis and acanthosis. No dysplasia is observed. Treatment Elimination of the primary cause of trauma is the first line of treatment. If lesions do not resolve, then a biopsy is mandatory.
A recent review article by Munro et al [43] concludes that the available clinical and animal data do not support the hypothesis that the use of Viadent toothpaste products may be associated with development of leukoplakia of the maxillary vestibule. Histopathology All cases demonstrated hyperorthokeratosis mixed with hyperparakeratosis. The dysplastic changes were minimal but included increased cellularity and hyperchromatism of the basilar one third of the epidermis. Treatment
Viadent-associated leukoplakia Viadent refers to a toothpaste and oral rinse that contain extracts of the bloodroot plant Sanguinaria canadensis, which are known to have anti-inflammatory, antibacterial, and antifungal activity [38]. The active ingredient in this extract is the benzophenanthridine alkaloids. The toothpaste has been shown in several clinical trials [39 41] to be effective against plaque build-up and gingivitis. The role of Viadent in the development of oral leukoplakia is controversial. Damm et al [42] showed that in a review of 74 patients with leukoplakia of the maxillary vestibule, 84.1% of them used Viadent toothpaste. All 74 patients were whites. The ages ranged from 38 to 89 years with a higher predilection in women or proportion of patients who were women. The maxillary leukoplakia was located in the anterior vestibule, sometime extending to the alveolar mucosa (Fig. 11). Lesions varied in size and consistency from a smooth to a corrugated texture. Discontinuation of the Viadent toothpaste and close follow-up of the lesions followed by surgical removal of lesions is recommended.
Tylosis Tylosis is an autosomal-dominant disorder associated with defective keratinization of the palms and soles. In addition to palmoplantar keratoderma, a growing number of kindreds have been identified who have had both tylosis and esophageal carcinoma. In some of the families oral leukoplakia is a prominent feature. Pathophysiology The causative gene, the tylosis esophageal cancer gene, is located on chromosome 17q25. This tumorsuppressor gene is also found in sporadic cancers of the esophagus. Numerous studies suggest that the loss of envoplakin function could be responsible for the formation of palmoplantar keratoderma [44]. Histopathology Recognizable dysplasia is noted in older individuals. Dysplasia was characterized by abnormal maturation with prominent basophilic inclusions and clear cell acanthosis. Parakeratinization and orthokeratinization were also noted. Inflammation and individual cell keratinization are noted in young affected individuals. The individual cell keratinization was significantly more common in affected younger individuals and was found to be a morphologic marker of increased risk [45].
Fig. 11. Viadent-associated leukoplakia. Ill-defined white plaques on the maxillary vestibule not associated with any risk factors other than with the use of Viadent rinse.
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Treatment Early diagnosis and frequent clinical evaluations are necessary if late sequelae of esophageal cancer is to be avoided.
Nicotinic stomatitis Nicotinic stomatitis (smokers palate) is a benign process with no malignant potential. Nicotinic stomatitis is always confined to the hard palate and begins as erythema of the palate. Later the palate assumes a grayish white and nodular appearance (Fig. 12). A characteristic finding is the appearance of multiple red dots, which represent the dilated and inflamed duct openings of the minor salivary glands. The lesions are asymptomatic and discovered during an oral examination. Nicotinic stomatitis occurs almost exclusively in heavy pipe smokers and rarely in cigarette or cigar smokers [46]. It is also observed in reverse smokers (lit end placed in the mouth). This observation suggests that a thermal effect is the cause of the clinical changes. Histopathology Biopsy specimens from reverse smokers show significant dysplasia and epithelial atypia [37].
Fig. 13. Tobacco pouch keratosis (smokeless tobacco pouch). Tobacco pouch of the left mandibular vestibule extending to the buccal mucosa. The lesion is corrugated and wrinkled and is restricted to the area in contact with the snuff.
Treatment Although nicotinic stomatitis is a benign finding the risk for malignant transformation elsewhere in these patients should not be ignored. Resolution of the changes of nicotinic stomatitis is noted within several months after the cessation of smoking.
Tobacco pouch keratosis (smokeless tobacco pouch) Lesions induced by smokeless tobacco characteristically have a wrinkled surface that ranges from opaque white to translucent and develop on the mucosal surfaces that contact the tobacco products. These lesions are called tobacco pouch keratosis. The mucosal surface has a velvety texture often with a cobblestone appearance and is asymptomatic (Fig. 13). Longstanding lesions in heavy users may become thickened and verrucous [35]. Studies have shown that about 2% to 6% of oral leukoplakia undergoes malignant changes over a period of 5 to 10 years [47]. The use of smokeless tobacco has increased tremendously in the past 25 years, especially among white men aged 15 to 34 years [47]. It is believed that 5% of the population is currently engaged in chewing tobacco or dipping snuff. Many tobacco smokers may see smokeless tobacco as a healthier alternative to smoking cigarettes, but literature has documented the association between smokeless tobacco use and oral and pharyngeal cancer. The use of snuff is associated with lesions that cause an increase in epithelial dysplastic changes greater than those associated with chewing tobacco.
Fig. 12. Tobacco-associated keratoses (nicotinic stomatitis). The openings of the minor salivary gland ducts appear as bright red umbilicated papules associated with a rim of white hyperkeratosis. These changes are not premalignant, although they are indicative of extensive exposure to tobacco, tars, and heat. A complete oral examination is indicated to identify other sites more at risk for dysplasia. (Courtesy of R.S. Rogers III, MD, Rochester, MN.)
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oral cancers; sarcomas and salivary gland tumors account for the remainder. Histopathology Findings range from well-differentiated (lowgrade) lesions, in which the tumors resemble normal epithelium, to poorly differentiated or anaplastic (high-grade) lesions, where the tumor cells lose their resemblance to the epithelial tissues [35]. Despite improvements in therapeutic and reconstructive modalities, oral cancer represents an important cause of cancer morbidity and mortality. The 5-year survival rates for malignancies of the oral cavity and pharynx remain lower than 50%. The head and neck is the only anatomic region in which 5-year survival rates have not improved significantly in the last decade. It is estimated that over 10,000 deaths from oral cancer will occur in the United States this year, which is approximately 2.4% of all cancers. It is the sixth most common type of cancer in whites and the fourth in blacks. The major risk factors are smoking and alcohol consumption. A number of oncogenic viruses may be associated with the development of SCC [35], especially HPV 16. Tumorsuppressor gene p53 has also been implicated in the pathogenesis of SCC [48]. The treatment of choice depends on the stage of the disease and varies from aggressive surgical intervention, sometimes accompanied by postsurgical radiation therapy. Radical neck dissection is performed when evidence of lymph node involvement is given.
Fig. 14. Squamous cell carcinoma. Discrete plaque with rolled borders extending along the maxillary alveolar ridge onto the hard palate and buccal vestibule. The lesion has features of both erythroplakia and leukoplakia.
Histopathology The findings are nonspecific acanthosis, orthokeratosis, and marked parakeratosis. Dysplasia is uncommon. Treatment Lesions usually resolve within 6 weeks of cessation of tobacco use.
Squamous cell carcinoma It is beyond the scope of this article to write a detailed overview of oral squamous cell carcinoma (SCC). A brief description is provided. Oral SCC appears in different clinical forms: leukoplakia, erythroplakia, and nonhealing ulcer. Depending on the amount of keratosis, SCC may vary in color appearing pink, white, or red (Fig. 14). The most common sites for oral SCC are the posterior lateral and ventral surfaces of the tongue; the floor of the mouth is the second most common site. Other sites include the gingival, buccal mucosa, and palate. The incidence of oral cancer has dramatically increased in the past decade because of an increase in tobacco and alcohol use. Men are affected twice as often as women. There is a higher incidence after the age of 40 years with a peak at 60 years. In the beginning of the twenty-first century, 31,000 new cases of oral cancer will be recognized each year, mostly occurring in the lips, tongue, floor of the mouth, palate, gingiva, alveolar and buccal mucosa, and oropharynx [49]. SCC accounts for 96% of all
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D.V. Messadi et al. / Dermatol Clin 21 (2003) 6378 JL, Strachan T. Localization of a gene for Dariers disease. Hum Mol Genet 1993;2:1937 9. Buxton RS. Yet another skin defect, Dariers disease, maps to chromosome 12q. Hum Mol Genet 1993;2: 1763 4. Davidson HR, Connor JM. Dyskeratosis congenita. J Med Genet 1988;25:843 6. Kagoura M, Morohashi M. Dyskeratosis congenita: a light microscopic and ultrastructural study. Eur J Dermatol 1998;8:307 9. Tchou PK, Kohn T. Dyskeratosis congenita: an autosomal dominant disorder. J Am Acad Dermatol 1982; 6:1034 9. Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001;413:432 5. Eisen D, Lynch DP. Viral infections. In: Eisen D, Lynch DP, editors. The mouth: diagnosis and treatment. St. Louis: Mosby; 1998. p. 108 27. Flaitz CM. Focal epithelial hyperplasia: a multifocal oral human papillomavirus infection. Pediatr Dent 2000;22:153 4. Tan AK, Tewfik TL, Moroz B, et al. Focal epithelial hyperplasia. Otolaryngol Head Neck Surg 1995;112: 316 9. Archard HO, Heck JW, Stanley HR. Focal epithelial hyperplasia: an unusual mucosal lesion found in Indian children. Oral Surg 1965;20:201 12. Steinhoff M, Metze D, Stockfleth E, et al. Successful topical treatment of focal epithelial hyperplasia (Hecks disease) with interferon-a. Br J Dermatol 2001;144: 1067 9. Jorizzo JL, Salisbury PL, Rogers III RS, et al. Oral lesions in systemic lupus erythematosus: do ulcerative lesions represent a necrotizing vasculitis? J Am Acad Dermatol 1992;27:389 94. Burge SM, Frith PA, Juniper RP, Wojnarowska F. Mucosal involvement in systemic and chronic cutaneous lupus erythematosus. Br J Dermatol 1989;121:727 41. Ballo FS, Gamisa C, Allen C. Pyostomatitis vegetans. J Am Acad Dermatol 1989;21:381 7. Van Hale HM, Rogers III RS, Zone JJ, Greipp PR. Pyostomatitis vegetans. Arch Dermatol 1985;121: 94 8. Thornhill MH, Zakrzewska JM, Gilkes JJ. Pyostomatitis vegetans: report of three cases and review of the literature. J Oral Pathol Med 1992;21:128 33. Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1985;60:285 98. Batsakis JG, Suarez P, El-Naggar A. Proliferative verrucous leukoplakia and its related lesions. Oral Oncol 1999;35:354 9. Silverman S, Gorsky M. Proliferative verrucous leukoplakia: a follow- up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:154 7. Palefsky JM, Silverman S, Abdel Salaam M, et al. Association between proliferative verrucous leukopla-
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kia and infection with human papillomavirus type 16. J Oral Pathol Med 1995;24:193 7. Fettig A, Pogrel AM, Silverman S, et al. Proliferative verrucous leukoplakia of the gingival. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90: 723 30. Collangettes S, Chollet P, Fonck Y. Oral florid papillomatosis. Oral Oncol 1993;29B:81 2. Appleton SS. Candidiasis: pathogenesis, clinical characteristics, and treatment. Calif Dent Assoc J 2000;28: 942 8. Eisen D, Lynch DP. Fungal infections. In: Eisen D, Lynch DP, editors. The mouth: diagnosis and treatment. St. Louis: Mosby; 1998. p. 128 34. Kurzai O, Werner JH, et al. Rapid PCR test for discriminating between Candida albicans and Candida dubliniensis isolates using primers derived from the pH- regulated PHR1 and PHR2 genes of C. albicans. J Clin Microbiol 1999;37:1587 90. Staab JF, Bradway SD, et al. Adhesive and mammalian transglutaminase substrate properties of Candida albicans Hwp1. Science 1999;283:1535 7. Greenspan D, Canchola AJ, MacPhail LA, et al. Effect of highly active antiretroviral therapy on frequency of oral warts. Lancet 2001;357:1411 2. Neville BD, Damm DD, Allen CM, Bouquot JE. Oral and maxillofacial pathology. Philadelphia: WB Saunders; 1995. p. 542 3. Eisen D, Lynch DP. The mouth: diagnosis and treatment. St. Louis: Mosby; 1998. p. 58 91. Lee JJ, Hong WK, Hittleman WN, et al. Predicting cancer development in oral leukoplakia: ten years of translational research. Clin Cancer Res 2000;6:1702 10. Eisen D, Lynch DP. The mouth: diagnosis and treatment. St. Louis: Mosby; 1998. p. 20 36. Frankos VH, Brusik DJ, Johnson EM, et al. Safety of sanguinaria extract as used in commercial toothpaste and oral rinses products. J Can Dent Assoc 1990;56: 41 7. Harper DS, Mueller LJ, Fine JB, et al. Clinical efficacy of a dentifrice and oral rinse containing sanguinaria extract and zinc chloride during 6 months of use. J Periodontol 1990;61:352 8. Harper DS, Mueller LJ, Fine JB, et al. Effect of 6 months use of a dentifrice and oral rinse containing sanguinaria extract and zinc chloride upon microflora of the dental plaque and oral soft tissues. J Periodontol 1990b;61:359 63. Kuftinec MM, Mueller-Joseph LJ, Kopczyk RA. Sanguinaria toothpaste and oral rinse regimen clinical efficacy in short-and-long term trials. J Can Dent Assoc 1990;56:31 5. Damm DD, Curran A, White DK, et al. Leukoplakia of the maxillary vestibule: an association with Viadent? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:61 6. Munro IC, Delzell ES, et al. Viadent usage and oral leukoplakia: a spurious association. Regul Toxicol and Pharmacol 1999;30:182 96.
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D.V. Messadi et al. / Dermatol Clin 21 (2003) 6378 [48] Regezi J, Sciubba J. Ulcerative conditions. In: Regezi J, Sciubba J, editors. Oral pathology: clinical pathological correlations. 3rd edition. Philadelphia: WB Saunders; 1999. p. 69 81. [49] Neville BD, Damm DD, Allen CM, Bouquot JE. Epithelial pathology. In: Oral and maxillofacial pathology. Philadelphia: WB Saunders; 1995. p. 263 5. [50] Storwick SG, Prihoda BM, Fulton JR, Wood SW. Pyodermatitis pyostomatitis vegetans: a specific marker for inflammatory bowel disease. J Am Acad Dermatol 1994;31:336 41.
[44] Field EA, Ellis A, Friedmann PS, Leigh IM, Field JK. Oral tylosis: a re-appraisal. Oral Oncol 1997;33:55 7. [45] Ashworth MT, Nash JR, Ellis A, Day DW. Abnormalities of differentiation and maturation in the esophageal squamous epithelium of patients with tylosis: morphological features. Histopathology 1991;19:303 10. [46] Mirbod SM, Ahing SI. Tobacco associated lesions of the oral cavity. Part I. Nonmalignant lesions. J Can Dent Assoc 2000;66:252 6. [47] Martin GC, Brown JP, Eifler CW, et al. Oral leukoplakia status six weeks after cessation of smokeless tobacco use. J American Dental Association 1999;130: 945 54.
The clinical manifestations and treatment of oral lichen planus

Drore Eisen, MD, DDS
Dermatology Associates of Cincinnati, 7691 Five Mile Road, Cincinnati, OH 45230, USA
Lichen planus is a relatively common mucocutaneous disorder with a reported incidence equal to or greater than such diseases as psoriasis [1,2]. The exact incidence of the disease is unknown, and the determination of the number of patients affected with the disease is complicated by the fact that lichen planus has many clinical forms and may involve one or more sites. For example, lichen planus may affect the skin alone; the oral cavity alone; both the skin and oral cavity simultaneously; or one or more mucosal and nonmucosal sites, with or without skin or oral involvement.
Extraoral manifestations Whereas over a third of patients who present to a dermatologist with cutaneous lichen planus are noted to have oral lesions [3], only 15% of patients with predominantly oral lichen planus (OLP) develop cutaneous lesions [4]. In most instances, cutaneous lichen planus typically develops within several months after the appearance of the oral lesions. Furthermore, the severity of the oral manifestations usually does not correlate with the extent of cutaneous involvement. Lichen planus may also involve the scalp, nails, esophagus, eyes, and genital mucosa. Often, patients have multiple sites of involvement, with over 5% developing the disease in three or more sites simultaneously [4]. Lichen planopilaris was detected in only 6 of 584 OLP patients, with the development of scalp lesions
E-mail address: drore@eos.net
preceding the onset of oral lesions by 1 to 3 years in five of the six women [4]. Perifollicular erythema and follicular spines accompanied by patchy alopecia are the most common findings, and histologic and often direct immunofluorescent studies are required for confirmation. Lichen planus of the nails develops in approximately 10% of patients with cutaneous disease; however, the development of lichen planus of the nails is an infrequent finding in patients with OLP. The most common clinical manifestations include thinning, ridging, and distal splitting of the nail plate, changes that typically precede the development of oral lesions. The clinical features of esophageal lichen planus have been well documented, and the disease seems to develop most commonly in patients with OLP [5]. Most patients with esophageal lichen planus are diagnosed as a result of symptoms brought to the attention of the gastroenterologist, with dysphagia being the predominant complaint. When patients with OLP are screened for esophageal involvement, however, the disease is detected in nearly a third of patients with asymptomatic white reticular lesions being the predominant form [6]. In all probability, esophageal lichen planus, in its erosive form and especially in its asymptomatic form, is undiagnosed in many patients and remains an unrecognized and underreported condition. Although malignant transformation has not been reported, untreated esophageal lichen planus may result in chronic pain and strictures [7]. All patients with OLP should be questioned about dysphagia and evaluated by endoscopy if symptomatic. Fortunately, conjunctival involvement resulting in cicatrizing conjunctivitis is a rare manifestation of
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lichen planus [8]. The few reported cases have occurred in patients with OLP. Because the institution of prompt treatment has been shown to control inflammation and halt cicatrisation, evaluation of conjunctival erythema and detection of the disease in its early state is of paramount importance. Lichen planus may affect the genitalia in men and women. In fact, the most frequent extraoral site of involvement in female patients with OLP is the genital mucosa and the clinical findings are described elsewhere in this issue.
Fig. 2. Although reticular lesions are usually asymptomatic, extensive involvement on the tongue may result in burning and dysgeusia.
Clinical manifestations Oral lichen planus develops in women more than twice as often as in men, with a mean age of onset in the sixth decade of life. OLP is uncommon in children but when it develops in this age group, it is frequently erosive and painful. Children with OLP often have concomitant cutaneous disease [9,10], and those of Asian descent may be predisposed to the development of the disease [11]. Classification Oral lichen planus may manifest in one of three clinical forms: (1) reticular; (2) erythematous (atrophic); and (3) erosive (ulcerated or bullous). Whereas reticular lesions occur as isolated lesions and are often the only clinical manifestation of the disease, erythematous lesions are accompanied by reticular lesions and erosive lesions are accompanied by reticular and erythematous lesions in almost all cases. This feature helps clinically differentiate OLP from other vesiculoerosive diseases, such as pemphigus and pemphigoid, which are characterized by isolated areas of erythema or erosions.
Reticular lesions may be papular, plaque-like, and lacey and are the most recognized form of OLP (Figs. 1 and 2). Multiple patterns of reticular lesions in a patient are commonly noted and the degree of involvement is variable with some patients exhibiting subtle disease and others displaying diffuse and confluent lesions involving multiple sites. Reticular lesions are asymptomatic unless they develop on the dorsal and lateral borders of the tongue where they cause burning and occasional taste disturbances. Erythematous and erosive (Fig. 3) OLP lesions result in varying degrees of discomfort. In addition to pain, the single most frequent complaint, patients also describe burning, swelling, irritation, and bleeding with tooth brushing. Sites of involvement The posterior buccal mucosa is the most frequent site of involvement followed by the tongue, gingiva,
Fig. 1. Reticular lesions on the posterior buccal mucosa are characteristic of oral lichen planus (OLP).
Fig. 3. Erosive lesions of lichen planus on the dorsal tongue accompanied by reticular and erythematous lesions.
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Precipitating factors Koebners phenomenon characteristic of cutaneous lichen planus, whereby lesions develop in response to trauma, is also observed in the oral cavity. Mechanical trauma from dental procedures, heat and irritation from tobacco products, friction from sharp cusps, rough dental restorations and poorly fitting dental prostheses, and oral habits including lip and cheek chewing are exacerbating factors. Koebners phenomenon may explain why erosive lesions develop most commonly in areas subjected to trauma, such as the buccal mucosa and lateral surfaces of the tongue. When such factors are minimized or eliminated, oral lesions either revert to the less severe forms of the disease or sometimes resolve completely. Dental plaque and calculus can also result in worsening gingival lichen planus and are associated with a significantly higher incidence of erythematous and erosive gingival lesions [15]. Gingival OLP can ultimately result in gingival recession, advanced periodontal disease, and rarely in tooth loss. Periodontal surgical procedures, which are required to correct these defects, may themselves exacerbate OLP [16]. Patients with OLP exhibit higher levels of anxiety, greater depression, and increased vulnerability to psychic disorders [17,18]. Those with erosive lichen planus exhibit higher depression scores than patients with nonerosive lichen planus. An association with depression, however, may be anecdotal because others have largely refuted this [19]. Stress is identified as the most frequent cause of acute exacerbations of the disease and is widely held to be an important etiologic factor.
Fig. 4. White reticular OLP lesions on the gingiva resembling leukoplakia.
labial mucosa, and vermilion of the lower lip. Lesions on the palate, floor of the mouth, and upper lip are uncommonly noted. Although OLP has a characteristic distribution that is bilateral and symmetric, the disease may also present a confusing array of patterns and forms clinically mimicking other disorders. Approximately 10% of patients with OLP have the disease confined to the gingiva [12]. Gingival lichen planus presenting as small, raised white, lacy papules or plaques, may resemble keratotic diseases, such as leukoplakia (Fig. 4). Erythematous lesions affecting the gingiva result in desquamative gingivitis, the most common type of gingival lichen planus (Fig. 5). Erosive lesions resembling those observed in other vesiculoerosive diseases including pemphigoid, pemphigus, and linear IgA disease also produce desquamative gingivitis not easily identified as lichen planus unless there are coexistent reticular lesions on the gingiva or elsewhere in the oral cavity. Lichen planus isolated to a single oral site other than the gingiva is an infrequent occurrence. Patients with isolated lip lesions [13] and tongue lesions [14] have been described although many patients who present with isolated lesions eventually develop more widespread disease. The profile of patients with OLP is as follows: Mean age, fifth to sixth decades of life Female to male ratio 2:1 Intraoral involvement: posterior buccal mucosa > tongue > gingiva Two third symptomatic, one third asymptomatic Increased levels of anxiety and depression 20% of women display genital involvement Cutaneous involvement in 15% of patients with OLP Increased risk for malignant transformation
Fig. 5. OLP presenting as a desquamative gingivitis. In addition to histology, immunofluorescence of perilesional mucosa is an effective technique that can exclude other causes.
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Diagnosis Histologic features The characteristic clinical features may be sufficient to diagnosis OLP correctly, especially if there are easily recognizable skin lesions. Because OLP is a chronic disorder often requiring long-term treatment and surveillance, biopsy is mandatory when the disease does not present with classic features. This is despite the fact that histopathologic assessment of OLP is a rather subjective and insufficiently reproducible process [20]. In addition to the superficial band-like infiltrate of lymphocytes and basal cell liquefaction degeneration, the histopathologic features diagnostic of lichen planus include focal hyperparakeratosis, irregular acanthosis, and an eosinophilic amorphous band at the basement membrane (Fig. 6) [2]. Gingival lichen planus may be more difficult to diagnose because the clinical appearance of lichen planus shares many clinical features with the vesiculoerosive diseases. Direct immunofluorescence of perilesional mucosa is an effective and accurate diagnostic technique, especially useful in excluding other causes [21]. Immunofluorescence reveals fibrin and shaggy fibrinogen in a linear pattern at the basement membrane zone (Fig. 7). Cytoids in the absence of deposition of fibrinogen are commonly detected in immunofluorescence biopsy specimens [22]. The value of direct immunofluorescence for confirmation of the disease is well
Fig. 7. Direct immunofluorescence of OLP reveals fibrin and shaggy fibrinogen in a linear pattern at the basement membrane zone. (Courtesy of Dr. James J. Sciubba, Baltimore, MD.)
accepted, especially with nondiagnostic histopathologic features and for the desquamative gingivitis form of lichen planus.
Oral lichenoid eruptions Although uncommon, OLP may be caused by a hypersensitivity reaction to dental restorations. An allergy or reaction to a dental filling material should be suspected when OLP lesions are confined to areas of the oral mucosa in close contact with or proximity to the filling. Amalgam restorations, especially those that are old and cracked, have been implicated most frequently, although reactions to composite and cop-
Fig. 6. Biopsy of OLP revealing superficial band-like infiltrate of lymphocytes, basal cell liquefaction degeneration, focal hyperparakeratosis, irregular acanthosis, and an eosinophilic amorphous band at the basement membrane. Hematoxylin and eosin 100X (H and E). (Courtesy of Dr. James J. Sciubba, Baltimore, MD.)
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per dental materials can also develop [23,24]. Oral lesions resulting from hypersensitivity reactions to dental materials clinically and histologically resemble lichen planus closely, but have an identifiable etiology. A positive patch test reaction to more than one mercurial allergen may increase the likelihood of the correct diagnosis and may justify the removal and replacement of all amalgam fillings with those made of other materials [25]. When identified, some lichenoid lesions can show considerable improvement or complete regression after replacement with another filling material [26]. Equally uncommon are drug-induced oral lichenoid reactions. The most commonly implicated drugs are the nonsteroidal anti-inflammatory agents and the angiotensin-converting enzyme inhibitors [27,28]. Although numerous other drugs have been linked with oral lichenoid reactions, the reports have been based on a single case or poor documentation. Because the most reliable method to diagnose lichenoid reactions is impractical, namely to monitor if the reaction remits with drug withdrawal and returns on rechallenge, drug-induced oral lichenoid reactions will remain either undiagnosed or overdiagnosed.
The association of OLP with both HCV infection and liver disease, however, may be dependent on geographic factors. Research studies on OLP patients in the United States, Britain, France, Scandinavia, and Germany failed to confirm an association between lichen planus and liver abnormalities [39]. In a US study consisting of 195 patients with OLP, none had had detectable antibodies to HCV or abnormal liver function tests [40]. OLP may be an early marker or manifestation of hepatitis in select populations; however, routine serologic screening in Western European and American OLP patients may not be warranted. The incidence of other systemic diseases in OLP patients including hypertension, arthritis, and diabetes is not higher than expected when compared with the incidence reported in the general population.
Malignant potential The development of squamous cell carcinoma is a feared complication of OLP with a reported frequency of 0.4% to over 5% over periods of observation from 0.5 to over 20 years [41]. Most carcinomas at presentation are reported in areas of atrophic or erosive OLP. Well-known risk factors for oral cancer, including tobacco consumption and heavy alcohol use, do not seem to be greater in OLP patients compared with the general population. Careful monitoring of patients with OLP has been demonstrated to result in the detection of carcinomas in the early stages (in situ and microinvasive) with favorable prognoses [42]. There is considerable controversy regarding the malignant transformation of OLP. Although more than 25 follow-up studies have focused on this topic, as recently reviewed by Barnard et al [43], several investigators have questioned the criteria used for diagnosing OLP in published reports [44,45]. For example, whereas some studies included patients diagnosed with OLP based on clinical and histologic criteria, others included patients that were based solely on clinical features [46]. Consequently, many published cases of OLP associated with malignant transformation diagnosed clinically as OLP may actually have been lichenoid dysplasia, a premalignant condition with lichenoid features. Patients with lichenoid dysplasia often display erythematous and erosive lesions clinically identical to OLP lesions [47]. The lack of reliable, well-defined, objective clinical criteria of epithelial dysplasia emphasizes the need to confirm by biopsy the diagnosis of patients with suspected OLP. Exceptions include
Systemic associations After the first report by Rebora [29] linking erosive OLP with severe liver disease, a number of studies have been published suggesting this possible relationship. For example, diseases affecting the liver including Wilsons disease, hemochromatosis, a1antitrypsin deficiency, and primary biliary cirrhosis have uncommonly been related to lichen planus [3,30]. In recent years, the attention has focused on the relationship between OLP and hepatitis. Several controlled studies have demonstrated a strong association between chronic hepatic disease or hepatitis C virus (HCV) infection and OLP [31 33]. A small but significant percentage of US patients with cutaneous lichen planus have also been shown to be HCV antibody positive [34]. Reported prevalence rates of HCV infection in OLP patients range from 20% in Spain to a high of 62% in Japan. In support of these studies, investigators have found HCV viral sequences in the serum of patients with OLP and in oral tissue samples [35,36]. Furthermore, OLP patients with HCV infection neither have evidence of autoimmune liver damage nor abnormal humoral immune responses [37]. Elevated liver function tests have also been detected most often in patients with oral erosive disease and seem to correlate with the severity of OLP [38].
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patients with classic bilateral, white reticulated lesions on the buccal mucosa and those with concomitant, easily recognizable skin lesions. Given the uncertainty of the premalignant nature of OLP and the fact that early detection of oral cancer results in improved survival, it is prudent to monitor patients with OLP carefully and long term.
Treatment Because no therapy for OLP is curative, the primary goal for symptomatic patients is palliation. It is tempting to speculate that aggressive treatment of patients with erosive and atrophic OLP lowers or eliminates the risk of malignant transformation; however, this hypothesis has never been substantiated or investigated. Historically, most OLP patients in large published studies have been treated with topical agents alone, which do not seem to alter the chronic and often lifelong course of this disease. Patients with OLP who display only white, reticular lesions usually do not require treatment. This form of the disease is asymptomatic and discovered incidentally during a routine dental visit. An exception may be the burning and taste alteration that can result from reticulated lesions on the dorsal and lateral tongue, which resolve when the lesions are treated. Patients with erosive and erythematous OLP often present significant management problems. The need to reduce the morbidity associated with these forms of the disease has triggered a continuing search for novel therapies, many of which have been reported. An approach to the diagnosis and treatment of OLP is suggested in Fig. 8.
experimental design of the trials and the criteria of response to therapy and differences in clinical severity of the treated lesions. Therapy with topical corticosteroids should be initiated with a potent preparation to achieve a rapid clinical response. Because potent corticosteroids may delay wound healing, it is advisable to lower the strength of the preparation as soon as erosions heal and erythematous lesions become asymptomatic. Once the disease is controlled as defined by the absence of lesions or the presence of only white reticular lesions, therapy temporarily may be discontinued. Patients should be cautioned about the off-label use of topical corticosteroids and the accompanying package inserts, which state for external use only. Although a number of studies have demonstrated the safety of topical corticosteroids when applied to mucous membranes for short intervals [52,53], the potential for adrenal suppression with prolonged use, especially for a disease that is chronic, necessitates careful and frequent follow-up examinations. Atrophy in the oral mucosa is rarely observed. As many as a third of OLP patients treated with topical corticosteroids, however, develop secondary candidiasis [54]. Because there is an increased prevalence of candidal carriage and infection among patients with OLP [55,56], antifungal therapy administered either topically or systemically is often helpful as an adjunctive therapy. For intractable erosive OLP lesions, intralesional triamcinolone acetonide (10 to 20 mg/mL) injections can be highly effective. As with alopecia areata, treatments are repeated every 4 weeks until results are achieved. The administration of corticosteroids intralesionally is especially beneficial for lesions on the lateral border of the tongue and buccal mucosa. Cyclosporine
Topical treatment Corticosteroids Topical corticosteroids remain the mainstay of treatment of OLP. A response to treatment with midpotency corticosteroids, such as triamcinolone, potent fluorinated corticosteroids, such as fluocinonide, and superpotent halogenated corticosteroids, such as clobetasol, has been reported in 30% to 75% of treated patients [48 51]. Higher-potency preparations seem to be more effective than lowerpotency preparations, although there have been few studies that have compared various strength corticosteroid preparations for OLP. The great variation in efficacy of topical corticosteroids is a reflection of the heterogeneity of published reports regarding both the The topical use of cyclosporine may be used as an adjunct to topical corticosteroids [57]. The standard solution (100 mg/mL) intended for systemic use in organ transplant recipients may be used as a mouthwash for patients with OLP. Topical cyclosporine is prohibitively expensive for routine use and should be reserved for patients who are symptomatic and who fail topical corticosteroids. Patients can either swish a small amount of undiluted solution for approximately 5 to 10 minutes and then expectorate it, or hold a cotton ball saturated with solution against their lesion. Topical corticosteroids may be used immediately after using topical cyclosporine, and although controlled
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Fig. 8. Evaluation and treatment of OLP.
studies are lacking, the combination of the two agents seems to be more beneficial than the use of either agent alone. Not all investigators have found benefit from using topical cyclosporine in OLP [58,59]. As with other treatments reported to be beneficial in OLP, reports consist of small and uncontrolled trials using various doses and methods of application making comparisons difficult. For example, cyclosporine mouthwash, in doses of 500 mg three times daily for 8 weeks, resulted in improvement in all patients with atrophic and erosive OLP [60]. In a subsequent study of 13 patients with OLP, however, randomly assigned to treatment with cyclosporine (500 mg as a swish-and-spit medication for 5 minutes three times daily) or a triamci-
nolone acetonide oral paste over 6 weeks, only slight, transient clinical improvement was noted in both groups [59]. A significant reduction of pain and increased rate of healing compared with placebo was demonstrated in a controlled study of 14 patients with erosive OLP who were treated with low doses of topical cyclosporine (500 mg/d) [61], and lower cost of drug. Beneficial effects have also been claimed by using cyclosporine in bioadhesive pastes. Systemic absorption is low with topical cyclosporine and the efficacy of the drug does not correlate with cyclosporine blood levels [62]. In patients who respond to cyclosporine, results are typically observed after 4 to 8 weeks of treatment.
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Tacrolimus Tacrolimus, a new topical immunosuppressive agent approved for the treatment of atopic dermatitis, is 10 to 100 times as potent as cyclosporine. Several publications have already documented the efficacy of this agent in erosive OLP [63], although all used a specifically formulated oral cavity preparation and not the commercial preparation intended for skin. Additionally, all studies were purely anecdotal and open labeled. When commercial tacrolimus is used, a significant number of patients often complain of burning at the site of application and a smaller number note worsening of the condition. Additional studies are warranted to confirm the efficacy of tacrolimus in OLP.
Systemic treatment Corticosteroids Systemic corticosteroids are widely used in OLP and seem to be the most effective short-term treatment modality to control the disease. There have been no controlled studies, however, to evaluate their true efficacy. Furthermore, the prolonged administration of systemic corticosteroids for a chronic and often lifelong disease is unjustified because of their inherent toxicity [64]. Systemic corticosteroids should be reserved for acute exacerbations or for recalcitrant, severe erosive or erythematous lesions where topical approaches have failed. The disease often relapses when corticosteroids are discontinued and the requirement frequently to reinstitute therapy indicates the need for a corticosteroid-sparing agent. When using prednisone, a starting dose of 30 to 80 mg may be administered once daily, tapering the dose over a 2- to 3-week period. Secondary oral candidiasis may complicate therapy, especially when topical corticosteroids are used concomitantly. Immunosuppressive therapies Systemic immunosuppressive agents have been used for the treatment of OLP patients with severe disease, unresponsive to topical agents. Although none produces long-term remission when discontinued, significant clinical benefits are achieved and maintained with long-term use. All immunosuppressive agents require administration by health care providers familiar with their adverse reactions. Monitoring for laboratory abnormalities is essential and even so, the drugs can cause undesirable adverse
effects. Topical therapy administered concomitantly is desirable and this strategy often results in a reduction of the dose of the immunosuppressive agent that is needed to achieve clinical improvement. The aromatic retinoids have been studied in patients with erosive OLP. Documented improvement in several studies was noted in most patients undergoing treatment with etretinate, in doses ranging from 0.6 to 1 mg/kg/d [65,66]. As expected, adverse reactions, including cheilitis and dry skin, were commonly observed necessitating discontinuation of treatment in a significant number of patients. By reducing the maintenance dose to 0.3 mg/kg/d, adverse reactions were minimized but the clinical benefits were not nearly as good as those achieved with higher doses [67]. Laurberg et al [68] has replaced etretinate with acitretin, and at daily doses of 30 mg, resulted in remission or marked improvement in 64% of patients compared with 13% receiving placebo. As with etretinate, complications are frequently observed [69]. Although most dermatologists are far more familiar with the retinoid isotretinoin, its use in OLP only produces modest benefits and it is difficult to justify its use [70]. In summary, the use of systemic retinoids results in significant improvement; however, given their adverse effects and the wide range of alternatives, their use should be reserved for patients who fail other therapies. Hydroxychloroquine at daily doses of 200 to 400 mg can be administered long term to patients with erosive disease with few adverse effects [71]. Treatment is not always effective and improvement often takes 4 to 6 months. In another anecdotal study of 30 patients with cutaneous lichen planus, four of whom had oral lesions, two with OLP had complete healing of their lesions with phenytoin [72]. Thalidomide has also been anecdotally reported to benefit patients with erosive lichen planus unresponsive to conventional therapies [73,74]. Additional studies are warranted to confirm the efficacy of these agents and furthermore, hydroxychloroquine, phenytoin, and thalidomide have all been reported to induce oral lichenoid reactions. Azathioprine has been reported to be an effective corticosteroid-sparing treatment for cutaneous lichen planus [75,76], and its use for OLP is advocated in the dental literature as a treatment for brief 2-week periods [77]. Azathioprine does seem to be an alternative beneficial therapy for OLP, especially when there are risk factors against corticosteroid use. An initial dose of 50 mg/d may be instituted and the dose advanced to 100 to 150 mg/d if the baseline laboratory parameters remain unchanged. The response to
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treatment is slow, and as many as 3 to 6 months may be needed to observe the maximum benefits. As with other diseases treated with azathioprine, no improvement should be expected after 2 weeks of therapy. Mycophenolate mofetil used after organ transplantation seems to be a promising new immunosuppressive drug used off-label for a variety of dermatologic diseases [78]. The authors own experience indicates that at doses of 2 to 3 g/d, it is both well tolerated and effective in OLP patients unresponsive to topical agents or other immunosuppressive drugs. As with azathioprine, mycophenolate results in improvement that is achieved over a course of many months. Treatment is expensive and at doses used to control the disease averages $600 to $800 per month. Gastrointestinal adverse reactions sometimes require discontinuing the drug. The systemic administration of cyclosporine in doses much less than those used to treat psoriasis (1 to 2 mg/kg/d versus 4 to 6 mg/kg/d) has been reported to be beneficial for the treatment of both cutaneous and oral lichen planus [79,80]. Systemic use of cyclosporine, however, should be reserved for severe and refractory cases because of the many potential adverse effects of this drug. Fortunately, clinical results are noted rapidly with cyclosporine, even at low doses. Once the disease is controlled, the drug should be replaced with an agent that is safer to administer long term.
Summary The progress in research on OLP and other autoimmune diseases has been significant. Coupled with a growing recognition of the clinical features and treatment options by dentists and physicians and fueled by the advances in immunosuppressive therapies, research will undoubtedly provide new insights into this complex disorder. It is likely that what is learned will enhance the understanding not only of OLP but also of many other mucocutaneous diseases.
References
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Erosive oral lichen planus with genital lesions The vulvovaginal-gingival syndrome and the peno-gingival syndrome
Roy S. Rogers III, MDa,*, Drore Eisen, MD, DDSb
a
Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 0001, USA b Dermatology Associates of Cincinnati, 7691 Five Mile Road, Cincinnati, OH 45230, USA
Lichen planus (LP) is an inflammatory mucocutaneous disorder that may involve mucosal surfaces, such as the oral, genital, and other mucosae, and the skin including the scalp and the nails. The exact incidence of LP is unknown, but it is equal to or greater than common skin diseases, such as psoriasis and alopecia areata [1 4]. The clinical manifestations of LP are protean and may be encountered as isolated or seemingly isolated involvement of an anatomic site. The disease is typically managed by dentists and dental specialists; dermatologists; stomatologists; gynecologists; gastroenterologists; and, rarely, otorhinolaryngologists or ophthalmologists. The clinical range of the manifestations of LP is broad, but the oral cavity and the skin are the major sites of involvement. Oral lesions are present as the sole manifestation in 15% to 30% of all patients with LP, whereas two thirds of patients with cutaneous LP have oral lesions. Andreason [5] classified the clinical presentation of oral lichen planus (OLP) into six variants: (1) reticular, (2) papular, (3) plaque, (4) atrophic, (5) erosive, and (6) bullous. A simpler classification with three clinical forms has been described: (1) reticular including raised hyperkeratotic lesions, such as papules and plaques; (2) erythematous including atrophic lesions; and (3) erosive including ulcerated and bullous
* Corresponding author. E-mail address: rogers.roy@mayo.edu (R.S. Rogers).
lesions. The oral and extraoral lesions of LP are discussed in detail elsewhere in this issue. Cutaneous lesions of LP are typically papulosquamous, characterized by pruritic, purple, polygonal papules often covered by a white hyperkeratotic reticular scale known as Wickhams striae. There are many cutaneous variants of LP including actinic; annular; hypertrophic; linear; ulcerative; LP lupus erythematosus overlap syndrome; and lichen planus pemphigoides, an overlap of pemphigoid and LP [2,6]. Lichen planopilaris represents LP involvement of the scalp and hair follicles causing a scarring alopecia. LP may also involve the nails producing thinning and ridging of the nail plate and splitting of the distal free edge of the nail. Healing with a scar produces a pterygium, an uncommon but characteristic LP nail manifestation. Other mucosal surfaces may be involved by LP. Unusual sites include ocular [7], esophageal [8], bladder, nasal, laryngeal, otic, gastric, and anal involvement [2,4,9,10]. Genital lesions of LP in women are well recognized and are identified as an important component of the practice of vulvar medicine. Micheletti et al [11] reported vulvar LP in 125 patients among 3350 women (3.7%) who had a vulvar biopsy during the period 1986 to 1999 at the Vulvar Clinic at the University of Turin. Vulvar LP has been recently reviewed by Lewis [12]. Genital lesions of LP are reported to be common among men with cutaneous LP [2]. A unique type of genital and oral mucosal LP was described by Pelisse et al [13] in 1982. The triad of
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Table 1 Characteristics of 122 patients with the vulvovaginal-gingival syndrome of erosive oral lichen planus Characteristic Number of patients Age range Median age Postmenopausal Oral before genital Oral = genital Genital before oral Cutaneous lesions Scalp involvement Desquamative gingivitis Nail involvement Pelisse [15] 19 27 70 44 N/A 5 7 7 3 1 1 N/A Bermejo [16] 3 44 65 57 N/A N/A N/A N/A 0 0 2 0 Eisen [17] 60 29 74 50 31 15 30 15 7 N/A 15 N/A Rogers [18] 40 18 78 51 26 20 15 5 12 7 13 6 Total 122 18 78 50 57/100 57% 40/119 33.6% 52/119 43.7% 27/119 22.7% 22/119 18.5% 8/62 12.9% 31/122 25.4% 6/43 14%
erosive or desquamative vulvitis, vaginitis, and gingivitis (the vulvovaginal-gingival [VVG] syndrome) was detailed in a series of publications in the 1980s [13 15]. Pelisse [15] reported 19 patients in 1989, Bermejo et al [16] reported 3 patients in 1990, and Eisen [17] reported 22 patients in 1994. Rogers [18] reported 25 more patients at the 1997 World Congress of Dermatology. Erosive LP lesions in men involving the oral and genital mucosa were reported in 1993 by Cribier et al [19] as the peno-gingival (PG) syndrome. An additional eight men with the PG variant of OLP were recently described, four with the erosive form of the disease [9]. Eisen [3] points out that Wilson [20], in the first reported series of patients with cutaneous LP, described 3 of 50 patients with oral involvement. Lewis [12] notes that one of Wilsons original 50 patients with cutaneous LP also suffered from pruritus vaginae. Although LP affecting the male genitalia was recognized early as a common disorder, vulvar LP was considered to be rare until the end of the last century. The recognition of erosive vulvovaginal disease as a form of LP evolved in the latter part of the twentieth century. Vaginal disease with atrophic vaginal mucosa was reported as desquamative inflammatory vaginitis by Gardner [21] in 1968. Lynch [22] reported a patient with desquamative inflammatory vaginitis and erosive OLP in 1975. Edwards [23,24] reported erosive vulvar LP and desquamative vaginitis in association with erosive OLP in 1989 and commented on the similarities to the patients reported by Pelisse et al [13] in 1982. In this article the authors describe patients with the unique chronic orogenital variant of erosive OLP in both men and women. Although treatment of genital LP is quite challenging [12,15,17,23 25], therapeutic benefit in this painful, protracted condition can be obtained.
VVG syndrome of erosive OLP Patient profiles of the VVG syndrome of erosive OLP The distinctive subset of female patients with erosive OLP who also have erosive genital disease is called the VVG syndrome of erosive OLP. Pelisse [15] described 19 patients in 1989, Bermejo et al [16] described 3 patients in 1990, Eisen [17] described 22 patients in 1995, and Rogers [18] described 25 patients in 1997. An additional 38 patients from Eisen and 15 patients from Rogers are added to this group to yield a total of 122 patients (Table 1). These patients are probably underreported or not recognized. Eisen [9] has carefully studied 584 patients with OLP, each of whom had histologic confirmation of the diagnosis. All patients were monitored for periods from 6 months to 10 years with a mean of 4 years. Extraoral LP was found in many of these patients (Table 2). It is clear that many patients with the VVG syndrome of erosive OLP are not questioned about genital lesions by their dentist [9]. Edwards [23 25], Lewis et al [12,26], and Eisen [9] have emphasized that gynecologists are often not familiar with vulvar LP. The authors experience
Table 2 Extraoral manifestations of oral lichen planus Number Number of patients Cutaneous Scalp Nails Vulvovaginal Male genitalia Esophagus Ocular Multiple sites simultaneously 584 93 6 11 77/399 8/174 4 1 33 Percent 100 16 1 2 19 5 <1 <1 6
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shows that the full extent of many patients disease is unrecognized until a careful history and physical examination are performed. Oral lesions of the VVG syndrome of erosive OLP All patients have oral LP. The characteristic lesion is gingival LP. The labial-buccal aspect of the maxillary gingivae is almost invariably involved. Clinically, the gingivae are erythematous and swollen (Fig. 1) Overlying the color changes is a white reticulated pattern similar to the patches of reticulation seen in typical buccal OLP. Occasionally, the epithelium peels away (desquamates) leaving an eroded base; 25% of patients present with desquamative gingivitis. Gingival LP is painful and most patients complain of pain, burning, or discomfort. Involvement of the buccal, labial, and tongue mucosae is seen in many of the patients (Fig. 2). These lesions are symptomatic when erosive. Some reticular lesions are relatively asymptomatic. Scarring was not seen in OLP associated with erosive genital lesions in these four large series. Oral lesions preceded the development of genital lesions in 33.6% of the combined series and occurred simultaneously with the genital lesions in 43.7% (see Table 1). Vulvovaginal manifestations of the VVG syndrome of erosive OLP Most patients have an erosive vulvitis with the remaining women displaying asymptomatic or erythematous lesions. The characteristic lesion is a tender, painful, erythematous atrophic or eroded introitus of the vulvovaginal area (Fig. 3) The erythema is de-
Fig. 2. Oral lichen planus. Note involvement of buccal mucosa with an erosion surrounded by hyperkeratosis and the typical reticulated pattern anterior and inferior to the erosion.
scribed by Pelisse et al [13,15] as erythroplakic and by Eisen [9,17] as varying degrees of erythema and erosions often accompanied by white reticulated lesions. These reticulated areas are very helpful in establishing a clinical diagnosis of LP.
Fig. 1. Oral lichen planus. Gingival involvement is typical of the vulvovaginal-gingival variant of erosive oral lichen planus. Note the erythema, edema, and desquamation of the maxillary attached gingivae. The white reticulated pattern is seen above the left central and lateral incisor teeth.
Fig. 3. Vulvar lichen planus. Vulvar involvement is typical of the vulvovaginal-gingival variant of erosive oral lichen planus. Note the erythema, edema, and desquamation of the introitus.
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involvement occurred in 14% of 62 patients with the VVG syndrome compared with 2% of patients with OLP (see Table 2). Even more striking is the involvement of the unusual sites, such as esophagus, conjunctiva, and ear canals, although the number of patients with the VVG syndrome who are affected with extraorogenital disease is unknown. Scarring of the scalp, nail beds, ear canals, conjunctivae, esophagus, and the vulvovaginal tissues represent a major source of morbidity and disability. The oral manifestations of the VVG syndrome do not scar.
Fig. 4. Oral lichen planus. Note the hyperkeratotic plaques of the buccal mucosa with the reticulated pattern adjacent to the plaques.
Diagnosis of the VVG syndrome of erosive OLP The VVG syndrome of erosive OLP is a dramatic clinical presentation when all three elements are present and recognized. The presence of the white reticulated pattern at the edge of the erythematous or hyperkeratotic patches (Figs. 3 and 4) or overlying the patches (Fig. 5) is quite helpful. Hyperkeratotic or hypertrophic lesions of the vulva may be mistaken for lichen sclerosus et atrophicus (LSA). Histologically, a lymphocyte infiltrate high in the dermis can obfuscate the hyalinization typically seen in LSA. Clinical features may overlap also. The VVG syndrome of erosive OLP, however, does not typically involve the perineum or perianal tissues, whereas these sites are typically involved in LSA. Oral lesions of LSA have been reported. Marren et al [27] reported seven patients with a mucosal lichen sclerosus LP overlap syndrome with both oral and genital lesions. Small erosions can develop in LSA but they are not as extensive as seen in the VVG syndrome or erosive OLP. Finally, architectural loss and fusion may be an end-stage phenomenon in both conditions but LSA does not affect the vagina [12,26].
More severe involvement is characterized by a diffuse vulvitis. Pelisse [15] states that all patients with an erosive vulvitis develop, at some time, an erosive vaginitis. The erosive vaginitis is similar to the desquamative inflammatory vaginitis described by Gardner [21]. The vulvovaginal lesions are often exquisitely painful. Most patients experience dyspareunia or cannot tolerate coitus at all. Postcoital bleeding is typical. Some patients develop synechiae of the vagina leading to a stenotic, fibrosed vaginal vault. The involvement may be so severe as to preclude obtaining cervical cells for a Papanicolaou smear. Patients may undergo one or more surgical reconstructive procedures for the scarring sequelae before the complete nature of the disease is recognized. Almost invariably, the scarring recurs in the postoperative period, probably reflecting a Koebner phenomenon. Other involvement of the VVG syndrome of erosive OLP Cutaneous involvement occurred in 18.5% of the 122 patients (see Table 1). The temporal association of the cutaneous LP was quite variable. Some patients gave a history of cutaneous LP in the distant past, whereas others had active cutaneous manifestations simultaneously with their VVG disease. This is similar to the 16% reported by Eisen [9] in his series of 584 patients with histologically confirmed OLP (see Table 2). Scalp involvement in the form of lichen planopilaris was present in 12.9% of 62 patients with the VVG syndrome. This is considerably higher than the 1% reported by Eisen [9] in his series of 584 patients with OLP. Similarly, nail involvement was much more common in patients with the VVG syndrome. Nail
Fig. 5. Oral lichen planus. Note the reticulated hyperkeratotic pattern overlying an erythematous plaque of the sulcular gingival mucosa.
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Erosive oral or vulvovaginal lesions may be seen in immunobullous diseases, such as mucous membrane pemphigoid, pemphigus, paraneoplastic pemphigus, and linear IgA bullous disease. The white reticulated pattern is usually absent in these conditions. It may be necessary to obtain a biopsy of the oral or genital lesions to exclude the immunobullous diseases and to establish the diagnosis of the VVG syndrome. Study by routine histopathology and direct immunofluorescence (IF) testing permits a definitive diagnosis in most circumstances [28]. Serum studies by indirect IF testing may be helpful to exclude mucous membrane pemphigoid, pemphigus, paraneoplastic pemphigus, or linear IgA bullous disease [28]. Pelisse [15] obtained 30 mucosal biopsy specimens of 19 patients. All five from the gingivae revealed LP. Of 20 vulvar biopsy specimens, 13 showed unequivocal LP and 7 were nonspecific. The vaginal biopsy specimens revealed LP in two of four specimens. Direct IF testing revealed no significant deposits in six patients. Eisen [9,17] obtained 60 oral biopsy specimens with 17 from the gingivae. All but four showed unequivocal changes of OLP. Vulvar biopsy specimens were performed in 18 patients with 16 showing characteristic changes of LP. Twelve oral specimens studied by direct IF methods showed cytoid bodies and fibrinogen in a shaggy deposition, a pattern typical of LP [28]. Rogers [18] studied oral biopsy specimens in 22 of 25 Mayo patients previously reported. Changes typical for OLP were identified in 18 of 22 patients. Genital biopsies were positive in 12 of 13 patients. Direct IF testing was positive for a lichenoid tissue reaction in 14 of 15 oral biopsy specimens and 5 of 5 genital biopsy specimens. Natural history of the VVG syndrome of erosive OLP The initial presentation of the VVG syndrome of erosive OLP occurs in middle-aged women. The age range was 18 to 78 years of age, and the median age was 50 years (see Table 1). Oral lesions preceded genital lesions in 33.6% or occurred simultaneously with genital lesions in another 43.7%. Genital lesions were first in 22.7%. The constellation of signs and symptoms usually came together within a few years. Rarely a decade would pass between components of the VVG syndrome. The prognosis for spontaneous remission of the VVG syndrome of erosive OLP is poor. Most patients continue to suffer from the disease for years. The development of squamous cell carcinoma in LP is an accepted but rare complication of LP [29]. Two of the
122 patients with the VVG variant of erosive OLP have developed oral squamous cell carcinoma to date, and fortunately both were detected in early and curable stages [3]. Treatment of the VVG syndrome of erosive OLP Treatment of this distressing and chronic condition is challenging. Pelisse [15] reported benefit from topical corticosteroids in only 5 of 19 patients but no benefit for the vulvovaginal adhesions and scarring. Systemic administration of corticosteroids was effective but patients relapsed when the corticosteroids were discontinued. Retinoids were administered systemically to three patients with one showing transient improvement. Dapsone was a failure in two patients and griseofulvin failed in one patient. Eisen [9,17] treated all his patients with topical corticosteroids (either fluocinonide 0.05% or halcinonide 0.1%). About 50% of patients improved with 12 weeks of therapy. Some patients developed oral or genital candidiasis as a side effect of therapy. Other effective topical therapy included topical tretinoin and corticosteroids for oral lesions. Nine of 14 patients with OLP responded. Topical cyclosporine and corticosteroids were effective in oral lesions of 10 of 15 patients and genital lesions of 7 of 12 patients. Systemic therapy with etretinate (50 mg) or acitretin (25 mg) daily plus topical corticosteroids benefited 12 of 19 oral LP and 6 of 12 genital LP manifestations. Failures occurred with dapsone (0 of 4); griseofulvin (0 of 4); and doxycycline (0 of 3). Systemic cyclosporine was effective in seven patients, and recently mycophenolate mofetil was found to be beneficial in seven of nine patients. Eisen [3,9,17] comments that no therapy or combination of therapies results in a long-term remission. The disease relapses when treatment is discontinued reflecting an ongoing inflammatory process. Among the first 25 patients treated by Rogers [18], systemic therapy with corticosteroids (11 of 11), hydroxychloroquine (8 of 10), cyclosporine (1 of 1), and cyclophosphamide (1 of 1) was effective. The disease flared when therapy was discontinued. Failures were also recorded with griseofulvin (0 of 8); dapsone (1 of 2); metronidazole (0 of 1); and tetracycline plus niacinamide (0 of 1). Recently, one of the authors [30] have noted benefit from topical tacrolimus therapy. Tacrolimus, an immunosuppressive agent used in organ transplantation, has been effective topically. Initially, the medication was suspended in Aquaphor in 0.03% or 0.1% concentration. Later, the authors used Protopic ointment 0.03% or 0.1% with good results.
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R.S. Rogers III, D. Eisen / Dermatol Clin 21 (2003) 9198 Table 3 Peno-gingival syndrome of erosive oral lichen planus in men Cribier et al [16] Eisen Number 1 Age range 52 Median age 52 Oral before genital 1 Genital = oral 0 Genital before oral 0 Cutaneous lesions 1 Desquamative 1 gingivitis Nail involvement 0 Rogers Total 12% 28 72% 49% 25% 75% 0% 25% 42% 0%
Topical tacrolimus was massaged into involved tissues three times daily. Patients were asked not to eat or drink for 30 minutes after applying the medication. Benefit was seen in oral and vulvar disease in 4 weeks. Maintenance therapy with less frequent dosing is required or the disease flares. Similar results have been reported with OLP [31]. The vaginal manifestations of the VVG syndrome of erosive OLP present a challenge. Topical therapy is difficult to apply. Walsh et al [32] describe a vaginal prosthetic device for use with topical therapy. Topical therapy with cyclosporine has also been reported to be effective [9,17].
7 4 28 72 35 60 47 52 2 0 10 4 0 0 3 0 2 2 0 0
PG syndrome of erosive OLP Patient profiles of the PG syndrome of erosive OLP Penile or male genital lesions are reported to be common in cutaneous LP [2]. These lesions are described as annular, papulosquamous lesions characteristically affecting the glans penis (Fig. 6). Male genital lesions were noted in 8 of 174 male OLP patients reported by Eisen [9]. Of these, four of eight had asymptomatic reticular or erythematous lesions rather than erosive genital lesions. Recognition of male genital lesions is important because squamous cell carcinoma can develop at penile sites of LP [33]. Cribier et al [19] described the male equivalent of the VVG syndrome of erosive oral LP in 1993. Eisen [9] has reported eight patients with OLP and LP lesions of the male genitalia, of whom four had erosive gingival and genital lesions. Since that report,
Eisen has seen three additional patients. Rogers has seen six patients with oral LP and male genital lesions, four of who had erosive gingival and genital disease (Table 3). Oral lesions of the PG syndrome of erosive OLP All patients have oral LP. The characteristic lesion is gingival LP; 42% of patients have desquamative gingivitis caused by OLP. Involvement of other sites is common. Reticular, erythematous, and erosive lesions are typically present. Patients are often symptomatic. Penile lesions of the PG syndrome of erosive OLP All patients have penile LP. Lesions are usually erosive and involve the glans penis. Some patients also have reticular and erythematous lesions of the glans penis and occasionally of the shaft of the penis. Patients are often symptomatic. Scarring is not typical. Other involvement of the PG syndrome of erosive OLP Although female patients with the VVG syndrome of erosive OLP have extraorogenital involvement of cutaneous, scalp, and nail sites and unusual mucosal sites, such as otic, ocular, and esophageal mucosae, the 12 male patients with the PG syndrome of erosive OLP do not exhibit involvement of other sites except skin in 25% of patients. Diagnosis of the PG syndrome of erosive OLP The differential diagnosis includes LSA and immunobullous diseases, such as mucous membrane pemphigoid, pemphigus, paraneoplastic pemphigus, and linear IgA bullous disease. Study of biopsy specimens by both routine histopathology stains and by the
Fig. 6. Penile lichen planus. Note the annular, papulosquamous plaque on the glans penis. The lesion is often a violet to purple color.
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direct immunofluorescence technique is helpful in excluding LSA and the immunobullous diseases and confirming the diagnosis of the PG syndrome of erosive OLP [28]. Natural history of the PG syndrome of erosive OLP The initial presentation of the PG syndrome of erosive OLP occurs in middle-aged men. The age range was 28 to 72 years of age, and the median age was 47 (see Table 3). Oral lesions preceded genital lesions in 25% or occurred simultaneously with genital lesions in 75%. The constellation of signs and symptoms usually came together within a few years. The prognosis for a spontaneous remission of the PG syndrome of erosive OLP is poor. Most patients continue to suffer from the disease for years. The development of squamous cell carcinoma in oral and genital LP is an accepted but rare complication of LP [33,34]. None of the 12 patients with the PG syndrome of erosive OLP have developed squamous cell carcinoma to date. Treatment of the PG syndrome of erosive OLP Treatment of this distressing and chronic condition is challenging. Systemic administration of corticosteroids, hydroxychloroquine, and azathioprine has been beneficial. One patient achieved remission with systemic griseofulvin and topical corticosteroid therapy. Topical corticosteroid, cyclosporine, and tacrolimus treatment has been beneficial, controlling the inflammatory elements of the disease. Male genital lesions respond to topical therapy better than female genital lesions.
References
[1] Bouquot JE, Gorlin RJ. Leukoplakia, lichen planus, and other keratoses in 23,616 white Americans over the age of 35 years. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1986;61:373 81. [2] Boyd AS, Neldner KH. Lichen planus. J Am Acad Dermatol 1991;25:593 619. [3] Eisen D. The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients. J Am Acad Dermatol 2002;46:207 14. [4] Scully C, Beyli M, Ferreiro MC, et al. Update on oral lichen planus: etiopathogenesis and management. Crit Rev Oral Biol Med 1998;9:86 122. [5] Andreason JO. Oral lichen planus: a clinical evaluation of 115 cases. Oral Surg 1968;25:31 41.
[6] Altman J, Perry HO. The variations and course of lichen planus. Arch Dermatol 1961;84:179 91. [7] Neumann R, Dutt CJ, Foster CS. Immunohistopathologic features and therapy of conjunctival lichen planus. Am J Ophthalmol 1993;115:494 500. [8] Abraham SC, Ravich WJ, Anhalt GJ, et al. Esophageal lichen planus: case report and review of the literature. Am J Surg Pathol 2000;24:1678 82. [9] Eisen D. The evaluation of cutaneous, genital, scalp, nail, esophageal, and ocular involvement in patients with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:431 6. [10] Scully G, El-Kom M. Lichen planus: review and update on pathogenesis. J Oral Pathol 1985;14: 431 58. [11] Micheletti L, Preti M, Bogliatto F, et al. Vulval lichen planus in the practice of a vulval clinic. Br J Dermatol 2000;143:1349 50. [12] Lewis FM. Vulval lichen planus. Br J Dermatol 1998; 138:569 75. [13] Pelisse M, Leibowitch M, Sedel D, Hewitt J. Un noveau syndrome vulvo-vagino-gingival. Lichen plan erosif plurimuqueux. Ann Dermatol Venereol 1982; 109:797 8. [14] Hewitt J, Pelisse M, Lessana-Leibowitch M, et al. Le syndrome vulvo-vagino-gingival. Rev Stomatol Chir Maxillofac 1985;86:51 65. [15] Pelisse M. The vulvo-vaginal-gingival syndrome: a new form of erosive lichen planus. Int J Dermatol 1989; 28:381 4. [16] Bermejo H, Bermejo MD, Roman P, et al. Lichen planus with simultaneous involvement of the oral cavity and genitalia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1990;69:209 16. [17] Eisen D. The vulvovaginal-gingival syndrome of lichen planus. Arch Dermatol 1994;130:1379 82. [18] Rogers III RS. Erosive orogenital lichen planus in women (vulvovaginal-gingival syndrome). J Oral Pathol Med 1998;27:362. [19] Cribier B, Ndiaye I, Grosshans E. Syndrome peno-gingival: Un equivalent masculin du syndrome vulvovagino-gingival? Rev Stomatol Chir Maxillofac 1993;94:148 51. [20] Wilson E. On lichen planus. J Cutan Med Dis Skin 1968;3:117 32. [21] Gardner HL. Desquamative inflammatory vaginitis: a newly defined entity. Am J Obstet Gynecol 1968;102: 1102 5. [22] Lynch P. Erosive lichen planus. In: Proceedings of the International Society for the Study of Vulval Diseases. Mexico; 1975:30 1. [23] Edwards L, Friedrich EG. Desquamative vaginitis: lichen planus in disguise. Obstet Gynecol 1988;711: 832 6. [24] Edwards L. Vulvar lichen planus. Arch Dermatol 1989; 125:1677 80. [25] Edwards L. Vulvovaginal disease. Curr Probl Dermatol 1994;6:185 220. [26] Lewis FM, Shah M, Harrington CI. Vulval involve-
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R.S. Rogers III, D. Eisen / Dermatol Clin 21 (2003) 9198 ment in lichen planus: a study of 37 women. Br J Dermatol 1996;135:89 91. Marren P, Millard P, Chia Y, et al. Mucosal lichen sclerosus/lichen planus overlap syndromes. Br J Dermatol 1994;131:118 23. Helander SD, Rogers III RS. The sensitivity and specificity of direct immunofluorescence testing in disorders of mucous membranes. J Am Acad Dermatol 1994; 30:65 75. Lewis FM, Harrington CI. Squamous cell carcinoma arising in vulval lichen planus. Br J Dermatol 1994; 131:703 5. Rozycki TW, Rogers III RS, Pittelkow MR, et al. Topical tacrolimus in the treatment of symptomatic oral lichen planus: a series of 13 patients. J Am Acad Dermatol 2002;46:27 34. Kaliakatsou F, Hodgson TA, Lewsey JD, et al. Management of recalcitrant ulcerative oral lichen planus with topical tacrolimus. J Am Acad Dermatol 2002; 46:35 41. [32] Walsh DS, Konzelman Jr. J, Sau P, et al. A vaginal prosthetic devise as an aid in treating ulcerative lichen planus of the mucous membrane: successful combination therapy with a corticosteroid-bioadhesive compound and iontophoresis. Arch Dermatol 1995;131: 265 7. [33] Bain L, Geronemus R. The association of lichen planus of the penis with squamous cell carcinoma in situ and with verrucous squamous cell carcinoma. J Dermatol Surg Oncol 1989;15:413 7. [34] Leal-Khouri S, Hruza GJ. Squamous cell carcinoma developing within lichen planus of the penis: treatment with Mohs micrographic surgery. J Dermatol Surg Oncol 1994;20:272 6.
[27]
[28]
[29]
[30]
[31]
Oral psoriasis
Alison J. Bruce, MDa,b,*, Roy S. Rogers III, MDa,b
a
Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA b Department of Dermatology, Mayo Medical School, Rochester, MN 55905, USA
Psoriasis is a common skin disease, affecting approximately 2% to 3% of the general population. Classic cutaneous lesions are thick, erythematous, well-demarcated plaques with adherent silvery scale. Plaques characteristically involve the extremities and extensor surfaces in a symmetric fashion. Elbows, knees, sacral area, and scalp are commonly affected. Nail involvement is frequent. Conversely, oral involvement is rare. Some physicians doubt whether psoriasis affects the oral mucosa, particularly because early reports of oral psoriatic lesions lacked histologic confirmation [1,2]. Nonetheless, many well-documented studies describe oral lesions in patients with psoriasis, and as far back as 1903, Oppenheim reported the first oral psoriatic lesions with confirmatory histologic findings [3]. More recent authors have reviewed, throughout the English and European literature, approximately 60 cases with clinical and histologic features consistent with oral psoriasis [2,4]. In general, oral lesions of psoriasis are probably quite uncommon, appearing more frequently in certain subtypes of psoriasis, specifically generalized pustular psoriasis [5 7]. In this disease, the oral lesions can take the form of a geographic tongue. The geographic tongue may represent the oral counterpart of cutaneous psoriasis. This supposition is based on the almost identical histologic features of the geographic tongue and the cutaneous lesion of
pustular psoriasis, both typified by an intraepidermal neutrophilic pustule. Naturally, the diagnosis of oral psoriasis is more convincingly made when the clinical course of the oral lesions parallels that of the skin disease [8]. Nevertheless, there are isolated reports of oral psoriatic lesions in patients without concurrent psoriatic skin lesions [2,3]. These oral lesions are histologically consistent with psoriasis vulgaris. Possibly, the oral lesions precede the development of the more classic skin lesions or, alternatively, occur in patients with previous cutaneous psoriasis in remission.
Spectrum of clinical involvement Psoriasis can affect the oral cavity in several ways. Temporomandibular joint Psoriasis is frequently associated with various patterns of arthritis, particularly in patients with HLA-B27 positivity. Although uncommon, temporomandibular joint dysfunction may develop in patients with psoriatic arthritis, appearing as localized jaw pain, swelling, and limitation of movement. Temporomandibular joint involvement is typically unilateral, and onset is in middle age, around the fourth decade. Men and women appear equally affected. Overall, temporomandibular psoriatic arthritis is less frequent than other joint involvement [9]. Lips
* Corresponding author. Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail address: bruce.alison@mayo.edu (A.J. Bruce).
Psoriatic involvement of the lips can take several forms. Typical scaly, erythematous psoriatic lesions
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Fig. 1. Typical scaly lesions extending from the cutaneous lip and crossing the vermilion to involve the mucosal surface. (From Bork K, Hoede N, Korting GW, et al. Diseases of the oral mucosa and the lips. Philadelphia: WB Saunders; 1996.)
Fig. 3. White hyperkeratotic polycyclic lesions on the labial mucosa of a patient with psoriasis.
Mucosal surfaces Psoriasis affecting the mucosal surfaces of the oral cavity has several clinical patterns. Chronic mucosal plaques, such as those on extremities, do not occur within the mouth. Instead, lesions are typically shortlived and migratory, changing in location and prominence daily, sometimes barely visible and at other times fairly florid. Oral lesions are usually white annular, serpiginous, or polycyclic plaques and papules, occurring on the buccal mucosa most commonly during flares of ordinary psoriasis or with pustular psoriasis (Fig. 3). Erythematous patches occur less frequently (Fig. 4), and erosions, which may represent areas of atrophy rather than true ulceration, develop rarely [2]. This pattern of involvement is generally known as migratory stomatitis but has been given a number of different names, including annulus migrans, stomatitis areata migrans, and geographic stomatitis [6,11]. These mucosal lesions are similar clinically to the evolving plaques of geographic tongue and hence may also be referred to as ectopic
may extend from the perioral cutaneous lip and cross the vermilion border to involve the mucosal surface (Fig. 1). An exfoliative cheilitis can rarely develop, either with flares of psoriasis vulgaris or, more commonly, with generalized pustular psoriasis (Fig. 2). ` che (angular cheilitis) with inflammation, erythePerle ma, and scaling at the corners of the mouth has also been reported in patients with psoriasis. It is not ` che is higher known whether the incidence of perle than that in the general population. Interestingly, the authors who noted this prevalence of angular cheilitis found that most patients affected were younger than 35 years, a suggestion that the phenomenon be attributed to psoriasis per se and not to the expected jaw laxity of aging [10].
Fig. 2. Severe exfoliative cheilitis affecting the lips of a patient during a flare of pustular psoriasis. (From Bork K, Hoede N, Korting GW, et al. Diseases of the oral mucosa and the lips. Philadelphia: WB Saunders; 1996: with permission.)
Fig. 4. An erythematous annular plaque of psoriasis (arrow) on the free mucosal surface.
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geographic tongue (Fig. 5) [8]. All areas of the oral mucosa can be affected by psoriasis, but the buccal mucosa is most commonly affected. Palatal involvement is rare, and most unusual is involvement of the attached gingivae [3]. These migratory lesions on either the tongue or the mucous membranes have identical histopathologic features, including the characteristic intraepidermal pustule. These similarities lend credence to the thought that both classic geographic tongue and ectopic geographic tongue are manifestations of oral psoriasis [8]. Geographic tongue is fairly common in the general population, affecting 1% to 2% of normal persons, but is more frequently encountered in patients with psoriasis, particularly generalized pustular psoriasis. Studies report incidences of geographic tongue in patients with psoriasis to be anywhere from 5% to 10% [5,8,10,12]. Geographic tongue has also been noted in other dermatologic conditions, including atopic dermatitis, but its incidence is higher in pustular psoriasis than in those conditions [12]. Other tongue disorders, such as fissured tongue, also are more frequent in patients with psoriasis.
Fig. 6. Histopathologic specimen from the oral mucosa showing acanthotic epithelium with enlargement of the rete ridges and hyperparakeratosis. (Hematoxylin and eosin; magnification 10)
Histopathology The clinical appearance of oral psoriatic lesions is not specific, and supportive pathologic information is necessary. In general, the pathologic changes seen within the mucous membranes parallel those of cutaneous psoriasis. Elongation and thickening of the rete ridges, with overall acanthosis, is noted. Parakeratosis
is evident, and this hyperplastic acanthotic epithelium macroscopically produces the white lesions of the mucosa. The papilla of the lamina propria is elongated and edematous, with thinning of the overlying suprapapillary epithelium and dilatation of superficial capillaries (Fig. 6). These changes mimic those in cutaneous biopsy specimens, and this prominence of the superficial vasculature produces the pinpoint bleeding provoked on skin lesions (Auspitz sign). Similar easy bleeding occurs in the mouth. One of the most characteristic features of psoriasis is percolation of neutrophils through the upper epithelium. These polymorphonucleocytes may collect in clusters known as Munros microabscesses ,
Fig. 5. Characteristic annular migratory keratotic plaques on the ventral tongue, representing migratory stomatitis in a patient with psoriasis. The lesions are similar in appearance to the typical plaques of geographic tongue, hence the alternative term ectopic geographic tongue.
Fig. 7. Neutrophils in clusters within the superficial epithelium form the characteristic intraepidermal spongiform pustule. (Hematoxylin and eosin; magnification 40)
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Table 1 Differential diagnosis of oral psoriatic lesions Distinguishing features Lichen planus Lichenoid inflammation on hematoxylin and eosin staining; shaggy BMZ immunoreactants on DIF Positive rapid plasma reagin test result Continuous granular deposition of IgG and IgM on DIF Characteristic linear BMZ staining on DIF on salt split skin; positive serum titer on IIF Intercellular staining pattern of immunofluorescence on DIF; positive serum titer on IIF Positive culture Supportive history and clinical appearance
Syphilis Lupus erythematosus Cicatricial pemphigoid
Pemphigus
Candidiasis Smoking, trauma, poor-fitting dentures
Abbreviations: BMZ, basement membrane zone; DIF, direct immunofluorescence; IIF, indirect immunofluorescence.
although they are not essential for the diagnosis of oral psoriasis, nor are they specific (Fig. 7). The lack of a stratum corneum in the nonmasticatory oral mucosa may explain why there are no macroscopically evident pustules in the mouth. One must remember, however, that these changes are not specific and are similar to other forms of nonspecific mucosal inflammation occurring in patients without psoriasis. As with most dermatologic diseases, clinicopathologic correlation is necessary.
Differential diagnosis The clinical differential diagnosis of oral psoriatic lesions is broad, because similar mucosal changes may be seen in other inflammatory, blistering, or ulcerative conditions. These include lichen planus, Reiters syndrome, syphilis, lupus erythematosus, pemphigoid, and pemphigus (Table 1) Infectious causes, such as candidiasis, need to be considered. Other causes of leukoplakia can mimic oral psoriasis both clinically and histologically. Factors to be excluded are habitual smoking; poor-fitting dentures traumatizing the oral mucosa; and other injurious oral habits (such as cheek biting), which may produce similar-appearing lesions. Many of these disorders can be excluded by history or by routine histology, direct immunofluorescence studies, cultures, and the lack of other cutaneous lesions or systemic markers. Nonetheless, even with appropriate biopsy techniques, a group of so-called psoriasiform disorders
remains, and these entities can be difficult to distinguish both clinically and histologically. Included are the oral lesions of psoriasis; Reiters syndrome; isolated benign geographic tongue; and ectopic geographic tongue (migratory stomatitis). These four conditions are clinically similar and have identical histologic features, with intraepidermal neutrophilic infiltrates with or without Munros microabscesses. The histologic similarity of geographic tongue, psoriasis, and the cutaneous lesions of oculomucocutaneous disorders, such as Reiters syndrome, suggests a possible relationship among these psoriasiform disorders. These conditions may represent a spectrum of disease with overlapping features (Table 2). Reiters syndrome most likely is a reactive phenomenon in genetically predisposed individuals to an antecedent urogenital or gastrointestinal infection. Patients have a triad of urethritis, conjunctivitis, and arthritis. Cutaneous manifestations include keratoderma blennorrhagicum (seen on palms and soles) and mucosal lesions on the genitalia (balanitis circinata). Oral lesions, indistinguishable from oral psoriasis, can occur with similar intraepidermal pustules histologically. Some dermatologists argue that the lesions of keratoderma blennorrhagicum are none other than palmoplantar psoriasis. Psoriasis, too, may be manifested as a reactive process and is well known to flare after streptococcal infection. Psoriasis also has arthritic manifestations, and the overlap with Reiters syndrome can be appreciated. There is no consensus, however, on whether these psoriasiform conditions are indeed interrelated, and the relationship is speculative. Although the spongiform pustule is common histologically to these inflammatory conditions, until the pathogenesis of these disorders is better elucidated, this overlap phenomenon will not be completely understood.
Treatment In general, the oral lesions of psoriasis are asymptomatic or temporary. Consequently, most patients do
Table 2 Oral disorders with the spongiform pustule histologically Disorder Oral psoriasis Reiters syndrome Geographic tongue Ectopic geographic tongue Associated features Skin lesions, arthritis Skin lesions, arthritis, conjunctivitis, urethritis Atopy
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not present for treatment of oral lesions alone but rather for management of their cutaneous disease, which usually flares synchronously. Management must focus on the removal of irritants and infective agents, which may drive psoriasis by the Koebner phenomenon or provide continued antigenic stimulation to intensify the disease. Measures include the removal and treatment of bacterial plaque and cavities and attention to poorly fitting dentures, other dental appliances, or abnormally sharp or broken teeth. Palliative treatment includes the use of a topical anesthetic, such as viscous lidocaine or diphenhydramine (Benadryl); a coating mucosal protectant, such as an emollient dental paste (Orabase) or magnesium and aluminum hydroxides (Maalox); and alkaline rinses. For symptomatic patients, topical corticosteroids, such as fluocinonide gel 0.05% (Lidex), can be applied to alleviate symptoms. Concomitant attention should be given to the possibility of simultaneous candidiasis, which may complicate or cloud diagnosis and management. In general, oral lesions resolve with control of cutaneous disease, and specific treatment is often not needed.
Summary It is strange that the existence of oral psoriasis seems so rare. Other papulosquamous disorders, such as lichen planus, are frequently associated with oral manifestations, yet oral psoriasis is rare given the prevalence of cutaneous disease. One explanation is that oral lesions are asymptomatic and do not come to the clinicians attention. Other explanations, however, are necessary. Epithelial turnover time is significantly increased in psoriatic plaques and may be as rapid as 3 to 7 days, whereas normal epithelial turnover is 28 days. Some have suggested that this abnormally increased turnover time in psoriasis approximates that of the normal regenerative time of the oral epithelium, and this possibility may account for the apparent lack of changes in the oral mucosa of patients with psoriasis [1]. It is also possible that oral lesions of psoriasis are altered both clinically and histologically by other factors within the oral microenvironment and are not recogized [1]. Although controversy has appeared in the literature about whether lesions of oral psoriasis exist, there is sufficient evidence that a subset of patients have oral lesions in association with skin disease. This occurrence is more common in patients with the severe forms of psoriasis, such as generalized pustular psoriasis. The diagnosis of oral psoriasis should
be based on good clinical and histologic evidence, and, in general, the clinical course of the oral lesions should parallel that of the skin disease. Exclusion of other causes is important, particularly if cutaneous lesions are absent and a diagnosis of isolated oral psoriasis is entertained. Because neither the clinical nor the histologic changes are absolutely specific for psoriasis, the patient requires holistic evaluation. That being said, in day-to-day practice it is most likely not practical to obtain a biopsy of asymptomatic oral lesions for definitive histologic or immunofluorescence studies. The clinician, however, must have a high degree of awareness and pay close attention to the oral mucosa in patients with psoriasis. A thorough examination is imperative, because asymptomatic oral lesions may be found more frequently in patients with psoriasis if clinicians habitually check mucous membranes during the generalized skin examination. Conversely, in patients with troublesome oral lesions, a cutaneous examination that reveals subtle changes suggestive of psoriasis may provide clues to the oral diagnosis. A detailed history remains the cornerstone of diagnosis, because a family history of psoriasis or a history of psoriasis now in remission may guide physicians when they note oral lesions.
References
[1] Cataldo E, McCarthy P, Yaffee H. Psoriasis with oral manifestations. Cutis 1977;20:705 8. [2] Younai FS, Phelan JA. Oral mucositis with features of psoriasis: report of a case and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:61 7. [3] Brice DM, Danesh-Meyer MJ. Oral lesions in patients with psoriasis: clinical presentation and management. J Periodontol 2000;71:1896 903. [4] Richardson LJ, Kratochvil FJ, Zieper MB. Unusual palatal presentation of oral psoriasis. J Can Dent Assoc 2000;66:80 2. [5] Dawson TA. Tongue lesions in generalized pustular psoriasis. Br J Dermatol 1974;91:419 24. [6] OKeefe E, Braverman IM, Cohen I. Annulus migrans: identical lesions in pustular psoriasis. Reiters syndrome, and geographic tongue. Arch Dermatol 1973; 107:240 4. [7] Wagner G, Luckasen JR, Goltz RW. Mucous membrane involvement in generalized pustular psoriasis: report of three cases and review of the literature. Arch Dermatol 1976;112:1010 4. [8] Weathers DR, Baker G, Archard HO, et al. Psoriasiform lesions of the oral mucosa (with emphasis on ectopic geographic tongue). Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1974;37:872 88.
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A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 99104 [11] Espelid M, Bang G, Johannessen AC, et al. Geographic stomatitis: report of 6 cases. J Oral Pathol Med 1991; 20:425 8. [12] Morris LF, Phillips CM, Binnie WH, et al. Oral lesions in patients with psoriasis: a controlled study. Cutis 1992;49:339 44.
[9] Bork K, Hoede N, Korting GW, et al. Diseases of the oral mucosa and the lips. Philadelphia: WB Saunders; 1996. [10] Buchner A, Begleiter A. Oral lesions in psoriatic patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1976;41:327 32.
Dermatol Clin 21 (2003) 105 114
Contact stomatitis
Benjamin W. LeSueur, MD, James A. Yiannias, MD*
Department of Dermatology, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
Contact stomatitis is inflammation or pain of the oral mucosa caused by external substances. These substances act either as irritant or allergic contactants. Irritants cause inflammation and activation of immunologic mediators without involvement of memory T-cell function or antigen-specific immunoglobulins. They require no previous exposure and tend to cause their untoward effect on the oral mucosa within minutes to hours. Because of this, patients are more likely to discover the causal contactant themselves. Although irritant contact stomatitis is more common than allergic stomatitis generally, many patients with irritant reactions, such as thermal burns from hot food or ulcerations from poorly fitting dentures, may treat themselves at home or visit their dentist rather than seeking the care of a dermatologist. In contrast, allergic contact stomatitis requires previous exposure to an allergen. This initial sensitization can occur through contact with the oral mucosa but may also arise by contact with keratinized skin. As a result of the initial exposure, memory T-cells are activated, but no clinical reaction is seen. With subsequent exposures, a type IV hypersensitivity reaction occurs, but is typically delayed at least 48 hours. This delay between antigen presentation and onset of symptoms makes uncovering the responsible substance challenging. The biologic and physiologic properties of oral epithelium make it more resistant than keratinized skin to irritants and allergens. For example, saliva provides a continuous solution that solubilizes, dilutes, and begins digesting potential contactants and
helps wash them away before they contact oral mucosa [1]. When the mucosa is damaged, saliva promotes healing because of a high concentration of epidermal growth factor. There is less protein in nonkeratinized oral mucosa resulting in fewer targets for allergens. Irritants and allergens that do contact the oral mucosa are removed more quickly because of higher vascularity and faster epithelial renewal rates than in keratinized skin [2]. Despite its specialized characteristics, the oral mucosa is occasionally damaged by contactants. The differential diagnosis of contact stomatitis is extensive and includes other causes of a sore mouth as follows: Contact stomatitis (irritant, allergic) Vesiculobullous diseases Pemphigus Pemphigoid Paraneoplastic pemphigus Ulcerative diseases Aphthous ulcers Behc ets syndrome Erosive lichen planus Erythema multiforme Stevens-Johnson syndrome Nutritional deficiencies Iron, vitamins B12 and B6, folate, zinc Connective tissue diseases Lupus erythematosus Scleroderma Dermatomyositis Lichen planus Drug reactions Infection Viral (herpes simplex virus, varicella-zoster, measles)
* Corresponding author. E-mail address: yiannias.james@mayo.edu (J.A. Yiannias).
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Fungal (Candida) Bacterial (syphilis, necrotizing ulcerative gingivostomatitis) Oral cancer Squamous cell carcinoma B-cell lymphoma Kaposis sarcoma Mesenchymal tumors Malignant melanoma Psychogenic Fear of cancer Depression, anxiety Gastroesophageal reflux Menopause Diabetes Xerostomia Inflammatory bowel disease An organized approach focusing on the patients history and clinical appearance of lesions is fundamental to making an accurate diagnosis. In addition, selected tests, such as patch testing, blood tests, and biopsy of specific oral mucosal lesions, can assist in differentiating possible diseases (Table 1).
Similarly, a patient may promptly note symptom onset or worsening after chewing certain types of gum. A patient with sensitivity to spearmint, for example, may have chronic exposure caused by widespread use of this flavoring in numerous oral care products, thereby making a temporal association more difficult. A thorough review of systems including questions about diet, changes in weight, and swallowing is also important to identify the cause of a sore mouth. A poor diet or an underlying disorder resulting in weight loss may be a marker for deficiencies in zinc, vitamin B12, folate, and iron. Similarly, odynophagia may indicate a scleroderma syndrome, whereas heartburn may suggest acid reflux that can result in a sore mouth.
Physical examination Recognizing differences in location and morphology of oral lesions caused by contact stomatitis can help to narrow the potential causes. Four general types of physical examination findings are seen in contact stomatitis including red lesions and erythema, white lesions and leukoplakia, erosions and ulcerations, and the normal mouth (see Table 1). Localized or diffuse red maculae and patches are caused by a variety of irritant and allergic substances. Contactants in metal dental restorations and flavorings found in toothpaste, mouthwashes and gum are common offenders [2]. Atypical gingivostomatitis is an uncommon, but dramatic presentation of contact stomatitis related to some gums and toothpaste [3]. Patients present with bright red erythema and edema involving the gingivae, tongue, and commissures of the lips. Histology shows a characteristic plasma cell infiltrate. White patches or plaques are usually localized and can have a homogeneous, wrinkled, or verrucous appearance (Fig. 1). They can arise because of mechanical trauma from friction of the teeth and illfitting or uneven dentures. Histologically, these lesions display mucosal hyperkeratosis and hyperplasia. White lesions may also be caused by inflammatory lichenoid reactions, which clinically and histologically can be similar in appearance to oral lichen planus (Fig. 2). In fact, many patients with lesions diagnosed as oral lichen planus have been found to have clinically relevant contact allergy to metals in their dental fillings [4 6]. Erosions and ulcerations in the mouth present with rough macerated bases and may develop irregular borders. They are often surrounded by a
History Obtaining a thorough history is particularly important in evaluating patients with suspected contact stomatitis because the symptoms are often more prominent than the physical examination findings. In fact, it is possible to have prominent subjective complaints associated with a normal-appearing mouth. The most common symptoms are pain and burning. Decreased sense of taste and numbness occur less frequently and itching is uncommon. It is essential to obtain information regarding contact with potential irritants or allergens, such as toothpaste, mouthwash, chewing gum, dentures, denture cleaners, and dental restorations. The site of mouth symptoms, whether it is diffuse or localized to a specific structure, such as the hard palate, buccal mucosa, or tongue, can give valuable clues to diagnosis. For example, complaints of soreness or pain localized to the buccal mucosa may suggest irritant stomatitis caused by frictional trauma from dentures or allergic stomatitis from a metal dental restoration. In contrast, diffuse mouth pain may represent allergy to an oral flavoring, which contacts most structures in the mouth during mastication. Temporal correlation can occasionally be helpful, such as a patient who notes onset of discomfort shortly after the placement of a dental restoration.
Table 1 Recommended work-up for patients with a sore mouth Mucosal appearance Bx Blood Erosions/Ulcer/Bullae Routine DIF IIF Hepatitis panel if LP suspected Syphilis serologies Erythema Routine +/ DIF / IIF Hepatitis panel if LP suspected Syphilis serologies Leukoplakia Routine Performed only if other investigations suggest need Hepatitis panel if LP suspected Syphilis serologies Normal appearance B.W. LeSueur, J.A. Yiannias / Dermatol Clin 21 (2003) 105114 Usually not performed CBC, basic chemistries Zinc B12 Folate Iron TSH Perform oral flavorings and metal and dental series if above ( ) Deficiency state Contact stomatitis Burning mouth syndrome Psychogenic
Patch testing
Diagnosis
Perform metal and dental series if lesions primarily adjacent to restorations Aphthae (nonspecific labs) Pemphigus, pemphigoid (characteristic Bx, DIF, IIF) LP (characteristic Bx, DIF) Drug (history, suggestive Bx) Erythema multiforme (Bx) Lupus erythematosus (Bx, DIF) Syphilis (suggestive Bx, serologies) Friction Contact stomatitis (may appear identical to aphthae)
Perform metal and dental series if lesions primarily adjacent to restorations Pemphigus, pemphigoid LP Drug Erythema multiforme Lupus erythematosus Friction Candidiasis, syphilis Contact stomatitis
Perform metal and dental series if lesions primarily adjacent to restorations LP Squamous atypia, SCC Friction Candidiasis, syphilis Contact stomatitis
Abrreviations: Bx, biopsy; CBC, complete blood count; DIF, direct immunofluorescence; IIF, indirect immunofluorescence; LP, lichen planus; SCC, squamous cell carcinoma; TSH, thyroid stimulating hormone.
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Fig. 1. Allergic contact stomatitis. White patches on the tongue. Note dental metal, right lower teeth.
Fig. 3. Irritant stomatitis. Ulcerations with surrounding erythematous on the hard palate caused by a pizza burn.
red halo (Fig. 3). Erosions can be caused by trauma in the form of friction from the teeth or irregular dental restorations. Burns from hot foods, radiation, and caustic chemicals typically cause erosions. In addition, allergic contact stomatitis can present with erosions and is sometimes indistinguishable from aphthous ulcers based on physical examination alone. Complaints of a burning or sore mouth with a normal-appearing oral mucosa on examination are the primary features of burning mouth syndrome. Contact stomatitis is thought to be responsible for burning mouth syndrome in some cases. Drage and Rogers [7] showed that 13% of patients with burning or sore mouth had positive patch tests that were thought to be clinically relevant. Oral flavorings were responsible for most reactions in their study. Dental metals and denture materials have also been
implicated as possible causes of burning mouth syndrome [8,9].
Irritant contact stomatitis Heat, frictional trauma, and chemicals can cause irritant contact stomatitis. Factors that determine the degree of inflammation include the inherent irritation potential of the agent; amount of exposure (concentration, duration, and frequency); ability to penetrate the tissue; and host factors, such as immune status [10]. Thermal burns from hot food and liquid commonly involve the hard palate, tongue, and lips. Occasionally, oral inflammation develops from mechanical trauma because of jagged teeth or poorly fitting dentures [11]. Friction from poor-fitting dentures can be combined with poor hygiene and trapped food to cause irritation in adjacent mucosa. Acidic and alkaline denture cleaning chemicals are also known to cause irritant lesions and patients should be reminded to rinse dentures thoroughly after soaking them in these cleaners. Medications, such as aspirin and vitamin C, may unintentionally not be swallowed, especially in a neurologically impaired patient, thereby resulting in an irritant oral lesion. Shohls solution, which continues to be used orally for the treatment of metabolic acidosis, can irritate the mouth and should be diluted with water or juice and rinsed thoroughly following administration. Gasoline and other caustic chemicals ingested either purposefully or accidentally can cause mild to severe erosive and inflammatory lesions in the mouth and esophagus. Treatment for irritant dermatitis primarily involves removal of the inciting cause. Usually, the discomfort then resolves spontaneously, but severe, painful involvement may require topical anesthetics, such as lidocaine.
Fig. 2. Allergic contact stomatitis. Lichenoid reticulated patch with ulceration of the buccal mucosa adjacent to gold restorations.
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Allergic contact stomatitis Oral flavorings, preservatives, and dental materials, such as metals, acrylates, resins, and impression compounds, are the most common cause of allergic delayed-type hypersensitivity reactions of the oral mucosa. Oral flavoring and preservatives are ubiquitous in commercially available personal hygiene products and foods, making exposure in developed countries nearly universal. Table 2 details examples of common oral flavoring allergens and lists the products in which these allergens are found. Table 3 lists recommended patch-test antigens for patients suspected to have contact stomatitis. Fragrance mix contains several antigens including cinnamic aldehyde and eugenol and is a useful screening tool that identifies common flavoring allergies [12]. Another screening allergen helpful in identifying oral flavoring allergies is balsam of Peru. The antigens found in these screening tests are often used in lipsticks, mouthwashes, oral analgesics, and toothpaste. The most common preservatives that cause allergic contact stomatitis are parabens and propylene glycol. Parabens are found in a variety of foods including salad dressing, spicy sauces, mustard, jellies, jams, fruit juices, syrups, and candies. They are also used in lipsticks and toothpaste. Propylene glycol is found in tobacco formulations, food colors, flavoring agents, and oral pharmaceuticals [1]. Although allergy to preservatives is infrequent, these antigens should be considered and included in patch test series for evaluating contact stomatitis. The most common and best-documented dental metals to cause oral contact allergy are mercury and gold [13]. Silver-colored amalgam dental fillings typTable 2 Oral flavoring allergens and examples of sources of exposure Oral flavoring Balsam of Peru
ically contain metallic mercury. Clinically significant mercury allergy more likely is found in patients with symptoms and examination findings localized to the mucosa adjacent to an amalgam dental restoration. Koch and Bahmer [5] found that 78.9% of patients with oral lichenoid lesions adjacent to amalgam fillings were sensitized to inorganic mercury. In contrast, only 12% of patients in this study with lichenoid lesions distant from amalgam and 4.3% of patients with burning mouth syndrome were allergic to mercury. The mercury allergies of patients with lesions adjacent to amalgam were believed to be clinically significant as evidenced by finding that 13 of 15 patients had considerable improvement in their symptoms after removal of their metal fillings [5]. Little et al [14] suggests that mercury salts released from fillings may act directly on oral keratinocytes to induce changes that attract lymphocytes, thereby promoting the development of lichenoid lesions. Specifically, oral keratinocytes cultured in the presence of mercuric chloride acquired subcytotoxic concentrations of mercuric chloride that induced a concentration-related increase in intercellular adhesion molecule 1 and consequent T-cell binding. Metallic gold is found in gold-colored dental fillings and restorative crowns. Gold is being recognized as a more important cause of contact dermatitis and stomatitis than previously thought [1,6,13,15,16]. Kanerva et al [13] evaluated patch test data of patients with either suspected contact reactions of the oral mucosa, or suspected occupational and nonoccupational contact reactions caused by dental products. Of 4508 patients from seven centers patch tested to gold sodium thiosulfate, 7.7% (range 4.1% to 15%) had positive reactions. The authors did not address
Commercial and medicinal products Cements and liquids in dentistry Flavoring in toothpaste, cough drops, throat tablets, and lozenges Spicy foods, such as curry; allspice; pickled vegetables; ketchup; tomatoes; barbecue sauce; and soft drinks Mouthwash and toothpaste Cola, chocolate, ice cream, gums, and candy Mouthwash, toothpaste, cough drops, candy, chewing gum, food, cigarettes, liqueurs, and mixed drinks Mouthwash, toothpaste, chewing gum, breath mints, candy, and liquors Antiseptic, periodontal dressings, zinc oxide cement, and impression pastes in dentistry Flavoring for toothpaste and mouthwash Food spices, such as allspice Over-the-counter inhalants and antiseptics
Cinnamon, Cinnamic aldehyde Menthol Peppermint Eugenol
(Data from Rietschel RL, Fowler JF. Contact dermatitis, ed 5. Philadelphia: Lippincott Williams and Wilkins; 2001. p. 736 817)
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Table 3 Antigens used in patch testing for contact stomatitis Standard series 1. Benzocaine 5% pet 2. Mercaptobenzothiazole 1% pet 3. Colophony 20% pet 4. P-phenylenediamine 1% pet 5. Imidazolidinyl urea 2% Aq 6. Cinnamic aldehyde 1% pet 7. Lanolin alcohol 30% pet 8. Carba mix 3% pet 9. Neomycin sulfate 20% pet 10. Thiuram mix 1% pet 11. Formaldehyde 1% Aq 12. Ethylenediamine dihydrochloride 1% pet 13. Epoxy resin 1% pet 14. Quaternium-15 2% pet 15. p-tert-Butylphenol formaldehyde resin 1% pet 16. Mercapto mix 1% pet 17. Black rubber mix 0.6% 18. Potassium dichromate 0.25% pet 19. Balsam of Peru 25% pet 20. Nickel sulfate 2.5% pet 21. Diazolidinyl urea 1% pet 22. DMDM hydantoin 1% pet 23. Imidazolidinyl urea 2% pet 24. Bacitracin 20% pet 25. Mixed dialkyl thioureas 1%pet 26. Methylchloroisothiazolinone/methylisothiazolinone 0.67% Aq 27. Paraben mix 15% pet 28. Methyldibromoglutaronitrile/phenoxyethanol 1% pet 29. Fragrance mix 8% pet 30. 2-Bromo-2-nitropropane-1,3-diol 0.5% pet 31. Thimerosal 0.1% pet 33. Methylchloroisothiazolinone/methylisothiazolinone 0.67% pet 34. Chloroxylenol (PCMX) 1% pet 35. DMDM hydantoin 1% Aq Metal series 1. Ammoniated mercury 1% pet 2. Potassium dichromate 0.5% pet 3. Nickel sulfate 2.5% pet 4. Cobalt sulfate 1% pet 5. Gold chloride 0.5% alc. 6. Copper sulfate 1% aq 7. Silver nitrate 1% aq 8. Palladium chloride 1% pet 9. Gold sodium thiosulfate 1% pet 10. Ammonium tetrachloroplatinate .25% pet 11. Aluminum 100% pet 12. Potassium dicyanoaurate 0.001% aq 13. Mercuric chloride 0.1% pet 36. Diazolidinyl urea 1% Aq 37. Phenoxyethanol 1% pet 38. Cobalt chloride 1% pet 39 Sesquiterpene lactone mix 0.1% pet 40. Budesonide 0.1% pet 41. Tixocortal 21 pivalate 1% pet 42. BHA 2% pet 43 Glutaraldehyde 0.2% pet 44. Glutaraldehyde 1% pet 45. BHT 2% pet 46. Ethyl acrylate 0.1% pet 47. Glyceryl thioglycolate 1% pet 48. Toluenesulphonamide formaldehyde resin 10% pet 49. Methyl methacrylate 2% pet 50. Ethyleneurea-melamine-formaldehyde mix 5% pet 51. Triamcinolone acetonide 1% pet 52. 2-Hydroxy-4-methoxyfenzophene 3% pet 53. 1H Benzotriazole 1% pet 54. Hexahydro-1,3,5-tris (2-hydroxyethyl) triazine 1% aq. 55. Hexylresorcinol 0.25% pet 56. Phenol formaldehyde resin 1% pet 57. Clioquinol 5% pet 58. Cetyl alcohol 5% pet 59. Isopropyl myristate 20% pet 60. Stearyl alcohol 30% pet 61. Triclosan 2% pet 62. Triethanolamine 2% pet 63. Chloquinaldol 5% pet 64. Hexachlorophene 1% pet 65. Benzalkonium chloride 0.1% aq. 66. Tocopherol (vitamin E) 10% 67. Dermatophagoides mix 20% 68. Gold sodium thiosulfate 0.5% 69. Natural fragrance mix 2%
14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
Metallic mercury 1% pet Chromium chloride 5% pet Mercury ammonium chloride 1% pet Tin 2.5% pet Zinc 2.5% pet Cadmium chloride 1% aq Ferric chloride 1% aq Manganese chloride 2% aq Zinc chloride 2% aq Molybdenum chloride 1% aq Titanium disk Beryllium sulfate tetrahydrate 1% aq Cobalt chloride 1% pet Amalgam 5% (continued on next page)
B.W. LeSueur, J.A. Yiannias / Dermatol Clin 21 (2003) 105114 Table 3 (continued ) Oral flavors and preservatives 1. Anethole 5% 2. Benzoic acid 5% 3. Dodecyl gallate 0.25% 4. Propyl gallate 1% 5. Sodium benzoate 5% 6. Dipentene (Limonene) 1% 7. Benzyl alcohol 1% 8. Octyl gallate 0.25% 9. Citric acid 1% Aq 10. Benzoyl peroxide 1% 11. Ammonium persulfate 2.5% 12. Propionic acid 3% 13. Ethyleneglycol dimethacrylate (EGDMA) 2% 14. Isoeugenol 2% 15. Glutamic acid 1% 16. Orange oil 2% 17. Triethyleneglycol dimethacrylate (TREGDMA) 2% 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. Tartrazine yellow 0.1% Theobroma 5% Sorbitan sesquioleate 20% Sorbic acid 2% BIS GMA 2% Methyl salicylate 2% Peppermint oil 2% Spearmint oil 2% Amyl cinnamaldehyde 2% Eucalyptus oil 2% Menthol 2% Eugenol 2% Clove oil 2% Vanillin 10% Lemon oil 2% Resorcinol 1%
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the clinical relevance of the positive reactions in their study. Yiannias et al [6] reported 46 patients with lichenoid lesions and a diagnosis of oral lichen planus. Patch tests showed 17 of these patients had positive reactions to metals, with gold accounting for 82% (14 of 17). Of the 14 patients with reactions to gold, 10 were thought to be clinically relevant based on finding that four patients symptoms resolved after removal of the gold, whereas the remaining six continued to have lichenoid lesions adjacent to gold-colored fillings. In 2001, gold was chosen as the contact allergen of the year by the American Journal of Contact Dermatitis [17]. Gold will likely be included more frequently in future patch testing series thereby potentially identifying increased numbers of relevant causes of oral contact stomatitis. As with mercury, gold allergy should be considered in a patient with a mucosal lesion adjacent to dental gold. Nickel is found in denture material and in instruments used in dental procedures. The role of nickel as the most common cause of metal allergy in contact dermatitis is well known. Although many stomatitis patients have a positive patch test to nickel, studies show these results are likely not clinically relevant. For example, Dawn et al [18] evaluated 137 patients with oral disease who underwent patch testing during a 12-month period. Of these, 23 (17%) had a positive reaction to nickel. The prevalence of allergic contact dermatitis from nickel, however, in the general patch test population at the same center in the same year was 22%. They concluded that the positive patch tests in patients with oral complaints were likely a reflection of the background prevalence of allergic contact dermatitis from nickel and that nickel alone
does not play a major role in oral disease. In a prospective trial of 16 patients with long-standing recurrent contact dermatitis to nickel, Speichowicz [19] found that placing dental crowns or bridges containing 66% nickel in the mouth did not result in any oral mucosal or systemic reactions. Copper, beryllium, chrome, cobalt, platinum, and palladium can be found in varying amounts in dental materials. For example, copper makes up a portion (approximately 10%) of some dental alloys used to make crowns. Beryllium, chrome, and cobalt are used in dental prostheses, such as partial dentures. Platinum and palladium are used in combination with or in place of gold for fillings and crowns [20,21]. As a group, these metals rarely cause relevant contact allergy. This may be because of the inherent lack of allergic sensitizing capability of the metal or to the small amounts usually present in dental materials. Most dentures are processed by the polymerization of acrylic monomers either by heat curing or by the use of autopolymerizing resins (cold curing). Heat curing requires no additional resins and leaves no residual monomer, whereas cold curing can leave varying amounts of monomer unpolymerized. It is this monomer that is thought to occasionally cause allergic contact stomatitis [22]. Koutis and Freeman [23] reported a patient who had pain and redness at the site of a new denture. Patch tests to an acrylate, 2-hydroxyethyl methacrylate, and the patients own denture material were positive. After boiling the denture he had reversal of his symptoms. Repeat patch testing to the prosthesis was negative. Common acrylate monomers are methacrylates and urethanebased dimethacrylates [1]. Resins, such as bisphenol
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A, used during cold curing are also known to cause oral allergy. In addition to denture manufacture, resinbased cold curing materials are used as sealants, orthodontic adhesives, glazes, repair kits for porcelain-fused-to-metal restorations, and temporary crowns [1]. They are also used by some dentists instead of amalgam as fillings. Dental impression compounds include such substances as stearin, paraffin wax, beeswax, gutta-percha, and many synthetic and natural resins [1]. Although chemicals in dental impression compounds are uncommon causes of stomatitis, when allergic reactions do occur, resins are the most likely substances of this group to be responsible.
Therapy The mainstay in treatment of contact stomatitis is avoidance of the causative agent. The number of potential irritants and allergens in commercially available products that come in contact with the mouth make this difficult. In general, before initiating patch testing the authors recommend that patients with a sore or painful mouth follow specific guidelines to avoid common contactants. Patients should use toothpaste that is free of flavorings or preservatives, such as plain PEELU (PEELU Products, Fargo, ND) or plain baking soda with instructions to brush gently using a soft bristle toothbrush. Flossing with plain nonflavored dental floss is recommended. Rough or crunchy foods, such as nuts, chips, popcorn, pretzels, or firm fruits like apples, should be avoided and replaced with soft foods. Patients are given instructions to take frequent sips of water and use only plain petrolatum for lip lubrication. Denture wearers should use only flavorfree cleaning products and adhesives, such as plain Efferdent Denture Cleanser tablets and Fixodent Free or flavor-free OraGrip. In addition, patients are instructed to avoid mouthwash; gum; mints; chocolate; cinnamon-flavored candy or food; carbonated beverages; and extremely salty, spicy, hot, or acidic foods. Smoking cessation is strongly encouraged. Resolution of symptoms usually occurs quickly after the offending agent is removed. If symptoms fail to improve with simplification of oral care as listed previously, and appropriate blood tests and biopsy specimens have ruled out other diagnoses, contact stomatitis can be confirmed by patch testing. When patch tests reveal a clinically relevant allergen, patients need recommendations guiding avoidance. This also includes instructions on avoiding substances that are known to cross-react. For example, if a patient is allergic to a flavoring agent, such as cinnamic aldehyde, all oral care products used by the patient should be flavor free, as listed previously. Similarly, if a patient is sensitive to balsam of Peru, they should also consider avoiding foods containing the components of balsam of Peru or their crossreactors as follows: Products that contain citrus fruits (oranges, lemons, grapefruit, bitter oranges, tangerines, and mandarin oranges), such as marmalade, juices, and bakery goods Flavoring agents, such as those found in Danish pastries and other bakery goods, candy, and chewing gum
Evaluation plan Successful treatment of a sore mouth is dependent on the history and physical examination, but a definitive diagnosis of contact stomatitis generally requires patch testing. Blood tests and tissue biopsy may help confirm the diagnosis or rule out other causes. Often, simplification of oral care and avoidance of common contactants is used as an initial therapeutic trial before proceeding to diagnostic testing. Contact stomatitis can have multiple physical examination and histologic findings (see Table 1). If lesions are present on physical examination, consideration should be given to proceed directly to obtain a biopsy. Histologically, spongiosis and a mixed cellular infiltrate of lymphocytes, macrophages, and eosinophils characterize allergic contact stomatitis. Chronic lesions can show epidermal hyperplasia. Biopsy with or without direct immunofluorescence testing can be helpful in ruling out other processes, such as immunobullous diseases or neoplasm. If no obvious lesions are present in a patient complaining of a sore mouth, laboratory blood tests are usually pursued first, followed by patch testing. Commercially available patch test kits, such as T.R.U.E test, screen for 23 antigens that commonly cause contact dermatitis. Although this kit screens for several common relevant causes of contact stomatitis, such as balsam of Peru, fragrance mix, paraben mix, and thimerosal, a number of potential causes can be missed. The authors recommend testing to broad standard, metal, and oral flavoring and preservative series (see Table 3) for all patients with mouth complaints in whom contact stomatitis is considered. Additionally, given the potential late reactions that can occur with metal patch testing, readings should be performed on day 7 in addition to the traditional readings performed on days 3 and 5 [5,6].
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Spices, such as cinnamon, cloves, vanilla, curry, allspice, anise, and ginger Spicy condiments, such as ketchup, chili sauce, barbecue sauce, chutney, and liver paste Pickles and pickled vegetables Wine, beer, gin, and vermouth Perfumed or flavored tea and tobacco, such as mentholated tobacco products Chocolate Ice cream Cola and other spiced soft drinks Chili, pizza, Italian, and Mexican foods with red sauces Caramels Tomatoes and tomato-containing products In addition, restaurant meals where these ingredients cannot be identified should also be avoided. In a patient with contact stomatitis, the number of positive metal patch tests is not necessarily predictive of relevance. Positive reactions to two formulations of gold may potentially be irrelevant, whereas a 1+ reaction to a single formulation of mercury may be significant. Indeed, several clinical factors must be considered to determine the relevance of the patch tests. For instance, avoidance therapy regarding dental metals can represent a straightforward management issue if the patient is allergic to two forms of gold, has only one oral lesion immediately adjacent to a solitary gold-colored filling, and the lesion developed within several months of the placement of the dental restoration. In this scenario, the evidence strongly supports relevance of the positive patch test and the patient only needs to have a single restoration replaced with a gold-free substitute. The clinician is faced with a greater challenge, however, in a patient who has a 1+ reaction to a single formulation of mercury; multiple silver-colored restorations; and erosions primarily, but not exclusively, adjacent to the intraoral mercury. In this case, several options should be considered: retest to the mercury formulations making sure that a final reading is done no earlier than day 7; patch test to a sample of the patients own silver-colored dental restoration; use topical immunomodulators as a diagnostic and therapeutic trial; and discuss with the patient the fact that the reaction may be relevant, but that costly and timeconsuming restoration removal may or may not result in significant improvement. Avoidance of identified antigens is not always possible and topical immunomodulators are regularly used. For example, a patient may unwittingly eat Mexican food without realizing that it was prepared with cinnamon. Similarly, a patient with
a mercury allergy may not have the opportunity for mercury dental restoration removal immediately. Fluocinonide 0.05 gel or tacrolimus 0.1% ointment are useful adjunctive therapies in these situations, particularly because they can be applied with relative ease to broad areas of the oral mucosa. Triamcinolone in a dental paste, such as Orabase, is best reserved for patients with only localized disease. Miracle Mouthwashes, of which many variants exist, are often used empirically at the outset of a sore mouth evaluation because they usually contain various anti-inflammatory and antiinfective drugs (eg, diphenhydramine, hydrocortisone, nystatin, and tetracycline). These formulations, however, are best avoided in a patient with proved flavoring allergies because the syrup base usually has flavorings.
References
[1] Rietschel RL, Fowler JF. Contact stomatitis and cheilitis. In: Rietschel RL, Fowler JF, editors. Contact dermatitis. 5th edition. Philadelphia: Lippincott Williams and Wilkins; 2001. p. 663 86. [2] Tosti A, Piraccini BM, Peluso AM. Contact and irritant stomatitis. Semin Cutan Med Surg 1997;16:314 9. [3] Perry HO. Idiopathic gingivostomatitis. Dermatol Clin 1987;5:719 22. [4] Camisa C, Taylor J, Bernat J, Helm T. Contact hypersensitivity to mercury in amalgam restorations may mimic oral lichen planus. Cutis 1999;63:189 92. [5] Koch P, Bahmer FA. Oral lesions and symptoms related to metals used in dental restorations: a clinical, allergological, and histologic study. J Am Acad Dermatol 1999;41:422 30. [6] Yiannias JA, el-Azhary RA, Hand JH, Pakzad SY, Rogers RS. Relevant contact sensitivities in patients with the diagnosis of oral lichen planus. J Am Acad Dermatol 2000;42:177 82. [7] Drage LA, Rogers III RS. Clinical assessment and outcome in 70 patients with complaints of burning or sore mouth symptoms. Mayo Clin Proc 1999;74:223 8. [8] Dutree-Meulenberg RO, Kozel M, van Joost T. Burning mouth syndrome: a possible etiologic role for local contact hypersensitivity. J Am Acad Dermatol 1992; 26:935 40. [9] Kaaber S, Thulin H, Nielsen E. Skin sensitivity to denture base materials in the burning mouth syndrome. Contact Dermatitis 1979;5:90 6. [10] Davis C, Squier C, Lilly G. Irritant contact stomatitis: a review of the condition. J Periodontol 1998;69: 620 31. [11] Fisher AA. Contact stomatitis. Dermatol Clin 1987;5: 709 17. [12] Wohrl S, Hemmer W, Focke M, Gotz M, Jarisch R. The significance of fragrance mix, balsam of Peru,
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B.W. LeSueur, J.A. Yiannias / Dermatol Clin 21 (2003) 105114 colophony and propolis as screening tools in the detection of fragrance allergy. Br J Dermatol 2001;145: 268 73. Kanerva L, Rantanen T, Aalto-Korte K, Estlander T, Hannuksela M, Harvima RJ. A multicenter study of patch test reactions with dental screening series. Am J Contact Dermatitis 2001;12:83 7. Little MC, Watson REB, Pemberton MN, Griffiths CEM, Thornhill MH. Activation of oral keratinocytes by mercuric chloride: relevance to dental amalgam-induced oral lichenoid reactions. Br J Dermatol 2001;144:1024 32. Fowler JF, et al. Gold allergy in North America. Am J Contact Dermat 2001;12:3 5. Marcusson JA. Contact allergies to nickel sulfate, gold sodium thiosulfate and palladium chloride in patients claiming side-effects from dental alloy components. Contact Dermatitis 1996;34:320 3. Fowler JF. Gold. Am J Contact Dermat 2001;12:1 2. [18] Dawn G, Gupta G, Forsyth A. The role of nickel in oral disease. Contact Dermatitis 2000;43:228 9. [19] Spiechowicz E, Glantz PO, Axell T, Grochowski P. A long-term follow-up of allergy to nickel among fixed prostheses wearers. Eur J Prosthodont Restor Dent 1999;7:41 4. [20] Aberer W, Holum H, Strohal R, Slavicek R. Palladium in dental alloysthe dermatologists responsibility to warn? Contact Dermatitis 1993;28:163 5. [21] Koch P, Baum H. Contact stomatitis due to palladium and platinum in dental alloys. Contact Dermatitis 1996; 34:253 7. [22] Fisher AA. Allergic sensitisation of the skin and oral mucosa to acrylic denture materials. JAMA 1954;156: 238 42. [23] Koutis D, Freeman S. Allergic contact stomatitis caused by acrylic monomer in a denture. Australas J Dermatol 2001;42:203 6.
[13]
[14]
[15] [16]
[17]
Dermatol Clin 21 (2003) 115 122
Denture sore mouth

Leo I. Kupp, DDS, PhD*, Phillip J. Sheridan, DDS, MS
Department of Dental Specialties, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
There are few dental rehabilitative options for edentulous patients, of which the soft tissue supported complete denture is the most common. In general, patients accept the fact that dentures are a poor substitute for natural teeth; consequently, they tend to tolerate discomfort and inefficient chewing. Quite often additional alveolar ridge resorption results from years of denture wearing, and unless the patient is willing to follow up with a dentist in a consistent and timely manner, ridge resorption can continue and mucosal problems can exacerbate. This article discusses the causes of common inflammatory disorders associated with denture wearing, namely denture sore mouth (DSM) and other related mucosal problems associated with the long-term denture patient. There are additional circumstances that contribute to problems associated with the fabrication and wearing of complete dentures. Denture patients are generally in their fourth through sixth decades of life and many have significant health problems. The side effects of many medications can contribute to decreased saliva production, which complicates denture wearing. Strokes can prevent normal jaw movement and mastication, and other debilitating diseases can decrease the patients oral function and ability to tolerate dentures. The patients demands and attitudes can also be responsible for denture problems; for example, some patients tend to have unrealistic expectations of what dentures can do. For many patients, the process of becoming edentulous and obtaining complete dentures is a troubling experience. These patients quite often have had lifelong dental problems and many of their experiences have been unpleasant. Even with the limitations
of complete dentures, it is still possible to deliver excellent denture services for edentulous patients. If the patient is compliant with professional treatment suggestions and the long-term commitment of daily denture maintenance, problems related to denture sores can be minimized. One of the main reasons for ill-fitting dentures and the subsequent problems especially for those patients that do not have regular dental visitsis the continuing resorption of the edentulous alveolar ridge. Therefore, a short discussion of ridge resorption may help clarify the nature of the denture-related problems outlined in this article.
Ridge resorption Progressive ridge resorption is one of the main causes of the loss of stability and retention of complete dentures. Ridge resorption is reported to be very rapid during the first year after extraction of teeth and continues progressively throughout the patients life. There is a large interindividual difference in the rate of resorption, which may be influenced by several nutritional and physiologic factors. Nahri et al [1] recently found that the amount of residual ridge resorption was significantly correlated with the number of years females were edentulous; however, this was not true in males. Ridge resorption was also found to increase after menopause; therefore, denture stability problems are more often associated with female patients. DSM complaints generally begin between the ages of 40 and 60 years (mean: 49 years). In most patients, complaints begin with the first prosthesis, and DSM appears to occur mainly in women. It is clear that factors such as osteoporosis may predispose female patients to increased alveolar bone loss and denturerelated problems.
* Corresponding author. E-mail address: kupp.leo@mayo.edu (L. Kupp).
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In the same study [1], the authors noted that 34% of edentulous patients needed additional dental treatment. The most common complaints were soreness in the denture-bearing mucosa (one third of the subjects) and fair or poor chewing ability (another third). Those patients who had lost more than 50% of supporting bone reported a need for dental treatment more often than those whose bone loss was less than 50%. Painful denture-bearing tissues and poor chewing ability was also more often reported by subjects with more extensive bone loss. In general, denture complaints increased with increased residual ridge resorption. Some patients resort to the use of commercial denture adhesives or self-reline materials to hold their dentures more securely in position; however, these products may actually increase the amount of soreness and inflammation of the oral tissues. Patients should have their dentures professionally relined or rebased to fit the changing denture-bearing area. The retention and stability of complete dentures is significantly improved if the denture-supporting area can be increased. Over the years there have been several surgical procedures to augment residual ridges using various osseous graft materials. The use of synthetic particulate hydroxyapatite to increase the denture-bearing area, especially in the mandibular arch, has been attempted. Generally, the results have not been encouraging, and the use of particulate graft materials is no longer advocated. More recently, manufacturers have encapsulated hydroxyapatite particles in a biologically inert mesh that prevents the particles from migrating. This mesh has been used to augment vertical height to resorbed ridges. Other surgical techniques using the patients ribs or other extra-oral bony sites have been used to augment and rebuild resorbed jaws. Quite often there is significant resorption of the grafted tissues, but the ideal graft material to achieve vertical ridge height is still not available. Currently, the most predictable way to provide support or retention for complete dentures in patients with severely resorbed jaws is to use dental implants. Titanium dental implants have been used successfully to support complete dentures and can be used to hold the dentures in place with a variety of retentive measures. The patient may also be able to have three to six implants placed in an arch and thereby have the complete denture screwed into the implant as a rigidly fixed prosthesis. Patients with severely resorbed alveolar ridges have found this to be very well tolerated, and function is increased significantly over a nonsupported denture prosthesis.
The use of dental implants enables patients who were wearing removable, soft tissue born prostheses to have a fixed or markedly improved removable prosthetic replacement supported by implants. This treatment restores function to the extent that it resembles that of natural teeth, though there may be continuing soft tissue problems in a noncompliant patient.
DSM (denture stomatitis) DSM is the most frequent diagnosis associated with denture wearers and is used for those patients whose subjective symptoms continue to exist after a period of 6 to 8 weeks. The term DSM is used to describe the pathologic changes that occur in the mucosa of the denture-bearing surfaces. Patients may complain of burning sensations, soreness, rawness, and dryness where the oral mucosa comes in contact with the dentures. Objective symptoms may also exist. The region covered by the denture is usually velvety red and swollen (Fig. 1). The tongue may also become erythematous and swollen. Salivation may be disturbed and blisters may develop. Studies have reported an 11% to 67% incidence of DSM in denture-wearing patients, whether wearing complete or removable partial dentures [2 4]. A major cause of DSM is tissue trauma from illfitting dentures, which predisposes the patient to oral fungal infection by Candida albicans. Another source of inflammation is an allergic response to some component to the denture base material. Although allergic responses to denture acrylics is uncommon, there is a female predilection. In a report by Fisher [5], 19 of 24 patients with allergic reactions to denture materials were female. Treatment consists of a good oral and denture hygiene regimen accompanied by a period of rest for the tissues that support the denture daily. Tissue rest is simply achieved by removing the denture for a period of time, or with the application of tissue conditioners to the denture base. Generally, DSM is complicated by a fungal infection of C albicans. Russotto [6] found that most denture patients (93.3%) presented with local or systemic factors that predisposed the oral cavity to proliferation of C albicans. In their study, there was a strong correlation between DSM and angular cheilosis. Approximately 83% of the experimental group wore either removable partial or complete dentures and complained of soreness in the tissues contacting the denture base. Examination of the patients in this study revealed findings compatible with DSM or
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Fig. 1. Typical presentation of denture sore mouth. The patient wears a removable partial denture in the maxillary arch and presents with red, swollen tissues that relate directly to the denture contact area.
chronic candidiasis. The conclusion was that the incidence of chronic C albicans infection is greater than previously believed. Angular cheilosis and DSM are often found together; the cause of both lesions is C albicans. Several histological studies have evaluated differences in the palatal soft tissues associated with denture wearing. In a study comparing palatal biopsies obtained from denture-wearing patients without DSM and nondenture wearers, the investigators found a mitotic index that was three times higher in denture wearers than in nondenture wearers [7]. Therefore, normal denture wearing is related to higher cellular activity and turnover. In addition, there is also reduced keratin density in the stratum granulosum and a flattening of the epithelial connective tissue interface after a considerable period of denture wearing. Van Mens et al [8] studied the histologic features of the palatal mucosa in DSM patients. All patients had worn their dentures for approximately 4 years. Palatal biopsies were obtained from DSM and healthy denture-wearing patients. The authors noted that the mean thickness of the epithelium did not change between the DSM and control group. The mitotic index in denture-bearing epithelium from patients suffering with DSM was three times lower than in the epithelium of the normal denture wearers. The patients suffering from DSM showed a lower mitotic index but displayed a relatively high number of Langerhans cells. Therefore, epithelial cell proliferation appears to be diminished at the same time an active immune response is occurring, as indicated by the presence of the Langerhans antigen-presenting cells.
Traumatic ulcers Traumatic ulcers are sore spots on the oral mucosa that occur when the denture base does not accurately conform to the anatomy of the residual ridge. Other causes include residual spicules of bone, root fragments, a rough inner surface of the denture, and uneven distribution of the forces exerted during the chewing cycle over the mucosal tissues. Clinically, ulcers appear as small, painful, irregularly shaped lesions occasionally covered by necrotic epithelium and are usually surrounded by an inflammatory, erythematous halo. Differential diagnosis for traumatic ulcer must include recurrent herpetic stomatitis and aphthous ulcers. The treatment consists of recontouring the denture base or the ridge anatomy. Sore spots associated with entrapment of food particles will disappear within several days, but soreness related to denture or ridge problems or excessive function will persist despite good oral hygiene efforts by the patient and requires professional dental evaluation.
Candidiasis Candidiasis is the most common fungal infection of the oral cavity, and it may manifest itself in several ways. The typical lesions (subacute form) appear as grayish-white patches that vary in size, shape, and distribution. The plaque-like area is composed of necrotic epithelial cells and C albicans organisms that can be wiped away with a cotton sponge. This form of the disease is easily recognized, diagnosed, and treated with antifungal agents. The chronic form of Candida infection is much more difficult to
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recognize or diagnose clinically because it resembles other soft tissue diseases, especially the oral lesions seen in individuals with malnutrition or allergic responses. In the past, oral candidiasis was considered to be the result of a serious systemic abnormality, except in pregnancy or early infancy. Often, an infection of the oral cavity by C albicans is the first sign of an underlying systemic disorder, therefore an accurate medical history is important. Candidiasis can also result from antibiotic treatment, or treatment with immunosuppressant drugs. In cases in which no history of debilitating disease can be elicited and the patient denies any history of prolonged use of antibiotics or immunosuppressant drugs, local factors such as ill-fitting dentures should be considered as the possible cause of oral candidiasis. Denture-related chronic candidiasis is often treated with nystatin oral (Mycostatin) suspension or creams. Clotrimazole troches (Mycelex troches) have been used with good success. Systemic medications such as fluconazole (Diflucan) are also very effective.
Early studies concluded that angular cheilosis was associated with nutritional deficiencies or reduction of the normal intermaxillary distance. These studies indicated that certain nutritional deficiencies or the loss of vertical dimension of occlusion were the primary causes of angular cheilosis, and only a few studies implicated microorganisms. Later studies demonstrated an association between angular cheilosis and C albicans; however, C albicans was still believed to be of secondary importance. Bacterial infection with staphylococcal organisms can also be a cause of angular cheilosis. Indeed, angular cheilosis is often multifactorial. More recently, Russotto [6] found a 100% correlation between angular cheilosis and the detection of C albicans. Many authors have reported angular cheilosis resulting from intraoral C albicans infection associated with DSM. Cawson [9] and Bodtz-Jorgensen [10] also reported that C albicans infection of the tongue was commonly associated with DSM.
Angular cheilosis Angular cheilosis is a nonspecific term that applies to all inflammatory reactions, erosions, ulcerations, and lesions at the corners or angles of the mouth. The lesions generally begin at the corners of the lips and extend onto the skin, following the skin folds (Fig. 2). Most angular cheilosis lesions reveal their inflammatory nature by being intensely red, fissured, or ulcerated. Others are crusted in the varying colors from pale yellow to dark brown. Generally, the lesions are accompanied by subjective symptoms of burning, tenderness, soreness, or pain.
Fibrous inflammatory hyperplasia (epulis fissuratum) Denture-induced fibrous inflammatory hyperplasia occurs around the borders or flanges of an illfitting complete denture. Initially, there may be a small ulcer, but as the flange continues to irritate the tissue, an inflammatory lesion develops. It is often described as being a raised, sessile lesion that may be single or multiple, and is composed of an altered epithelium overlying hypertrophic connective tissue resulting from the trauma and inflammation caused by the presence of the flange (Figs. 3, 4). It is often asymptomatic and may be limited to tissues around
Fig. 2. Angular cheilosis seen at both corners of the lips of a patient wearing a maxillary complete denture.
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Fig. 3. Fibrous inflammatory hyperplasia in a patient a complete mandibular denture. There are two large hyperplastic tissue folds in front of the thin residual mandibular alveolar ridge.
the borders of the dentures. The light microscopic appearance of biopsies from the lesion has been discussed by Cutright [11]. In most lesions, hyperkeratotic epithelium alternates with parakeratosis or orthokeratosis. The spinous layer of viable cells is usually acanthotic but can be normal or atrophic in places. The basal layer of proliferative cells may be hyperplastic (up to four cell layers thick) or may display the complex rete ridge pattern known as pseudoepitheliomatous hyperplasia. The connective tissue of the lamina propria is usually grossly thickened and displays many areas of chronic inflammation, coexisting with dense fibrosis. Fibrous inflammatory hyperplasia predominantly affects females at a proportion of 5:1 [12]. The explanation for the frequency of fibrous inflammatory hyperplasia among females is not well understood
and is possibly a result of the fact that female patients wear their dentures for longer periods each day. Another possible mechanism may be related to hormonal influences. During or after menopause, there is atrophy of the mucosa of the oral cavity, concomitant with decreased ovarian secretion. The thin, atrophic oral epithelium offers less protection against irritation, and may be more prone to develop an inflammatory reaction as a result of chronic trauma. Usually, the greatest proportion of patients with fibrous inflammatory hyperplasia is in their fifth and sixth decades of life. Some studies have reported the frequency of all denture-related lesions increasing with patient age, length of denture use, and have found the mean length of denture use was 8.7 years in patients with fibrous inflammatory hyperplasia. The useful life of a
Fig. 4. Patient in Fig. 3 with the mandibular complete denture in place. Notice how the denture flange rests between the two folds of fibrous tissue and does not contact the bony (alveolar) ridge.
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Fig. 5. Inflammatory papillary hyperplasia of the hard palate. The soft tissue of the hard palate is covered with hyperplastic epithelium with a nodular or pebbly appearance. Tissues are highly inflamed and bleed easily when palpated.
complete denture is about 5 years. The presence of fibrous inflammatory hyperplasia is due to the extended period of denture wearing without relining or modification resulting in an overextended denture periphery because of ridge resorption. Fibrous inflammatory hyperplasia is considered to be benign in nature. However, sites of chronic irritation may be predisposed to the development of squamous cell carcinoma, and neoplastic changes have been reported. Hobaek [13] studied the relationship of chronic irritation by an ill-fitting complete or partial denture in the development of cancer. He reported on 560 cases of oral cancer and verified that 204 patients were denture patients and in 86 of these patients there was a relationship between cancer and irritation caused by dentures. He suggested that the possibility of a direct transition to carcinoma from
fibrous inflammatory hyperplasia cannot be excluded. The irritant effect of the denture base materials and the tissue changes in these patients should be thoroughly evaluated.
Inflammatory papillary hyperplasia Inflammatory papillary hyperplasia is a benign, persistent, and usually painless lesion of the oral mucosa that is the result of epithelial proliferation (Figs. 5 7). Inflammatory papillary hyperplasia is generally observed on the hard palate and is a nonneoplastic lesion characterized histologically by significant epithelial hyperplasia and an inflammatory infiltrate usually in response to trauma and C albicans infection.
Fig. 6. The poorly fitting maxillary partial denture of the patient in Fig. 5. The partial denture is providing inadequate function for the patient and the patient requires a new denture.
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Fig. 7. Inflammatory papillary hyperplasia of the maxillary alveolar ridge. Notice the extreme pebbly appearance of the tissues, which bleed profusely when manipulated.
Kaplan et al [14] examined the p53 antigen and the proliferative cell nuclear antigen (PCNA) in biopsies from denture wearers and controls. Both p53 and PCNA are cell-cycle regulators and may reflect malignant transformation. All cultures from both the palatal mucosa and dentures were positive for C albicans. The epithelial width and inflammatory infiltrate were significantly higher in inflammatory papillary hyperplasia than in controls. In addition, a threefold increase in positively stained cells for p53 and a twofold increase in positively stained cells for PCNA were seen in inflammatory papillary hyperplasia compared with controls. The authors concluded that a significant increase in the immunodetection of p53 and PCNA may indicate a malignant potential, but inflammatory papillary hyperplasia has never been reported to undergo malignant transformation, and there were no cytologic signs of dysplasia. Treatment of inflammatory papillary hyperplasia consists of surgical excision of the hyperplastic tissue followed by rebasing or remaking the denture.
asked about the fit and comfort of their dentures, and referred to their dental health care team for appropriate follow-up when required.
References
[1] Narhi TO, Ettinger RL, Lam EWM. Radiographic findings, ridge resorption, and subjective complaints of complete denture patients. International Journal of Prosthodontics 1997;10:183 9. [2] Cawson RA. Chronic oral candidiasis and leukoplakia. Oral Surg 1966;22:582 91. [3] Nater JP, Groenman NH, Wakkers-Garritsen BG, Timmer LH. Etiologic factors in denture sore mouth syndrome. J Prosthet Dent 1978;40:367 73. [4] Newton AV. Denture-sore mouth. Br Dent J 1962; 112:357. [5] Fisher AA. Allergic sensitization of the skin and oral mucosa to acrylic denture materials. JAMA 1954; 156:238. [6] Russotto B. Role of Candida albicans in the pathogenesis of angular cheilosis. J Prosthet Dent 1980;44: 243 6. [7] Van Mens PR, Pinkse-Veen MJ, James J. Histologic features of the palatal mucosa in denture sore mouth. Journal of Oral Rehabilitation 1975;2:273 80. [8] Van Mens PR, James J. The Langerhans cell density of palatal epithelium in denture and non-denture wearers, as correlated with other parameters of the palatal mucosa. Journal of Oral Rehabilitation 1979;6(4):337 44. [9] Cawson RA. Symposium on denture sore mouth. II. The role of Candida. Dental Practitioner and Dental Record 1965;16(4):138 42. [10] Budtz-Jorgensen E. The significance of Candida albicans in denture stomatitis. Scand J Dent Res 1974;82: 151 90.
Summary The majority of the lesions associated with DSM are preventable and can be managed successfully by the dental professional. The hyperplastic tissue response seen in denture wearing patients generally requires surgical excision and follow-up. Health care providers should be encouraged to ask patients to remove their prostheses during a thorough examination of the oral tissues. In addition, patients should be
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L.I. Kupp, P.J. Sheridan / Dermatol Clin 21 (2003) 115122 [13] Hobaek A. Dental prostheses and intraoral epidermoid carcinoma. Acta Radiol 1949;32:259 75. [14] Kaplan I, Vered M, Moskona D, Buchner A, Dayan D. An immunohistochemical study of p53 and PCNA in inflammatory papillary hyperplasia of the palate: a dilemma of interpretation. Oral Dis 1998;4:194 9.
[11] Cutright DE. The histopathologic findings in 583 cases of epulis fissuratum. Oral Surgery 1974;37:401 11. [12] Coelho CMP, Zucoloto S, Lopes RA. Dentureinduced fibrous inflammatory hyperplasia: a retrospective study in a school of dentistry. International Journal of Prosthodontics 2000;13:148 51.
Dermatol Clin 21 (2003) 123 134
Glossitis and other tongue disorders

Julie A. Byrd, MD, Alison J. Bruce, MD*, Roy S. Rogers III, MD
Department of Dermatology, Mayo Clinic, 200 First Street South West, Rochester, MN 55905, USA
The tongue can often provide clinical clues to systemic conditions and demonstrate a number of conditions unrelated to other systemic disease. Because it is visible to patients easily, they may present for evaluation of a variety of incidentally noted disorders. Understanding normal anatomy and architecture and reassuring patients is often all that is necessary. When tongue abnormalities are present, however, recognizing them as benign or associated with other disease is a valuable clinical skill. Examination of the tongue and oral mucosa is an essential part of a physical examination. Clinicians need to recognize and know a spectrum of disorders affecting the tongue. This article reviews a number of tongue conditions encountered including furred tongue, black hairy tongue, smooth tongue, fissured tongue, median rhomboid glossitis, geographic tongue, sublingual varices, oral hairy leukoplakia (OHL), herpetic geometric glossitis, and macroglossia.
Anatomy The tongue is a muscular organ necessary for speech, taste, food manipulation, and mastication. It is composed largely of skeletal muscle. The intricate movements of the tongue are made possible by a complex arrangement of intersecting muscles in multiple directions. The hypoglossal (XII) nerve supplies motor innervation to these muscles. On the dorsum, the tongue is divided centrally by the median sulcus. The median sulcus begins proximal to the apex of the tongue and ends at the foramen cecum, which is the embryonic origin of
* Corresponding author. E-mail address: bruce.alison@mayo.edu (A.J. Bruce).
the thyroid gland. The foramen cecum forms the apex of a V-shaped groove known as the sulcus terminalis, which divides the anterior two thirds from the posterior one third of the dorsal tongue (Fig. 1). The anterior portion embryologically develops from the first branchial arch and is innervated by a branch of the VII nerve, the corda tympani. The posterior third of the tongue develops from the second and third brachial arch and is supplied by the glossopharyngeal (IX) nerve. The posterior portion is known as the base or root of the tongue. The distinctive texture and appearance of the dorsal tongue are caused by papillae, which are adapted for mastication and taste. Three types of papillae are present on the anterior two thirds of the tongue serving differing functions. The filiform papillae are the most prevalent papillae uniformly distributed on the dorsum. They are 1- to 2-mm thin papillae without taste buds. The pointed filiform papillae morphologically provide the rough texture and facilitate mechanical function of licking and mastication. The fungiform papillae are scattered on the anterior tongue, mostly on the tip and lateral margins. Clinically they are identified by their red color and dome or mushroom shape. The circumvallates are the largest papillae (3 to 10 mm) but the least prevalent. They are present in a single row distal and parallel to the sulcus terminalis. Both the fungiform and circumvallate papillae have taste buds. The posterior tongue lacks papillae and is composed of the lingual tonsils, lymphoid tissue, and mucin secretory glands covered by a thin mucosal epithelium. The ventral tongue contains the lingual frenulum, lingual veins, and the submandibular glandular ducts. The frenulum attaches the ventral tongue to the floor of the mouth extending from the ventral tongue tip to
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Fig. 2. Protrusion of the tongue to one side to enable adequate examination of the lateral margin. Using a tongue blade to retract the cheek allows better visualization.
Fig. 1. Anatomy of the dorsal tongue.
the mid-mandible. The lingual veins and submandibular ducts run parallel to the frenulum.
Physical examination A thorough examination of the tongue is an integral part of the physical examination and may provide clues to systemic disorders [1]. Good lighting, preferably with natural light or a hand-held light, is important for adequate examination. A systematic approach to the examination, beginning with inspection of all aspects of the tongue (dorsum, lateral margins, and ventral surface) and concluding with palpation of the entire surface from the tip proximally, provides a thorough and complete examination. Initially note the shape and color of the tongue as it rests in the mouth. The presence of notching on the lateral margins of the tongue (also known as a scalloped tongue) is indicative of macroglossia or a tongue thrusting habit, because the pressure from the teeth on the tongue creates the notches. The normal tongue is pink in color and the papillae easily visualized. Many conditions present with alterations in color or texture of the tongue and clinicians should be familiar with normal appearance to appreciate best changes to normal architecture. Protrusion of the tongue elicits any muscular or neurologic abnormalities, such as lateral deviation and fasciculations, and also allows for better visualization of the dorsal tongue. Next, inspect the lateral margins on the tongue by having the patient protrude
the tongue to one side enabling examination of the opposite lateral margin (Fig. 2). A tongue blade may be useful for better visualization. Have the patient elevate the tip of the tongue to the roof of the mouth to examine the ventral surface. Note any nodules or varicosities on the ventral tongue. Palpation of the entire tongue is a crucial part of the examination. Use gauze to grasp the tongue and allow manipulation. Particularly note the texture, consistency, and any tenderness of the tongue. Nodularity or masses within the tongue may be worrisome for cancer, and tender areas may raise concern for infection.
Furred tongue Clinical manifestations The furred tongue is a common benign condition caused by hypertrophy of the filiform papillae. Clin-
Fig. 3. Furred tongue. The white fur on the middle of the dorsal tongue is caused by hypertrophy and hyperplasia of the filiform papillae.
J.A. Byrd et al. / Dermatol Clin 21 (2003) 123134 Table 1 Furred tongue Clinical Etiology Predisposition Prognosis Diagnosis Treatment White coating of tongue Hypertrophy of filiform papillae Mouth breathing, dehydration, fever, or smoking Benign Clinical Brush tongue with dentifrice
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ically it presents as a complete or partial white coating of the anterior tongue giving the appearance of thin white fur for which the condition is named (Fig. 3, Table 1). The furring may vary in color from white to brown [2]. Particularly in smokers, the fur may take on a tan color. It typically involves the middle portion of the tongue, with other areas in the mouth unaffected. The filiform papillae become hypertrophied and hyperkeratotic because of a decreased rate of desquamation. The desquamated epithelial debris is trapped between the enlarged filiform papillae. The condition is seen commonly in otherwise healthy individuals who are smokers, mouth breathers, or with poor oral hygiene. Patients on a soft diet lacking roughage may also develop fur. In the ill patient, the furred tongue is usually caused by dehydration or fever. The furred tongue is usually asymptomatic, although halitosis can result from degeneration of food and other debris trapped within the plaque of fur. Diagnosis and treatment The diagnosis is based on clinical findings and biopsy is not necessary. Smoking cessation, rehydration, resolution of febrile illness, and correction of mouth breathing, respectively, are important management steps in otherwise well patients. Treatment includes increasing roughage and fiber in the diet to promote desquamation. Brushing the tongue with 5 to 15 strokes daily using a soft-bristled toothbrush and dentifrice is helpful.
Fig. 4. Black hairy tongue. The appearance of black hair of the tongue is created by filiform papillae hyperplasia with trapped normal flora and bacterial metabolic products.
filiform papillae are elongated with pointed ends and have a brown to black coating, appearing to be covered with a thick brown-black hair. This condition is caused by hyperplasia and hyperkeratosis of the filiform papillae. The dark color results from normal flora and bacteria that become trapped in the hyperplastic papillae. Because only the filiform papillae are affected, the characteristic brown-black discoloration occurs distal to the sulcus terminalis. Prevalence has been report as 3.4% of the population [3]. Most patients are asymptomatic but some experience halitosis, abnormal taste, or nausea presumably because of the elongated papillae. Similar to the furred tongue, smoking and poor oral hygiene have been implicated as causative. It may also develop following antibiotic treatment, typically penicillin and tetracycline [5]. The black pigment represents porphyrins, which are metabolic products of oral bacteria, most likely caused by alteration in the normal mouth flora as a consequence
Table 2 Black hairy tongue Clinical Etiology Brown-black coating of tongue Bacteria and pigmented metabolites trapped among hyperplastic filiform papillae Antibiotic use, smoking, or poor oral hygiene Benign Clinical Brush tongue with 1% 2% hydrogen peroxide
Black hairy tongue Clinical manifestations The black hairy tongue is also known as lingua villosa nigra and hyperkeratosis lingual. Patients present with a dark brown to black tongue, which also may appear hairy (Fig. 4, Table 2). As with the furred tongue, the involved area is usually the middle anterior two thirds of the dorsal tongue [3,4]. The
Predisposition Prognosis Diagnosis Treatment
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J.A. Byrd et al. / Dermatol Clin 21 (2003) 123134 Table 3 Smooth tongue Clinical Etiology Predisposition Prognosis Diagnosis Treatment Smooth glossy tongue Atrophy of filiform or fungiform papillae Systemic: nutritional deficiency, malabsorption, Riley-Day syndrome Varies with etiology History, examination, and laboratory work-up Correct underlying etiology, and bland diet
of antibiotic therapy. Long-term use of antacids and oxidizing mouthwashes has also been reported to cause black hairy tongue [4]. Chronic Pepto-Bismol use can produce a similar clinical picture. Diagnosis and treatment Biopsy is not necessary for diagnosis. Treatment involves brushing the tongue with 1% to 2% hydrogen peroxide. As with furred tongue, increasing roughage, correction of mouth breathing, and smoking cessation are important therapeutic interventions. Avoiding further antibiotics allows the normal flora to reconstitute, diminishing the prevalence of the pigment-producing microflora.
Smooth tongue Clinical manifestations The smooth tongue presents as a smooth glossy tongue (Fig. 5, Table 3). This condition is also known as bald tongue and atrophic glossitis. Patients usually complain of a burning sensation or painful tongue. On inspection, the tongue lacks the normal rough appearance created by the papillae. The background color may be red, pink, or magenta [2]. Biopsy shows atrophy of the filiform papillae accounting for the smooth appearance. With time fungiform papillae may also atrophy [6]. Diagnosis and treatment This condition is the manifestation of a systemic disorder, such as malabsorption or nutritional deficiencies of iron (anemia), folic acid, vitamin B12 (pernicious anemia), riboflavin, or niacin (pellagra).
Correction of the nutritional deficiency results in rapid regeneration of papillae. The smooth tongue can also be a manifestation of syphilis infection, amyloidosis, celiac disease, or cardiac failure. Sjo grens syndrome, Plummer-Vinson syndrome, and Riley-Day dysautonomia syndrome can present with smooth tongue. Riley-Day syndrome is an autosomal recessive hereditary sensory and autonomic neuropathy consisting of labile blood pressure, lack of deep tendon reflexes, decreased perception of temperature and pain, lack of tearing, and absence of filiform papillae [7,8]. This disorder is differentiated from the other sensory and autonomic neuropathies by the lack of filiform papillae. A thorough history, physical examination, and laboratory evaluation should be directed to detect systemic disease. Treatment involves correction of underlying systemic cause if possible. Symptomatic treatment with a soft bland diet is necessary because patients usually complain of a painful sore tongue.
Fissured tongue Clinical manifestations This condition is also called lingua plicata. Older terminology includes scrotal tongue. The authors discourage this descriptor. The condition presents as a central long deep groove on the dorsal tongue with multiple irregular side grooves (Fig. 6, Table 4). The fissures can occur elsewhere on the dorsal tongue, including the lateral margins. Papillae are present in the fissures up to a limited depth. In marked fissuring, the deeper portions may be without papillae contributing to bacterial overgrowth and inflammation [9]. The fissured tongue is normal with aging. It is the most common developmental defect of the tongue. Prevalence has been reported in dental studies to be 5% to 11.4% [3,10]. The fissures are typically asymptomatic unless inflamed because of trapped food debris, bacterial overgrowth, and low-grade infection.
Fig. 5. Smooth tongue. Atrophy of filiform papillae leaving the tongue with a smooth glossy appearance.
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patients, and unless the history suggests otherwise no additional evaluation is needed. The condition is diagnosed clinically. Patients should be reassured of its benign nature. Treatment involves brushing the tongue (5 to 15 strokes) with dentifrice and a soft bristled toothbrush after meals and before sleeping to prevent buildup of food debris and bacteria in the fissures, which can cause halitosis. If pain is a problem, a topical anesthetic, such as viscous lidocaine, can be applied before meals.
Median rhomboid glossitis Clinical manifestations Median rhomboid glossitis has also been termed chronic candidiasis and central papillary atrophy of the tongue. It is uncommon with a prevalence less than 1% [16]. Men are affected three times more often than women. The condition clinically appears as a rhomboid-shaped plaque in the central tongue with surface changes of hypertrophy or atrophy (Fig. 7, Table 5) [17,18]. Patients may complain of slight burning sensation on the tongue when eating spicy foods, although most are asymptomatic. On examination a flat or raised sharply circumscribed red to red-white patch is present on the midline of the tongue anterior to the foramen cecum. On palpation the tongue may feel normal or firm. The involved tongue surface is smooth. Histology reveals an absence of filiform papillae and dense chronic inflammation. Candidal organisms have been reported in a large number of cases [17,19].
Fig. 6. Fissured tongue. Deep fissures in the central tongue with multiple fissures branching off in an irregular pattern.
Diagnosis and treatment The fissured tongue has been associated with Down syndrome, acromegaly, Sjo grens syndrome, psoriasis, geographic tongue, and Melkersson-Rosenthal syndrome. Melkersson-Rosenthal syndrome is a rare entity characterized by relapsing orofacial edema (usually lower lip edema); facial nerve palsy; and severe fissuring of the tongue [11 15]. The fissured tongue is usually an incidental finding. It is a common condition, particularly in older
Table 4 Fissured tongue Clinical Etiology Associations Prognosis Diagnosis Treatment Central long deep groove with multiple irregular side grooves Developmental defect Age, Down syndrome, psoriasis, Melkersson-Rosenthal syndrome Benign Clinical Brush tongue with dentifrice to keep grooves clean
Fig. 7. Median rhomboid glossitis. The central tongue shows smooth, red to red-white plaque without filiform papillae.
128 Table 5 Median rhomboid glossitis Clinical Etiology Prognosis Diagnosis Treatment
Central rhomboid-shaped hyperkeratotic or erythematous plaque Chronic candidiasis; ?developmental anomaly Benign Viral culture, fungal smear, biopsy to exclude malignancy on occasion None; antifungals if symptomatic
The cause is unknown. Until recently, it was thought to be caused by congenital persistence of the tuberculum impar, although in general the changes are not present at birth. The tuberculum impar is visible when a fusion defect of the two lateral portions of the posterior tongue occurs. Lately, it has been associated with chronic Candida infection [17,19 21], with one author reporting 90% of patients with median rhomboid glossitis demonstrating candidal infection [21]. Characteristically the patients lack evidence of candidal infection on other mucosal surfaces in the mouth. Although the presence of Candida has been suggested to play an etiologic role, the mechanism is unclear. The development of the abnormality in adulthood, however, does argue against a congenital defect. Some clinicians or patients may be concerned about the possibility of oral cancer. If this is a significant concern, a biopsy to exclude squamous cell carcinoma may be indicated. Diagnosis and treatment The condition is benign with no specific systemic association. Fungal cultures or fungal smears may confirm the presence of Candida but are not essential for diagnosis, because the diagnosis is made clin-
ically. No treatment is necessary. Topical antifungals (nystatin suspension applied twice daily, or clotrimazole [Mycelex troches]) can result in temporary improvement but complete resolution is rare. When median rhomboid glossitis is found in association with palatal inflammation corresponding to contact with the involved area on the tongue, immunosuppression should be suspected [19]. This condition is called candidal infection of the tongue and nonspecific inflammation of the palate. It is considered a thumbprint of AIDS [4], so HIV status should be sought in these patients.
Geographic tongue Clinical manifestations Geographic tongue has multiple other names including benign migratory glossitis, erythema migrans, and glossitis areata migrans. Patients present with erythematous and white patches on the dorsum of the tongue (Fig. 8, Table 6). The red patches lack papillae and are atrophic, whereas the white areas have either normal or hypertrophied papillae. The patches are irregular and sharply demarcated resembling a map, hence the terminology. Patches may occur on the lateral margins or ventral tongue. Characteristically the plaques vary in location and shape hourly to daily. Prevalence ranges from 1% to 14.4%, affecting all age groups and females more often than males [4,9,10,16,22,23]. A familial history of this disorder may be present. This benign inflammatory disorder is usually asymptomatic unless fissures are present. Forty percent of patients with geographic tongue have fissured tongue [19]. When fissures are present pain may occur if they are inflamed. Diagnosis and treatment Diagnosis is usually made clinically by the typical appearance of the lesions and their migratory nature.
Table 6 Geographic tongue Clinical Etiology Predisposition Migratory erythematous and white patches on tongue Denuded papillae and hypertrophied papillae; disorder of keratinization Unknown, associated with psoriasis and atopy Benign Clinical Reassurance
Fig. 8. Geographic tongue. Erythematous areas of denuded papilla with surrounding white rim in an irregular pattern. Characteristically this pattern changes hourly to daily.
Prognosis Diagnosis Treatment
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Fig. 10. Subungual varices. Vascular dilatations of the ventral tongue and lateral margins. Fig. 9. Histopathology of the geographic tongue demonstrating acanthosis and hyperkeratosis of the epithelium with intraepithelial neutrophilia (Hematoxylin and eosin stain, original magnification 40).
On biopsy the erythematous patches are devoid of papillae and the white patches contain hypertrophied papillae. Some patients with a geographic tongue have a mucosal variant of pustular psoriasis. Histology reveals areas with absent granular layer, acanthosis, and subcorneal neutrophilic abscesses consistent with the features of pustular psoriasis (Fig. 9) [24]. Geographic tongue has been associated with atopy [25], although it can occur as an isolated abnormality. This is a self-limited disorder usually lasting several months to years. Treatment is reassurance. If patients are experiencing discomfort with spicy, sour, or salty foods these should be avoided. Palliative therapy with antiyeast treatment, topical corticosteroids, or topical analgesics may be helpful [23].
should be sure, however, to exclude hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). The lesions of this syndrome are small pinpoint telangiectatic mats that occasionally appear as 1- to 2-mm papules. Varices are generally larger, compressible papules and nodules. Blue rubber bleb nevus syndrome and the superior vena cava syndrome should also be considered in the differential but are usually excluded with a thorough clinical evaluation.
Oral hairy leukoplakia Clinical manifestations Oral hairy leukoplakia is the term used to describe a benign white lesion on the lateral margins of the tongue. It is traditionally seen in immunosuppressed patients infected with Epstein-Barr virus (EBV) [26]. OHL presents as a white linear hairy appearance on the lateral margin of the tongue or buccal mucosa (Fig. 11, Table 8). A thorough examination of the lateral margin is essential for diagnosis. Early lesions appear corrugated because there are white plaques on the ridges of the lateral tongue and erythematous mucosa in the troughs created by muscle attachments. With time the lesions become completely white. The white hyperkeratotic patches are adherent and do not scrape off with a tongue blade or gauze. These lesions
Table 7 Sublingual varices Clinical Etiology Predisposition Prognosis Diagnosis Treatment Blue ventral tongue varices Vascular dilatation Increasing age Benign Clinical None; reassurance
Sublingual varices Clinical manifestations Sublingual varices are benign vascular dilatations. Patients may note a discoloration of the ventral tongue (Fig. 10, Table 7). In this condition the lingual veins become dilated and tortuous, causing the blue nodularity on the ventral tongue. The varices are usually asymptomatic and incidentally noticed by the patient. Ten percent of the population over the age of 40 is affected. Diagnosis and treatment No clinical significance has been established. No treatment but reassurance is necessary. The clinician
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Fig. 11. Oral hairy leukoplakia. White corrugated plaques on lateral tongue that are not removable.
Fig. 12. Formalin fixed, parafin embedded tissue demonstrating Epstein-Barr virus infection in OHL using in situ hybridization (original magnification 60).
can become secondarily infected with Candida but even then the hyperkeratosis remains adherent. Histology reveals acanthosis, parakeratosis, and irregular projections of keratin [26,27]. Vacuolated keratinocytes are present in the spinous layer and EBV has been identified in these cells [28,29]. Oral hairy leukoplakia has been reported almost exclusively in immunodeficient patients. Originally it was believed only to affect homosexual HIV-positive men but OHL has been reported in other HIV patients and in patients with other causes of immunodeficiency, such as organ transplant recipients [30 33]. The lesions appear as HIV progresses, yet no association with decreasing CD4 counts has been observed [34]. More than one third of AIDS patients develop OHL, but the disorder is not limited to HIV patients. Other immunosuppressed patients may be affected, particularly renal and bone marrow transplant recipients [31,35,36]. Infection with EBV has been reported in the plaques of OHL [26,35]. In fact, it has been proposed that identification of EBV DNA by in situ polymerase chain reaction be used for diagnosis because in one study a 17% false-positive rate was found by using clinical criteria alone (Fig. 12) [37,38]. If OHL is found in patients without known immuno-
suppression, HIV testing and an evaluation for other immunosuppression states should be pursued. Diagnosis and treatment Diagnosis is made clinically with supportive histology and confirmation of EBV infection. OHL is usually asymptomatic and no treatment is necessary. Without treatment the lesions persist. Oral
Table 8 Oral hairy leukoplakia Clinical Adherent white hairy lesions on lateral tongue margin or buccal mucosa Epstein-Barr virus infection Immunosuppression Benign Clinical None, topical tretinoin, oral antivirals, antiretrovirals
Etiology Predisposition Prognosis Diagnosis Treatment
Fig. 13. Herpetic geometric glossitis. A tender shiny patch is located on the central tongue. Often they are in a geometric pattern, but as in this case not always.
J.A. Byrd et al. / Dermatol Clin 21 (2003) 123134 Table 9 Herpetic geometric glossitis Clinical Etiology Predisposition Prognosis Diagnosis Treatment Painful linear fissures Herpes simplex virus Immunosuppression Benign Viral culture, Tzanck smear, biopsy Oral antiviral therapy Table 10 Macroglossia Clinical Etiology Predisposition Prognosis Diagnosis Treatment
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Tongue proportionally larger than jaw Congenital or acquired Varies Varies History, examination, laboratory tests, and biopsy Depends on etiology
antivirals, topical tretinoin, and antiretrovirals can provide temporary remission. If secondarily infected with Candida, antifungal treatment may provide symptomatic relief.
Herpetic geometric glossitis Clinical manifestations Herpetic geometric glossitis is a recently described entity found in immunosuppressed patients with herpes simplex virus infection on the tongue [39]. Patients present with extremely tender linear fissures on the dorsal tongue. Often they have a striking geometric pattern with right angle radiation, but this is not consistently present (Fig. 13, Table 9). The lesions are found on the central tongue and notably herpetic lesions on other mucosal surfaces are absent. Diagnosis and treatment This condition has been reported only in immunocompromised hosts and is thought to be caused by chronic herpes simplex virus infection because the glossitis responds to treatment with oral antiviral therapy. Viral culture, Tzanck smear, or biopsy establishes diagnosis. With antiviral treatment herpetic
geometric glossitis usually resolves in 3 to 12 days [39]. Symptomatic treatment with a bland, soft diet and local anesthesia may be necessary until healing occurs. The condition may be recurrent. It usually responds to antiviral therapy after a recurrence.
Macroglossia Clinical manifestations Macroglossia is enlargement of the tongue out of proportion to the jaw size [4]. The condition may be congenital or acquired. On examination the tongue appears large within the mouth. The lateral margins are scalloped from the constant pressure of the teeth (Fig. 14, Table 10). If a few teeth are missing, the tongue may expand into the available space to produce a pseudotumor appearance. Hemorrhages may be evident if the enlargement is sufficient to interfere with talking or mastication such that tongue biting occurs. On palpation the tongue typically has a hard woody induration. Diagnosis and treatment Many associations exist including Down syndrome, amyloidosis, and hypothyroidism (Table 11).
Table 11 Causes of macroglossia Etiology Primary Tumors Diseases Down syndrome, or developmental Hemangioma, lymphangioma, neurofibroma, neurilemmoma, or thyroglossal duct cyst Actinomycosis, tuberculosis, histoplasmosis, or syphilis Hypothyroidism, acromegaly, multiple myeloma, or amyloidosis Angioedema, sarcoidosis, or superior vena cava syndrome
Infections Metabolic Fig. 14. Macroglossia. This enlarged tongue has a scalloped border. Other
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Fig. 15. Amyloidosis. (A) Smooth tongue with macroglossia. (B) Purpura on the arm on a patient with amyloidosis, demonstrating pinched purpura. (C) Histopathology of amyloidosis demonstrating amorphous eosinophilic fissured masses in lamina propria (hematoxylin and eosin, original magnification 10).
Amyloidosis may present with macroglossia and pinch purpura (purpura following trauma). Fig. 15 demonstrates the characteristic smooth tongue and associated purpura seen in patients with amyloidosis. Evaluation should be tailored to elicit the cause. Infection should be ruled out by taking fungal, bacterial, and mycobacterial cultures. Laboratory evaluation including a complete blood count, routine chemistry, thyroid-stimulating hormone, serum protein electrophoresis, urinary screen for Bence Jones
protein, work-up for myeloma, and serologic test for syphilis should be performed. Biopsy may be necessary for diagnosis. Treatment depends on the cause of the macroglossia.
Summary Patients frequently present complaining of tongue abnormalities. Knowledge of normal tongue ana-
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tomy and architecture enable the clinician to differentiate variations of normal from abnormal conditions. Many tongue conditions are benign and require reassurance and explanation, with little to no treatment. Others can signify systemic disorders. Examination of the tongue is an integral part of a complete physical examination. Recognizing the disorders of the tongue that are benign and do not require treatment or further evaluation prevents unnecessary testing for the patient. Careful evaluation of the tongue may provide valuable clues to a systemic disorder.
[15]
[16]
[17]
[18]
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[19] [1] Powell FC, Rogers III RS. A practical approach to oral lesions. Prim Care 1983;10:495 511. [2] Beaven DW, Brooks SE. Coatings of the tongue. In: Beaven DW, Brook SE, editors. Color atlas of the tongue in clinical diagnosis. Chicago: Year Book Medical Publishers; 1988. p. 73 86. [3] Darwazh AM, Pillai K. Prevalence of tongue lesions in 1013 Jordanian dental outpatients. Community Dent Oral Epidemiol 1993;21:323 4. [4] McNally MA, Langlais RP. Conditions peculiar to the tongue. Dermatol Clin 1996;12:257 72. [5] Wolfson SA. Black hairy tongue associated with penicillin treatment. JAMA 1949;140:1206 8. [6] Brightman VJ. Diseases of the tongue. In: Lynch MA, Brightman VJ, Greenberg MS, editors. Burkets oral medicine. 9th edition. Philadelphia: JB Lippincott; 1994. p. 257 73. [7] Johnson RH, Spalding JMK. Arterial hypertension. In: Johnson RH, Spaulding JMK, editors. Disorders of the autonomic nervous system. Philadelphia: FA Davis; 1974. p. 103 4. [8] Siddique N, Sufit R, Siddique T. Degenerative motor, sensory, and autonomic disorders. In: Goetz CG, Pappert EJ, editors. Goetz: textbook of clinical neurology. 1st edition. St. Louis: WB Saunders Company; 1999. p. 711 7. [9] Powell FC. Glossodynia and other disorders of the tongue. Dermatol Clin 1987;5:687 93. [10] Halperin V, Kolas S, Jefferis KR, et al. The occurrence of Fordyce spots, benign migratory glossitis, median rhomboid glossitis and fissured tongue in 2,478 dental patients. Oral Surg 1953;6:1072 7. [11] Alexander RW, James RB. Melkersson-Rosenthal syndrome: review of literature and report of a case. J Oral Surg 1972;30:599 604. [12] Greene RM, Rogers III RS. Melkersson-Rosenthal syndrome: a review of 36 patients. J Am Acad Dermatol 1989;21:1262 70. [13] Luscher E. Syndrome von Meldersson-Rosenthal. Schweiz Med Wochenschr 1949;79:1 3. [14] Rogers III RS. Melkersson-Rosenthal syndrome and
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J.A. Byrd et al. / Dermatol Clin 21 (2003) 123134 for immunosuppression. Dermatologica 1988;177: 126 8. Lifson AR, Hilton JF, Westenhouse JL, et al. Time from HIV seroconversion to oral candidosis or hairy leukoplakia among homosexual men enrolled in three prospective cohorts. AIDS 1994;8:73 9. Shiboski CH. Epidemiology of HIV-related oral manifestations in women: a review. Oral Dis 1997;3: S18 27. Samet JH, Muz P, Cabral P, Jhamb K, Suwanchinda A, Freedberg KA. Dermatologic manifestations in HIVinfected patients: a primary care perspective. Mayo Clin Proc 1999;74:658 60. Greenspan D, Greenspan JS, DeSuwza YG, et al. Oral hairy leukoplakia in an HIV-negative renal transplant recipient. J Oral Pathol Med 1989;18:32 4. [36] Syrjanen S, Laine P, Niemela M, et al. Oral hairy leukoplakia is not a specific sign of HIV-infection but related to immunosuppression in general. J Oral Pathol Med 1989;18:28 31. [37] Capple IL, Hamburger J. The significance of oral health in HIV disease. Sex Transm Infect 2000;76: 236 43. [38] Felix DH, Jalal H, Cubie HA, et al. Detection of Epstein-Barr virus and human papillomavirus type 1b DNA in hairy leukoplakia by in-situ hybridization and the polymerase chain reaction. J Oral Pathol Med 1993;22:277 81. [39] Grossman ME, Stevens AW, Cohen PR. Brief report: herpetic geometric glossitis. N Engl J Med 1993;329: 1859 60.
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Burning mouth syndrome

Lisa A. Drage, MD*, Roy S. Rogers III, MD
The burning mouth syndrome (BMS) is defined as a symptom complex of those patients with mouth pain who have a clinically normal oral mucosal examination. BMS is a diagnosis of exclusion. Many oral mucosal diseases present with mouth pain; a few examples include lichen planus, recurrent herpes simplex virus infections, and recurrent aphthous stomatitis. A thorough oral examination must be completed to exclude these and other oral diseases before diagnosing BMS. Synonyms for BMS have included glossodynia, glossopyrosis, glossalgia, stomatodynia, stomatopyrosis, sore tongue and mouth, burning tongue, oral or lingual paresthesia, and oral dysesthesia. Burning mouth syndrome is often stereotyped as a purely psychosomatic disorder occurring in postmenopausal women, which is resistant to therapy. Although BMS can be a diagnostic and therapeutic challenge, multiple studies have linked BMS to real organic and psychiatric disease and show an improvement in symptoms in about 70% of patients with directed therapy [1 6]. Faced with a patient who has BMS, dermatologists and other clinicians need to be familiar with its associations and management, and optimistic about potential outcome. The patient variably describes a burning, tingling, painful, hot, scalded, or numb sensation in the oral cavity. The magnitude of BMS pain is quantitatively similar to a toothache [7]. This sensation occurs most commonly on the anterior two thirds and tip of the tongue. Multiple oral sites may be involved. These may include the upper alveolar region, palate, lips, and lower alveolar region [1,2,5,6,8]. Less commonly
affected are the buccal mucosa, floor of the mouth, and the throat [4]. With prevalence in the general population of 3.7% [9], BMS affects women seven times more frequently than men [5]. It particularly affects the middle-aged and elderly population (mean age 60) [2,6,10] and has not been reported in children. The average duration of BMS is 2 to 3 years [2,11], with rare patients suffering for decades. Most BMS patients have consulted multiple dentists, physicians, and other health care providers for their complaint and may have tried a host of over-the-counter and prescription medications before their presentation [2,4]. Over half state they received insufficient information about BMS from their health care provider [12]. Burning mouth syndrome has been divided into three subtypes based on the daily variation of the symptoms (Table 1) [13]. Type 1 BMS (35%) is characterized by daily pain that is not present on awakening but progresses throughout the day with the greatest problems occurring in the evening hours. Type 2 BMS (55%) patients awake with a constant daily pain, whereas Type 3 BMS (10%) patients have intermittent pain with symptom-free intervals and the pain occurs in unusual sites, such as the buccal mucosa, floor of mouth, and throat. Nonpsychiatric factors have been linked with Type 1 BMS, chronic anxiety with Type 2, and food additives or flavoring allergies with Type 3 BMS. The patients with Type 2 BMS tend to be most resistant to therapy [13,14].
Associated factors Many conditions have been associated with BMS (Table 2) [2]. It should not be surprising that oral pain like any type of pain can have more than one cause. The four main categories are (1) systemic, (2) local,
* Corresponding author. E-mail address: drage.lisa@mayo.edu (L.A. Drage).
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Table 1 Lamey classification of subtypes of BMS [13] Clinical course Type 1 Type 2 Type 3 Daily pain, not present on awakening, increases throughout day Daily pain, constant Intermittent pain, unusual sites (buccal mucosa, floor of mouth) Association Nonpsychiatric Psychiatric, especially chronic anxiety Allergic contact stomatitis to flavorings, additives
From Lamey PJ, Lamb AB, Hughes A, et al. Type 3 burning mouth syndrome: psychological and allergic aspects. J Oral Pathol Med 1994;23:216 9; with permission.
(3) psychiatric or psychologic, and (4) idiopathic factors. The most common associations include psychiatric or psychologic disorders, xerostomia, nutritional deficiencies, allergic contact stomatitis, denture-related factors, parafunctional behavior, candidiasis, diabetes mellitus, and menopause or hormonal alterations [2]. Multifactorial In more than a third of patients, multiple, concurrent causes of BMS may be identified and need to be
Table 2 Reported etiologic agents of BMS [2] Systemic Deficiencies Iron Vitamin B12 Folate Zinc B complex vitamins Endocrine Diabetes mellitus Hypothyroidism Menopause or hormonal Xerostomia Connective tissue disease Sjo grens syndrome Sicca syndrome Drug-related Anxiety or stress Medication ACE inhibitor Esophageal reflux Anemia Local
addressed simultaneously to achieve the best outcome possible [1 5,12,15]. Psychiatric or psychologic disorders Psychiatric disease is a common underlying factor in patients with BMS. A psychiatric disease association has been reported in many series ranging from 19% to 85% [3 5,9,11,13 25]. At least one third of patients may have an underlying psychiatric diagnosis, most commonly depression or anxiety disorders [2]. A phobic concern regarding cancer is also
Psychogenic and psychiatric Psychiatric Depression Anxiety Obsessive compulsive disorder Somatoform disorder Cancerphobia Psychosocial stressors
Idiopathic
Denture factors Dental work Mechanical Oral habit or parafunctional behavior Clenching Bruxism Tongue thrusting Myofascial pain Allergic contact stomatitis Dental restoration or denture materials Foods Preservative, additives, flavorings Neurologic Referred from tonsils or teeth Lingual nerve neuropathy Glossopharyngeal neuropathy Acoustic neuroma Infection Candidiasis Antibiotic related Denture related Local trauma Corticosteroid Diabetes mellitus Fusospirochetal Xerostomia Irradiation Local disease
From Drage LA, Rogers RS III. Clinical assessment and outcome in 70 patients with complaints of burning or sore mouth symptoms. Mayo Clin Proc 1999;74:223 8; with permission.
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prominent in 20% of patients [5]. The BMS patient may be concerned that the symptoms are caused by oral or systemic cancer, although the patient rarely shares this concern spontaneously with the physician. Repeated self-examination may be a marker for cancerphobia [4]. Although BMS may be a somatic symptom of depression in some cases, the association does not always equate to a causal relationship. Depression and psychologic disturbance are common in chronic pain populations and may be secondary to chronic pain rather than the cause of BMS. Studies have reported similarities between the personality characteristics of chronic oral pain patients and other chronic pain populations [7]. Similar sleep disturbances have also been documented in these populations [8]. In addition, many of the medications used to treat psychiatric disease can cause xerostomia and exacerbate BMS. Although psychiatric disorders are clearly significant for some patients with BMS, it is important not to leap to the conclusion that all BMS is caused by psychiatric problems. Unfortunately, psychiatric causes are frequently postulated when no easy answer is apparent. Each patient with BMS should receive a careful evaluation for both psychiatric and organic causes of pain. This thorough examination may unveil a local or systemic cause for their symptomatology and is often therapeutic, reassuring the patient about concerns regarding oral cancer. During the evaluation, direct questions about depression, anxiety, and fear of cancer and a family history of psychiatric disorders or oral cancer should be posed. When warranted, further evaluation and documentation of psychiatric disease by psychiatric consultation should be sought. A team approach is important; psychiatric staff may not feel as comfortable confirming the diagnosis of BMS because they are less familiar with oral disease. Xerostomia A dry mouth is a frequent complaint among BMS patients and can be found in up to 25% [2,5,6] of patients with these complaints. Decreased oral lubrication may result in increased friction and discomfort leading to BMS (Fig. 1). Xerostomia itself can be multifactorial. Drug-related xerostomia is common [2,22] and can occur with many medications including tricyclic antidepressants, benzodiazepines, monamine oxidase inhibitors, antihypertensives, and antihistamines. Connective tissue diseases, such as Sjo grens syndrome or sicca syndrome, can cause xerostomia [2,8], as can a history of local irradiation or diabetes mellitus. Even stress and anxiety can lead
Fig. 1. Xerostomia. A dry mouth is a common complaint of patients with burning mouth syndrome (BMS). Note the dry, erythematous, fissured tongue plus angular cheilitis.
to a dry mouth. Although hypothesized, age-related or menopausal xerostomia has not been conclusively documented [26]. Nutritional deficiencies Because of rapid cell turnover and trauma, the oral cavity is especially sensitive to nutritional deficiencies and may be the first indicator of such a problem. Iron deficiency anemia, pernicious anemia (an autoimmune B12 deficiency), zinc deficiency, and B complex vitamin deficiency [20] have all been reported to cause BMS. Nutritional deficiencies have been claimed to cause BMS in as few as 2% [15] and as many as 33% [1] of patients. The mucosal alterations associated with these deficiency states, such as erythema, glossitis, loss of papillae, or atrophy, may be absent in BMS patients (Fig. 2). Replacement therapy may be helpful in BMS patients with documented deficiencies [2,5,6,20,27]. Allergic contact stomatitis The role of allergens in BMS is somewhat controversial. Although some studies claim a high prevalence of allergy to dentures and dental materials, such as acrylates, nickel, mercury, gold, and cobalt [28 30], more recent studies [2,31] were unable to implicate denture or denture materials as a frequent cause of BMS. Because true allergies to denture materials are rare, patients should not be considered allergic to denture or dental material until controlled patch testing has been correlated with clinical symp-
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design faults, but only half of these patients improved after denture replacement. The main denture design faults of concern are (1) restricted tongue space, (2) lack of freeway space, and (3) underextended denture bases [4]. These denture design faults can increase the stress on surrounding tissues or change the normal function of the tongue. Most BMS patients with dentures or significant dental work benefit from referral for a formal dental consultation to assess dental work, dentures, occlusion, and the need for modification or replacement. This topic is addressed by Kupp and Sheridan elsewhere in this issue. Parafunctional behavior Burning mouth syndrome associated with parafunctional behavior is probably more common than is realized and is often under appreciated by physicians. Lamey and Lamb [5] found parafunctional activity a concern in 13% of a group of patients with BMS. Patients who clench or grind their teeth, thrust their tongue repetitively (Fig. 3), run their tongue against
Fig. 2. Smooth tongue. A smooth tongue is atrophic with loss of filiform papillae. This permits an increased sensitivity to irritants causing BMS. A smooth tongue may indicate a systemic condition, such as pernicious anemia, iron deficiency anemia, or gluten-sensitive enteropathy.
toms. Patients with Type 3 BMS (intermittent pain) are more likely to have positive patch tests [13]. Flavoring or food additives have been implicated. This subtype clearly merits patch testing. Lamey et al [13] noted 65% of Type 3 BMS cohort had positive patch tests and 80% of this group improved with avoidance of the implicated allergen. Cinnamon aldehyde (cinnamon), sorbic acid, tartrazine, benzoic acid, propylene glycol, menthol, and peppermint have all been identified as potential causes of mouth pain [2,13,31]. Note the contribution of LeSueur and Yiannis on contact stomatitis elsewhere in this issue. Denture-related problems Pain affecting only denture-bearing tissue, a temporal association with denture use, or improvement with discontinuation of dentures is a clue to denturerelated BMS. Rather than an allergic response to denture material, denture-related pain is usually caused by faulty design, irritation, or parafunctional behavior. Candidiasis can also contribute to denturerelated pain. Main and Basker [6] attributed BMS to denture design faults in 50% of patients; with replacement of dentures the patients improved. Lamey and Lamb [5] noted 60% of BMS patients had denture
Fig. 3. Tongue thrusting. Parafunctional habits, such as tongue thrusting, may cause, or occur secondary to, the symptoms of BMS. Note the crenulated or scalloped borders to the tongue. Similar findings are seen with macroglossia.
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their teeth, or try to reseat an ill-fitting denture with their tongue may develop oral pain. These behaviors may be unconscious or may only occur at times of stress. Examination of the tooth surface and dentures can sometime give clues to parafunctional behavior. Dental consultation may be helpful in identifying and managing these behaviors. Candidiasis Reported as a causative factor in 6% [5] to 30% [15] of patients with BMS, the mucosal alterations typically associated with candidiasis may be minimal or absent in BMS patients. Osaki et al [32] reported subclinical candidiasis as a cause of BMS in 25% of a patient cohort. Glossal pain subsided with treatment with 3% amphotericin mouthwash solution. Oral candidiasis is an opportunistic infection. A normal constituent of the mouth in 40% of patients, candidal overgrowth occurs with xerostomia, corticosteroid treatment, antibiotic treatment, denture use, and diabetes mellitus. Empiric treatment for oral candidiasis is often prescribed to patients with BMS. Diabetes mellitus Metabolic alterations in the oral mucosae, diabetic neuropathy, and angiopathy are all proposed mechanisms behind BMS in patients with diabetes mellitus. Xerostomia and oral candidiasis may also contribute to the problem. About 5% of BMS patients have diabetes mellitus [4]. BMS is the second most common oral complaint after xerostomia in a study of diabetic patients [1]. Control of diabetes mellitus may lead to improvement or cure of BMS. Menopause or hormonal alterations Most patients seen by physicians for BMS are women. All the literature on BMS finds that this condition is more common in women than men with a ratio of 7 to 1 [4]. Other oral pain syndromes are also seen more commonly in women [33]. In light of the prevalence of BMS in postmenopausal women, a role for a hormonal impact on BMS has long been suspected [1,34]. In controlled clinical trials with systemic or local estrogen treatment, however, neither was more effective than placebo in the treatment of BMS [10,35]. No significant differences are found between women with mouth pain and a control group in number of years since menopause, use of estrogen replacement therapy, or number of years of use of estrogen replacement therapy [8,33]. Although clearly a significant link between BMS and this age
group of women exists and may be tied with menopause, there is currently no proven benefit of hormone replacement therapy in BMS. Drug-related BMS The ACE inhibitors enalapril, captopril, and lisinopril can cause scalded mouth or BMS. There is improvement with reduction or discontinuation of the medication [36]. Normal mucosal findings Often regarded as asymptomatic variants of normal, multiple studies have shown geographic (Fig. 4), fissured (Fig. 5), or scalloped tongues more frequently in patients with tongue pain [2,15,37,38]. Although the patient with oral pain and these findings technically does not fit under the rubric of BMS, the connection between these oral findings and oral pain has been documented and should be recognized. These findings can also increase the patients fear of cancer. The article on glossitis by Byrd et al elsewhere in this issue addresses this topic in greater detail.
Evaluation and work-up of the patient with BMS The many causes and multifactorial nature of BMS make an organized approach to evaluation important (Table 3). Diagnosis and treatment may
Fig. 4. Geographic tongue. The geographic tongue is a combination of an atrophic tongue with a red base caused by diminished filiform papillae (with resultant hypersensitivity) and a furred tongue with a white base and hyperplasia of filiform papillae. The geographic tongue may be symptomatic. (From Drage LA, Rogers RS III. Clinical assessment and outcome in 70 patients with complaints of burning or sore mouth symptoms. Mayo Clin Proc 1999;74:223 8; with permission.)
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Laboratory examination should include the pertinent tests in Table 2. Biopsy specimens are unlikely to be beneficial if a normal clinical examination is confirmed. Patch testing is especially important and fruitful in the patient with Type 3 BMS and should include a standard series, metal series, and oral flavorings and preservatives (Box 1). The list of allergens is discussed in the contribution by LeSueur and Yiannis elsewhere in this issue.
Management
Fig. 5. Fissured tongue. The fissured tongue is rare in neonates and more common with age. About one sixth of older patients have grooves and fissuring of the tongue dorsum. Impaction of food and keratin debris can predispose to inflammation and halitosis.
be achieved best by a multidisciplinary approach involving the dermatologist and the primary care provider, dentist, psychiatrist, and otorhinolaryngologist. Simply treating the patient in a sympathetic manner may improve the interaction and perhaps the outcome [2,3,12]. Directed history concentrating on the medical, dental, and psychologic or psychiatric history and review of symptoms should occur. The description of oral pain should include the following: duration; character; level (scale of 1 to 10); site of involvement; and subtype or pattern. Frank questions about depression, anxiety, and fear of cancer should be posed. Exacerbating factors, such as food and oral preparations (mouthwash, gum, mints, toothpaste, lip cosmetics, and smoking), should be elicited. Relationship of pain to denture use, dental work, and parafunctional oral behavior (tongue thrusting, bruxism, or jaw clenching) should be documented. All medications must be assessed for xerostomic potential. Physical examination with emphasis on a thorough oral examination must be completed. Besides identifying other diseases that could cause mouth pain, this reassures the patient that cancer is not present. Evaluation should include assessment for erythema, glossitis, atrophy, candidiasis, geographic tongue, lichen planus, and xerostomia. Clinicians with knowledge and experience in the broad range and presentation of oral disease are best equipped to certify a truly normal oral mucosal examination. Examination of dental work, dentures, denture function, and signs of parafunctional behavior may be assessed best by a dental consultation.
Burning mouth syndrome is a manageable problem with most patients responding to tailored therapy (Box 2). Management should focus on controlling or eliminating all potential causes of BMS, keeping in mind that in many patients more than one factor plays a role. Because of the number of conditions causing oral pain, a single treatment protocol is not appropriate. Treatment is tailored to the proposed
Table 3 Work-up of BMS Thorough history and review of symptoms Medications causing xerostomia Dental or denture work Oral care, oral products Oral habits or parafunctional behavior History of depression, anxiety, cancerphobia Family history of oral cancer, psychiatric diagnoses, and connective tissue disease Oral examination Erythema, candidiasis, xerostomia or other mucosal abnormalities Tongue disorders, such as a geographic, fissured, or atrophic tongue Dental work or dentures Laboratory tests Complete blood count Iron, total iron binding capacity, iron saturation, ferritin Vitamin B12, folate, zinc Glucose, glycosylated hemoglobin Culture for Candida Patch testing Include standard series, metal series, oral flavors and preservatives Further consultation if indicated by history and review of systems Psychometric testing and psychiatric consultation Dentistry Neurology Otorhinolaryngology
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Box 1. Patch testing in BMS 1. Standard series (The Mayo Clinic series includes 68 different allergens) 2. Oral flavorings and preservatives 3. Metal series The allergens tested should include (but not be limited to) the following: Methyl methacrylate Ethyl acrylate Ethyleneglycol dimethacrylate Triethyleneglycol dimethacrylate BIS GMA Benzoyl peroxide Propylene glycol Sorbic acid Benzoic acid Tartrazine yellow Peppermint Spearmint Cinnamic aldehyde Menthol Fragrance mix Balsam of Peru Cobalt chloride Nickel sulfate Gold sodium thiosulfate Amalgam Mercuric chloride Cadmium chloride Potassium dichromate Formaldehyde p- Phenylenediamine
stomia and may be a good choice in this setting. Reassurance that cancer is not present should be stated clearly and repeatedly. Denture or dental-related pain Evaluation of dental work, dentures, denture design faults, and parafunctional behavior by a specialist should be sought. Adaptation or replacement may lead to relief of BMS. Removal of dentures at night may be helpful. Avoidance of irritants, treatment of dentures with anti-candidal agents, and a review of dental hygiene should occur. Deficiency syndromes Replacement of iron, B12, folate, or zinc should occur in patients with documented deficiencies. Gradual improvement may follow. Evaluation into the cause of the document deficiency must occur before supplementation. Supplementation in absence of documented deficiency is difficult to justify aside from B vitamin replacement [20]. Lamey [3] recommends empiric replacement of vitamins B1 (300 mg, once a day) and vitamin B6 (50 mg, three times a day) for 4 weeks. Allergic contact stomatitis Patch testing to dental and denture components, metals, additives, preservatives, flavors and a standard series should occur under the supervision of a dermatologist who is experienced in their proper use and interpretation. The clinical correlation between the patch test results and patient exposure history is the most important component of the testing. Patient education and training regarding the avoidance of identified allergens is imperative. Candidiasis Because Candida is a normal part of the oropharyngeal flora, a positive culture does not equate to a pathologic process. Tests that quantitate Candida infection are not available routinely. Typically, empiric treatment for oral candidiasis is offered to the patient with BMS and may benefit a subset of patients. Treatment may include use of nystatin or clotrimazole, which are available in multiple forms including creams, rinses, and troche. One example of an effective treatment regimen includes the use of oral fluconazole, 100 mg Number 15: Day 1, two pills; days 2 7, one pill; days 8 21, one pill every other day. Dentures should also be treated for
causes. Management plans for different scenarios are reviewed. Psychiatric disorders A supportive environment is beneficial for continued treatment of the patient and may aid resolution of the symptoms in concert with other therapies [2,3]. Psychiatric evaluation, medication, and psychotherapy [39] may play a role in alleviating the symptoms. Although optimally undertaken with the guidance of a psychiatrist or psychologist; some patients are resistant to psychiatric evaluation. Antidepressants and anxiolytics with less anticholinergic impact (hence less xerostomia) are preferred. Serotonin reuptake inhibitors typically cause less xero-
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Box 2. Management strategies for BMS Tenets of treatment: 1. Focus on controlling or eliminating all potential causes of BMS 2. Tailor treatment for individual patient based on suspected causes 3. Resort to empiric therapy only if no cause of BMS is found or failure of treatment
Behavioral therapy Sugar-free chewing gum Xerostomia Discontinue medications that cause xerostomia General measures Saliva substitute Sialogogues Idiopathic (empiric treatment) Avoid irritants Trial of treatment with anti-candidal agent B-vitamin replacement Doxepin trial Low-dose tricyclic antidepressants Local clonazepam Consider referral to specialist in oral medicine
Management plans may include the following: Psychiatric and psychologic disorder Maintain supportive environment Psychiatric evaluation and management Appropriate medication or psychotherapy Reassure cancer is not present Denture or dental work Evaluation by dentist Adaptation or replacement as needed Deficiency syndromes Document deficiency Evaluate cause of deficiency Replacement therapy Allergic contact stomatitis Referral to dermatologist with experience in use and interpretation of patch tests Patch test to standard, metal, oral preservatives, flavor series Clinical correlation Patient education in avoidance of identified allergen Candidiasis Culture Treatment with anti-candidiasis agents Diabetes mellitus Referral for management and education Parafunctional behavior Dental evaluation
candidiasis and dental hygiene reviewed. Dentures should always be removed at night. Many patients sleep with dentures in place all night. This predisposes to parafunctional habits and recurrent candidiasis (denture stomatitis). Diabetes mellitus All patients with BMS need to have diabetes mellitus excluded with fasting blood glucose levels. Patients with abnormal findings should be referred for management and education. Control of diabetes mellitus many lead to decrease in BMS. Change of the diabetic medications can sometimes be helpful. Some patients may need oral agents or some may need insulin therapy. Parafunctional habits Once identified, management many include modification of denture design; behavioral therapy consisting of habit monitoring, biofeedback, and relaxation techniques [12]; and use of sugar-free chewing gum, mouth guards, and even hypnotherapy. Xerostomia A number of general measures may be instituted to counteract xerostomia (Box 3). The discontinuation or substitution of medications with potential for
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Box 3. Xerostomia management General measures include the following: Review medications and replace those with known xerostomic potential. Discontinue unnecessary medications. Increase water intake throughout the day Use humidifier in bedroom Avoid alcohol and alcohol-containing mouthwash Avoid caffeine Use sugar-free candy, gum, and beverages Use petroleum jelly on lips before bed and throughout day Frequent dental examination. Patients with xerostomia have increased risk of cavities and gum disease. Commercial saliva substitutes: use as often as needed and before bed; available without a prescription. Examples include the following: Mouth Kote (spray) Moi-stir-spray and swabs Optimoist (spray) Sialogogue Pilocarpine, 5 mg tid Civemeline, 30 mg tid
treatment with anti-candidal agents; and trial treatment with B complex vitamins [3]. Doxepin, familiar to many dermatologists, is often prescribed in doses up to 75 mg for its antianxiety and antidepressant affects. At higher doses doxepin has a greater potential for cardiac arrhythmia, xerostomia, and full antidepressant effect and needs to be carefully monitored If no response is seen, tricyclic antidepressants may be used in a chronic pain protocol manner [2,5,26]. Typical doses include amitriptyline, 10 to 75 mg. Low doses of tricyclic antidepressants may have an analgesic affect that is separate from their action as antidepressants [33]. Use of benzodiazepines [40,41] including systemic clonazepam [18] have been reported to be effective in BMS. Although the mechanism for their action may not rely solely on their anxiolytic effect, concerns regarding the chronic nature of BMS and the potential for abuse of this class of medication merits cautious use. Interestingly, Woda et al [42] reported benefit in 52% of patients treated with local application of clonazepam (0.5 to 1 mg) two to three times a day. They theorized that local application of clonazepam acts locally to disrupt the neuropathologic mechanism that underlies BMS. More unusual treatments reported have included use of capsaicin [43] and infrared laser [44]. Burning mouth syndrome is a treatable syndrome. Treatment is associated with improvement in about 70% of patients [1 6] using a directed approach. If that fails, an empiric approach is warranted. Spontaneous remissions have also been noted to occur [45,46].
causing xerostomia should be sought. Because xerostomia is a very common medication side effect, sometimes a simple reduction in the number of drugs used may improve xerostomia. Artificial saliva substitutes may be helpful. Sialogogues, such as pilocarpine, are sometimes used [32]. Note the contribution by Parks and Lancaster on oral manifestations of systemic disease elsewhere in this issue for additional discussion of xerostomia and therapy of the dry mouth. Idiopathic If no underlying cause for BMS is found or treatment targeted to a proposed etiology is not beneficial, treatment options may follow a more empiric approach. This may include discontinuation of irritating substances (alcohol-based mouthwashes, cinnamon or mint products, and smoking); a trial
Summary Burning mouth syndrome is the occurrence of oral pain in a patient with a normal oral mucosal examination. It can be caused by both organic and psychologic or psychiatric factors, which can be broken down into local, systemic, psychologic or psychiatric, and idiopathic causes. The most frequently associated conditions are psychiatric (depression, anxiety, or cancerphobia); xerostomia; nutritional deficiency; allergic contact dermatitis; candidiasis; denturerelated pain; and parafunctional behavior. Multiple different factors contributing to the oral pain are common, and a systematic approach to the evaluation is important. Identification of correctable causes of BMS should be emphasized and psychiatric causes should not be invoked without thorough evaluation of the patient. A
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L.A. Drage, R.S. Rogers III / Dermatol Clin 21 (2003) 135145 mouth syndrome: psychological and allergic aspects. J Oral Pathol Med 1994;23:216 9. Lamb AB, Lamey PJ, Reeve PE. Burning mouth syndrome: psychological aspects. Br Dent J 1988;165: 256 60. Zegarelli DJ. Burning mouth: an analysis of 57 patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1984;58:34 8. Bogetto F, Maina G, Ferro G, et al. Psychiatric comorbidity in patients with burning mouth syndrome. Psychosom Med 1998;60:378 85. Grinspan D, Blanco FG, Allevato MA, et al. Burning mouth syndrome. Int J Dermatol 1995;34:483 7. Grushka M, Epstein J, Mott A. An open-label, dose escalation pilot study of the effect of clonazepam in burning mouth syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:557 61. Haneke E. Burning mouth syndrome. In: Burgdorf WHC, Katz SB, editors. Dermatology: progress and perspectives. New York: Parthenon Publishing; 1993. p. 584 5. Lamey PJ, Allam BF. Vitamin status of patients with burning mouth syndrome and the response to replacement therapy. Br Dent J 1986;160:81 4. Lamey PJ, Lewis MA. Oral medicine in practice: burning mouth syndrome. Br Dent J 1989;167:197 200. Maresky LS, van der Bijl P, Gird I. Burning mouth syndrome: evaluation of multiple variables among 85 patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1993;75:303 7. Rojo L, Silvestre FJ, Bagan JV, et al. Psychiatric morbidity in burning mouth syndrome: psychiatric interview versus depression and anxiety scales. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1993;75: 308 11. van der Ploeg HM, van der Waal N, Eijkman MAJ, et al. Psychological aspects of patients with burning mouth syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987;63:664 8. van der Waal I. The burning mouth syndrome. Copenhagen: Munksgaard; 1990. Grushka M. Burning mouth syndrome. Dent Clin North Am 1991;35:171 84. Schmitt RJ, Sheridan PJ, Rogers III RS. Pernicious anemia with associated glossodynia. J Am Dent Assoc 1988;117:838 40. Dutree-Meulenberg ROGM, Kozel MMA, van Joost Th. Burning mouth syndrome: a possible etiologic role for local contact hypersensitivity. J Am Acad Dermatol 1992;26:935 40. Kaaber S, Thulin H, Nielsen E. Skin sensitivity to denture base materials in the burning mouth syndrome. Contact Dermatitis 1979;5:90 6. van Joost TH, van Ulsen J, van Loon LAJ. Contact allergy to denture materials in the burning mouth syndrome. Contact Dermatitis 1988;18:97 9. Helton J, Storrs F. The burning mouth syndrome: lack of a role for contact urticaria and contact dermatitis. J Am Acad Dermatol 1994;31:201 5.
directed history and careful oral examination must be completed to exclude local diseases and identify clues to potential causes. Assessment of medications, psychiatric history and background, and selected laboratory and patch tests may help identify the etiologies of these symptoms. Treatment should be tailored to each patient and may best be managed in a multidisciplinary approach with input from dermatologists, dentists, psychiatrists, otorhinolaryngologists, and primary care providers. A thoughtful and structured evaluation of the patient with BMS has been associated with improvement in about 70% of patients. The remaining patients may benefit from empiric therapy with a chronic pain protocol and continued supportive interactions.
[14]
[15]
[16]
[17] [18]
[19]
References
[1] Basker RM, Sturdee DW, Davenport JC. Patients with burning mouths: a clinical investigation of causative factors, including the climacteric and diabetes. Br Dent J 1978;145:9 16. [2] Drage LA, Rogers III RS. Clinical assessment and outcome in 70 patients with complaints of burning or sore mouth symptoms. Mayo Clin Proc 1999;74:223 8. [3] Lamey PJ. Burning mouth syndrome: approach to successful management. Dent Update 1998;25:298 300. [4] Lamey PJ. Burning mouth syndrome. Dermatol Clin 1996;14:339 54. [5] Lamey PJ, Lamb AB. Prospective study of aetiological factors in burning mouth syndrome. BMJ 1988;296: 1243 6. [6] Main DM, Basker RM. Patients complaining of a burning mouth: further experience in clinical assessment and management. Br Dent J 1983;154:206 11. [7] Grushka M, Sessle BJ, Miller R. Pain and personality profiles in burning mouth syndrome. Pain 1987;28: 155 67. [8] Grushka M. Clinical features of burning mouth syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987;63:30 6. [9] Bergdahl M, Bergdahl J. Burning mouth syndrome: prevalence and associated factors. J Oral Pathol Med 1999;28:350 4. [10] Ferguson MM, Carter J, Boyle P, et al. Oral complaints related to climacteric symptoms in oophorectomized women. J R Soc Med 1981;74:492 8. [11] Browning S, Hislop S, Scully C, et al. The association between burning mouth syndrome and psychosocial disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987;64:171 4. [12] Tourne LP, Fricton JR. Burning mouth syndrome: critical review and proposed clinical management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1992; 74:158 67. [13] Lamey PJ, Lamb AB, Hughes A, et al. Type 3 burning [20]
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L.A. Drage, R.S. Rogers III / Dermatol Clin 21 (2003) 135145 [32] Osaki T, Yoneda K, Yamamoto T, et al. Candidiasis may induce glossodynia without objective manifestation. Am J Med Sci 2000;319:100 5. [33] Mott AE, Grushka M, Sessle BJ. Diagnosis and management of taste disorders and burning mouth syndrome. Dent Clin North Am 1993;37:33 71. [34] Wardrop RW, Hailes J, Burger H, et al. Oral discomfort at menopause. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1989;67:535 40. [35] Pisanty S, Rafaely B, Polishuk WZ. The effect of steroid hormones on buccal mucosa of menopausal women. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1975;40:346 53. [36] Savino LB, Haushalter NM. Lisinopril induced scalded mouth syndrome. Pharmacol Ther 1992;26: 1381 2. [37] Gorsky M, Silverman Jr S, Chinn H. Burning mouth syndrome: a review of 98 cases. J Oral Med 1987;42: 7 9. [38] Powell FC. Glossodynia and other disorders of the tongue. Dermatol Clin 1987;5:687 93. [39] Bergdahl J, Anneroth G. Burning mouth syndrome:
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literature review and model for research and management. J Oral Pathol Med 1993;22:433 8. Gorsky M, Silverman Jr S, Chinn H. Clinical characteristics and management outcome in the burning mouth syndrome: an open study of 130 patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1991;72:192 5. Huang W, Rothe MJ, Grant-Kels JM. The burning mouth syndrome. J Am Acad Dermatol 1996;34:91 8. Woda A, Navez ML, Picard P, et al. A possible therapeutic solution for stomatodynia (burning mouth syndrome). J Orofacial Pain 1998;12:272 8. Epstein JB, Marcoe JH. Topical application of capsaicin for treatment of oral neuropathic pain and trigeminal neuralgia. Oral Surg Oral Path 1994;77:135 40. Cekic-Arambasin A, Durdevic-Matricc A, MravakStipetic M, et al. Use of soft laser in the treatment of oral symptoms. Acta Stomatol Croat 1990;24:281 8. Gilpin SF. Glossodynia. JAMA 1936;106:1722 4. Grushka M, Katz RL, Sessle BJ. Spontaneous remission in burning mouth syndrome (BMS) [abstract]. J Dent Res 1986;66:274.
Dermatol Clin 21 (2003) 147 155
Halitosis
Diana V. Messadi, DDS, MMSc, DMSc*, Fariba S. Younai, DDS
Section of Oral Medicine, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, CHS 63-019, 10833 LeConte Avenue, Los Angeles, CA 90095, USA
Halitosis, also known as bad breath or oral malodor, is defined as offensive odors emanating from the mouth or air-filled cavities, such as nose, sinuses, and pharynx [1]. The cause of halitosis has been localized to the oral cavity in up to 85% of people suffering from bad breath; most frequently it is produced in the mouth by the action of gram-negative anaerobic bacteria on sulfur-containing proteinaceous substrates in the saliva, such as debris and plaque. The primary molecules responsible for oral malodor are volatile sulfur compounds (VSC), such as hydrogen sulfide and methylmercaptan. Any intraoral site where food is trapped and stagnates can produce oral malodor. The most common sites include the dorsum of the tongue, interdental, and subgingival area [2,3].
What is halitosis Halitosis, fetor ex ore, fetor oris, and oral malodor or bad breath are terms that have frequently been used to describe unpleasant or offensive odors emitted in the expired air. The term fetor ex ore has long been used to depict malodors that arise from conditions within the mouth and associated sinuses. Halitosis is from the Latin halitus meaning breath and osis is condition. It is bad breath stemming from systemic conditions, such as respiratory conditions, gastrointestinal tract, and kidney (Table 1). It has been suggested that another term, oral malodor, be used to describe offensive odors originating from the mouth [4].
Halitosis can be either physiologic (nonpathologic) or pathologic. Physiologic halitosis is of temporary nature and occurs when volatile odoriferous hematologically borne substances are liberated into the lungs from food, such as herbs; spices; and some vegetables, such as onion and garlic. These odors are mostly reversible, transient, and generally responsive to traditional oral hygiene practices. Hunger or morning breath also causes temporary halitosis, the result of stagnation of epithelial and food debris because of decreased salivary flow and decreased activity of tongue and cheek muscles during sleep [1]. Pathologic halitosis is more intense and is not easily reversible. It arises by practically the same mechanism as the physiologic type, also by pulmonary release of blood-borne substances. This type of malodor originates from regional or systemic pathosis, such as diabetic ketosis, gastritis, gastric ulcer, esophagitis, pyloric stenosis, or hepatitis. These odors are distinct in quality, persistent, and require treatment of the underlying disease [5].
Sources of oral malodor Oral sources Tongue The most common source of bad breath in individuals with good oral hygiene and healthy periodontal tissues is from the posterior dorsum of the tongue. Several review articles have shown that the oral cavity is the main contributor to bad breath in 85% of patients with halitosis [4 6]. Scientific analysis of odors using chemical and organoleptic analysis demonstrated that the major elements in the
* Corresponding author. E-mail address: dmessadi@dent.ucla.edu (D.V. Messadi).
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Table 1 Role of systemic diseases in halitosis Systemic diseases Liver diseases Kidney diseases Diabetes mellitus Description Cirrhosis and hepatic failure have been linked to bad breath displaying rotten egg smell or sulfur odor. Uremia associated with kidney failure gives a distinct ammonia smell. Early dialysis also gives a fishy odor. Produces ketoacidosis, xerostomia secondary to dehydration, increases susceptibility to oral infections. Ketoacidosis gives a distinct acetone smell. A metabolic disorder of the liver associated with the metabolism of trimethylamine to trimethyaminoxide. Mainly caused by deficiency or absence of flavin containing monooxygenase, leading to the accumulation of trimethylamine in the blood, urine, sweat, saliva, and exhaled air The main pathogentic factor of inflammatory and ulcerative changes in the gastric mucosa. Studies show that treatment of bacteria in these dyspeptic patients eliminated their bad breath. References [8,17] [27,51,52] [23,30]
Trimethylaminuria
[50,52]
Helicobactor pylori infections
[48]
production of oral malodor are VSC, primarily hydrogen sulfide (H2S), methylmercaptan (CH3SH), and dimethyl sulfide (CH3SCH) [7]. Several studies have implicated the dorsum of the tongue as the primary site of microflora putrefaction and the production of VSC [7,8]. These sulfur-containing proteins and peptides are hydrolyzed by gram-negative anaerobic bacteria in an alkaline environment. In 1977, Tonzetich [6] found that malodor production is enhanced by elevations in the saliva concentrations of the VSC precursors, such as cystine and methionine, whether appearing as free amino acids or in peptide configuration. The production and release of these volatile compounds, and subsequent detection of these oral malodorous substances, seems to depend on multiple local factors, which include salivary pH, reduced ambient oxygen concentration, bacterial production, and the substrate available for bacterial metabolism. The production of bad breath is generally associated with oral conditions contributing to a shift from gram-positive to gram-negative bacteria. These conditions include a decrease in salivary flow; stagnation of saliva; reduction in the carbohydrate content available as bacterial substrate; and rise in the oral pH (malodor occurs primarily in an alkaline microenvironment) [9]. Xerostomia Xerostomia (dry mouth) is a major contributory factor to bad breath. Decreased salivary flow jeopardizes the normal cleansing mechanism of the mouth and changes the oral flora toward the gram-negative organisms responsible for the malodor. The role of saliva in the oral cavity is multifaceted. It is known to aid in lubrication, digestion, destruction of micro-
organisms, and cleansing of the hard and soft tissues of the mouth. Saliva secreted from the various major and minor salivary glands, whether in the stimulatory or resting phases, contains intrinsic salivary components and desquamated epithelial cells, lysed leukocytes, hemopoietic cells, food debris, and microbes [10]. Xerostomia can be caused by several mechanisms. It can occur secondary to local salivary gland diseases and autoimmune disease, such as Sjo grens syndrome, rheumatoid arthritis, systemic lupus erythematosis, and scleroderma. It also occurs in diabetic patients, patients with chronic hepatitis, patients undergoing radiotherapy and chemotherapy, and also in mouth breathers. It also can occur in cases of dehydration, vitamin deficiencies, menopause, and emotional disturbances. Various medications can cause dry mouth, such as antihistaminics, anxiolytics, antipsychotics, antidepressant, antihypertensives, anticholinergics, diuretics, and narcotics. Oral tissues should be examined for signs and symptoms of xerostomia, including decrease of taste sensation; difficulty in swallowing; loss of salivary electrolytes and immunoproteins that protect against bacterial infections; inflamed, painful, and erythematous oral mucosa; rampant caries, especially at the cervical margins; and loss of filiform papillae causing the tongue to be atrophic, shiny, and erythematous [11]. During sleep, the flow of saliva from the salivary glands is minimal; also proteinaceous materials accumulates, alkaline pH develops, and gramnegative bacteria increases initiating putrefaction and the development of morning breath [12]. Treatment of xerostomia is warranted for elimination of bad breath. When xerostomia is drug-related, a medical consultation is important to find other alter-
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natives without jeopardizing the patients health. The patient is advised to take a lot of fluids and restrain from drinking caffeine-containing drinks. Salivary stimulation is recommended with sugarless candies or gums and also the use of an artificial salivary substitute, which is usually composed of carboxymethylcellulose. In severe cases of dry mouth, a cholinergic agonist is prescribed. The most common is pilocarpine at a dosage of 5 to 10 mg/day [13]. Recently cevimeline hydrochloride (Evoxac), 30 mg three times a day, was found to be effective in treating dry mouth [14]. Periodontitis and other inflammatory conditions Degenerative process resulting in ulceration, necrosis, and harboring of gram-negative bacteria, such as Fusobacterium nucleatum, Veillonella, Porphyromonas gingivalis, and Prevotella intermedia, may be the source of bad breath. Gingivitis and periodontitis are the most common inflammatory conditions in the mouth known to contribute to oral malodor. They produce a very distinct, foul, or putrid smell [15]. The saliva from patients with clinically active periodontitis contains significantly more damaged epithelial cells, leucocytes, and bacteria compared with normal individuals [16]. There is a direct correlation between poor oral hygiene and the intensity of bad breath. Also, oroantral fistula or abscessed tooth can contribute to the malodor process [7]. Dental caries can contribute to bad breath through food retention and impaction of the affected teeth causing putrefaction and emission of putrid odors [12]. Open ulcers, fissures, and entrapped papillae can trap food particles and desquamated tissues [2,17]. Other infections involving the tongue and mucous membrane, such as herpetic gingivostomatitis, Vincents stomatitis, measles, diphtheria, and herpangina, are conditions causing significant tissue destruction, changes in salivary flow, and putrefaction. Oral inflammations associated with excessive use of irritants, such as tobacco, can cause an increase in salivary proteins, such as cystine and methionine. These amino acids are known to be the precursors for VSC, causing an enhancement of oral malodor in these patients [18]. Oral candidiasis Long-term treatment with antibiotics or corticosteroids can cause the development of fungal infections in the oral cavity. Immunosuppressed patients, such as those undergoing chemotherapy or radiotherapy, HIV-infected patients, and diabetics can develop Candida infections at any time during the course of their diseases. Candidiasis can be presented
in any number of its forms, such as pseudomembranous, hyperplastic, erythematous, and angular cheilitis. Candida infections produce a distinct sweet, fruity odor (Table 2). To diagnose Candida infection, a cytology smear is taken and sent for the appropriate stains. Antifungal agents, such as clotrimazole troches or nystatin ointment, can clear the condition and help decrease oral malodor [7]. Oral cancer Primary malignant or benign tumors of the oral cavity, may contribute to bad breath through secondary infections, necrotic tissues, oozing of blood, and food entrapment, which cause putrefaction and gas production. Leukemic patients or patients undergoing cancer chemotherapy or radiotherapy are more susceptible to tissue destruction, multiple infections, and bleeding. These factors provide a rich substrate for protein breakdown and accumulation of anaerobic bacteria and release of fetid gases [19,20]. Nonoral sources Although the oral cavity is the main source of bad breath in most individuals, several systemic conditions can cause halitosis. The most common sources are discussed next. Respiratory Nose and sinuses. To distinguish between oral and nasal sources of malodors, one must separate the expired air. This is performed by directing the patient to close the mouth and exhale through the nose to test if the odor originates from the nose. Then the patient is instructed to pinch the nose and exhale through the mouth [12]. If a stronger smell originates from the nose, this is indicative of lesions or disease of the nose, nasopharynx, or sinuses. Normal rhinorrhea does not produce malodor, but chronic sinusitis may
Table 2 Breath odor emitted by systemic diseases Disease Diabetic ketoacidosis Intestinal dysfunction High dairy diet Hepatic failure Uremia Kidney dialysis Trimethylaminuria Fatty meal Leukemia Candida Breath malodor Acetone Sour Sweety sour Sulfur odor, rotten eggs Ammonia Fishy odor Fishy odor Bitter, fetid Decaying blood Sweet fruity
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be the primary cause of bad breath originating from the nose [7,13]. The most common complaint of patients suffering from chronic sinusitis is postnasal drip; these patients suffer from cough, coated tongue, and the urge constantly to clear their throat [11,17]. It is hypothesized that the postnasal drip, which contains purulent material, drops onto the base of the tongue, which already contains microbiota, developing a chronic infection and the production of bad breath [21]. It is hard to diagnose postnasal drip by regular oral examination or anterior rhinoscopic examination. Nasal endoscopy or CT is required to achieve the best diagnosis [22,23]. Whenever sinusitis is diagnosed, its cause should be determined, which could be an upper respiratory tract infection, chronic mucosal disease, or malformed intranasal structures. Patients suffering from halitosis and diagnosed with chronic nasal and paranasal sinuses diseases should be referred to an ear-nose-and-throat specialist for the correct diagnosis and treatment. Foreign bodies. Several foreign objects may accidentally be inserted into the nose and neglected for a long time [24]. Children and mentally handicapped persons place peanuts, beads, seeds, pieces of paper, and parts of toys in their nose [49]. Any foreign body present in the nose induces an inflammatory response, which becomes secondarily infected and produces malodors. Tonsils. Repetitive infections of the tonsils and adenoids cause chronic follicular tonsillitis [26]. Deep crypts forming in the tonsillar crypts collect food, saliva, and necrotic matter. If these materials are not washed away by natural mechanisms, these collections form tonsilloliths. These are concretions lying on an inflammatory base, which eventually cause halitosis [22,26]. On examination, the tonsils may or may not be hypertrophied and are usually not hyperemic. Pharynx. Any infections, ulcerations, swellings, or neoplasms in the oropharynx can cause halitosis and immediate referral to the appropriate medical specialist is important for adequate diagnosis and treatment [12]. Chronic use of inhaled corticosteroids in asthmatic patients can generate a change in the respiratory tract flora and induce the development of oropharyngeal candidiasis, which can produce bad breath [25]. Zenkers diverticulum, an outpouching that occurs in the junction of the posterior hypopharynx and the esophagus, a known site of natural weakness, can cause oral malodor. When the diverticulum is large, food and saliva
lodge in these outpouches and decomposition releases noxious gases. Usually these malodors are not continuous and depend on the esophageal peristaltic activity [20]. Pulmonary Bronchitis and pneumonia from aerobes, mycoplasma, or viruses, even if productive of a substantial amount of sputum, do not usually cause halitosis. Anaerobic lung abscess, necrotizing pneumonia, empyema, lung cancer, and tuberculosis can present with halitosis as an important symptom [15,25]. Bronchiectasis, a congenital or acquired condition marked by chronic dilatation and destruction of the large bronchi, can cause bad breath. This condition causes paroxysmal cough, which produces a malodorous mucopurulent exudate that has been reported to produce foul odors in expired air [27]. Foreign bodies lodging along the respiratory tract can act as a nidus for the collection of bacteria, causing infection and pus formation [7]. Lungs in general are also the source of odors that arise secondarily to metabolism. These products reach the lungs through the circulation and are vented through the expired air. These include aromatic foods, such as garlic; alcohol; high-fat diets; and ketosis (diabetic ketoacidosis). Some medications, such as nitrates, alcohol, chloral hydrate, and iodine-containing drugs, can produce this effect [22,23]. Gastrointestinal In general, any condition that causes weakening or inhibition in the esophageal closure, such as esophageal reflux, pyloric stenosis, or hiatal hernia, can cause oral malodor [23]. Achalasia is a motor disorder that results in loss or altered peristalsis of the esophagus. This causes a partial relaxation of the lower esophageal sphincter and incomplete emptying into the stomach, resulting in retention of food, liquid, and saliva. The breakdown of these substances with eructation of the resultant gases can cause halitosis [24,28]. Gastroesophageal reflux, an extremely common disorder, rarely causes halitosis. The most frequent symptom is heartburn. The odor associated with gastroesophageal reflux like that of simple belching, resembles odor of the most recently ingested meal [29]. Malabsorption syndromes, gastric carcinomas, and some enteric infections have been noted to contribute to halitosis. Bezoars, which are stomach masses formed by compaction of repeatedly ingested material that does not pass in the intestine, can cause bad breath [29,30].
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Systemic diseases Patients suffering from some systemic diseases can present with halitosis (see Tables 1 and 2). Imaginary halitosis There are some individuals who complain of halitosis that cannot be detected by others (halitophobia) [11,31]. These patients cannot be helped and some of them who seriously imagine halitosis may become depressed and the belief may become so profound that it dominates their lives, and even leads to the thought of suicide [11]. This imaginary halitosis is an olfactory reference syndrome, which is a recognized psychiatric condition where the patient has an olfactory delusion that they emit a foul smell from the mouth or elsewhere [31].
Diagnosis and treatment of oral malodor Patient evaluation The evaluation of a patient with a complaint of bad breath consists of three distinct steps. The first step involves procurement of an adequate history of the patients chief complaint (bad breath) and the related local and systemic factors. The next step involves a complete clinical patient examination followed by instrumental and sensory evaluation of the patients breath. Establishing an accurate medicalsocial history is accomplished best by a written questionnaire and a face-to-face interview with the patient. Although routine health questionnaires are useful in obtaining the health history, a customized intake form containing several key questions related to the patients psychologic health is preferred [32]. Through a detailed interview, the practitioner can investigate and document the entire local and systemic factors that may be related to the bad breath complaint (Fig. 1). Any contributing systemic element must be ruled out carefully, such as sinus and allergic diseases; respiratory problems; gastrointestinal, endocrine, and metabolic disorders; and a history of neoplastic processes involving chemotherapy or radiation therapy. A complete medication history should be obtained. Local factors including a history of dental problems like impactions, tooth decay, periodontal disease, faulty restorations or prostheticorthodontic devices, oral mucosal diseases, or xerostomia, should be investigated. In addition, questions that help to uncover a psychosomatic component to the bad breath complaint should be included. They usually focus on the length of time a patient has been
aware of the problem, the patients perception of reactions of family members and co-workers, the history of expert consultations and various professional treatments and home remedies sought by the patient, and the frequency and the vigor of the oral hygiene practices used by the patient. Questions dealing with a history of an eating disorder, any special diet (vegetarian or ethnic foods), or habits (tobacco or alcohol) should also be included. The clinical examination involves a thorough physical evaluation of the head and neck structures, and intraoral examination of the dentition, periodontal tissues, various oral mucosal sites, and the salivary glands. Radiographic examination of the dentition should be included when feasible. Several health centers also include an endoscopic sinus examination as part of their routine patient evaluation [33,34]. The two main methods of detecting oral malodor are sensory (organoleptic) and instrumental measurements of VSCs. Organoleptic measurement is a sensory test scored usually on a five-point scale on the basis of the examiners perception of a subjects oral malodor [12]. The measurement of VSC may be accomplished by using gas chromatography or by using a portable sulfide monitoring unit known as a Halimeter (Interscan, Chatsworth, CA). Gas chromatography units are equipped with highly sensitive flame photometric detectors specific for sulfur compounds, such as methylmercaptan, hydrogen sulfide, and dimethyl sulfide in mouth air [35,36]. Gas chromatography is considered the gold standard for measuring oral malodor because of its specificity for VSCs. The gas chromatography equipment is not compact, however, and the procedure requires a skillful operator; therefore, it is impractical for practitioners in nonresearch settings. The portable sulfide monitor uses a suction pump to bring mouth air into the instrument, where the VSC are measured with an electrochemical sensor [12,37,38]. Although compact sulfide monitors are portable and easy to use, because of their specificity for mainly hydrogen sulfide and to a much lesser extent methylmercaptan, a significant contributor to halitosis caused by periodontal disease, they are mostly used for monitoring malodor and treatment rather than detection [11,39]. Organoleptic measurement is the most reliable and practical procedure for evaluating a patients level of oral malodor. Clinical measurements The recommended examination procedure is as follows: patients are instructed to abstain from ingesting any food, chewing, and drinking; to omit their
152
Fig. 1. Breath odor history and review of systems.
usual oral hygiene practices; and to abstain from using oral rinse and breath fresheners and smoking for 2 hours before the assessment [40]. Patients are also instructed to avoid using scented cosmetics for 24 hours before the assessment; to abstain from eating garlic, onion, and spicy foods for 48 hours;
and to abstain from taking antibiotics for 2 weeks before the assessment. The oral malodor examiner, who should have a normal sense of smell, is required to refrain from drinking coffee, tea, or juice, and to refrain from smoking and using scented cosmetics before the assessment [41].
153
Fig. 1 (continued ).
Organoleptic measurement can be carried out simply by smelling the patients expired breath (sniff test) being positioned 4 to 6 inches away from the patients mouth, and scoring the level of oral malodor on a five-point scale (zero for no detectable malodor and five for most overwhelming
offensive odor). The tongue odor is measured by scraping the dorsal surface with a plastic spoon and smelling and rating its odor on the same scale. For reliable diagnosis, the oral malodor assessment should be carried out by two or three independent odor judges.
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Portable sulfur monitor (Halimeter) testing involves examination of the patients mouth and nose air. The monitor is adjusted to zero for ambient air. A flexible plastic straw is inserted into the partially open mouth or into the nostrils as the patient holds his or her breath. The digital reading of peak VSC level in parts per billion is recorded. Treatment of halitosis The results of a complete oral soft tissue examination and evaluation of the dentition and the periodontal tissues determine the course of malodor treatment. All faulty restorations, active decay, or dental pulp pathology must be addressed. Treatment of active periodontal disease, a major contributor to oral VSC levels [42], should receive a high treatment priority. Oral mucosal diseases, such as chronic ulcerative conditions, chronic oral candidiasis, and xerostomia, must be diagnosed and treated appropriately. In the absence of any specific oral pathology, the origin of physiologic halitosis is mainly the presence of excessive tongue coating. Gentle mechanical cleaning of the dorsal aspect of the tongue is a key component of the daily oral hygiene routines for oral malodor management. To prevent patients excessively scraping the tongue and causing bleeding, detailed and comprehensive instruction about tongue cleaning should be offered. It is important to demonstrate to patients the position of the terminal sulcus of the tongue and the anatomic limits for cleaning. The patient should gently brush the dorsum of the tongue with a soft-bristled toothbrush and a dentifrice using 5 to 15 strokes. Attention should be paid to the middle third of the tongue anterior to the terminal sulcus. The terminal sulcus is the division between the posterior and middle third of the tongue. This area tends to build up bacterial deposits and keratin and food debris contributing to physiologic halitosis. Removal of these materials lessens the release of VSCs. The remaining treatments include routine oral hygiene procedures and the use of chemical disinfecting mouth rinses. Currently, several formulations of mouthwashes containing chlorine dioxide, cetylpyridinuim chloride, phenolic flavor oil, zinc chloride, triclosan, and chlorohexidine are available. Unfortunately, very few clinical trials for the efficacy of these products are available [43]. Products containing chlorite anion and chlorine dioxide have been shown to be effective in oxidizing and inactivating the oral VSC demonstrating long-lasting effects [44,45]. Chlorohexidine rinses with or without cetylpyridinuim chloride and zinc have also been shown to
reduce significantly the microbial load of the tongue and saliva [45]. A two-phase oil-water mouthwash seems to be effective in treatment of malodor by reducing the oral bacterial load through the oil phase capture of the bacteria with a hydrophobic coat [46,47]. Patients exhibiting signs or describing symptoms of systemic diseases contributing to oral malodor should be referred to the appropriate medical specialists. Patients with pseudohalitosis or halitophobia should be counseled appropriately and referred for psychologic evaluation and treatment.
References
[1] Ayers KMS, Colquhoun ANK. Halitosis: causes, diagnosis and treatment. N Z Dent J 1998;94:156 60. [2] Messadi DV. Oral and nonoral sources of halitosis. Calif Dental Assoc 1997;25:127 31. [3] Rosenberg M. Clinical assessment of bad breath: current concepts. J Americ Dental Assoc 1996;127:475 82. [4] Touyz LZG. Oral malodor: a review. Can Dent Assoc J 1993;59:607 10. [5] Tonzetich J. Oral malodor: an indicator of health status and oral cleanliness. Int Dent J 1978;28:309 17. [6] Tonzetich J. Production and origin of oral malodor: a review of mechanisms and methods of analysis. J Periodontol 1977;48:13 20. [7] Rosenberg M. Bad breath: diagnosis and treatment. Univ Tor Dent J 1990;3:7 11. [8] Rosenberg M. Bad breath: research perspectives. Tel Aviv, Israel: Ramot Publishing; 1995. p. 1 12. [9] Grapp GL. Fetor oris (halitosis): a medical and dental responsibility. Northwest Med 1933;32:375 80. [10] Spielman A, Bivona P, Rifkin BR. Halitosis: a common oral problem. N Y Soc Dental J 1996;62(10):36 42. [11] Richter JL. Diagnosis and treatment of halitosis. Compendium 1996;17:370 86. [12] Rosenberg M, Leib E. Experiences of an Israeli malodor clinic. In: Rosenberg M, editor. Bad breath: research perspectives. Tel Aviv, Israel: Ramot Publishing; 1995. p. 137 48. [13] McDowell JD. Kassebaum: treatment of oral and nonoral sources of halitosis in elderly patients. Drugs Aging 1995;6:397 408. [14] Fox RI, Michelson P. Approaches to the treatment of Sjo grens syndrome. J Rheumatol Suppl 2000;27: 15 21. [15] McNamara TF, Alexander JF, Lee M. The role of microorganisms in the production of oral malodor. Oral Med Oral Pathol 1972;34:41 8. [16] Attia EL, Marshall KG. Halitosis. Can Med Assoc J 1982;126:1281 5. [17] Kleinberg I, Westbay G. Oral malodor. Crit Rev Oral Biol Med 1990;1:247 59. [18] Chow AW, Roser SM, Brady FA. Orofacial odontogenic infections. Ann Intern Med 1978;88:392 402.
D.V. Messadi, F.S. Younai / Dermatol Clin 21 (2003) 147155 [19] Johnson BE. Halitosis, or the meaning of bad breath. J Gen Intern Med 1992;7:649 56. [20] Sulser G, Brening R, Foskick L. Some conditions that affect the odor concentration of breath. J Dent Res 1939;18:355 9. [21] Finkelstein Y. The otolaryngologist and the patient with halitosis. In: Rosenberg M, editor. Bad breath: research perspectives. Tel Aviv, Israel: Ramot Publishing; 1995. p. 175 88. [22] Bogdasarian RS. Halitosis. Otolaryngol Clin North Am 1986;19:1111 7. [23] Lucente FE, Werber JL, Guffin TN. Bad breath. In: Lucente FE, editor. Essentials of otolaryngology. 3rd edition. New York: Raven Press; 1993. p. 257 77. [24] McDowell JD, Kassebaum DK. Diagnosing and treating halitosis. J Americ Dental Assoc 1993;124:55 64. [25] Lorber B. Bad breath and pulmonary infections. Ann Rev Resp Dis 1975;112:875 7. [26] Pruet CW, Duplan DA. Tonsil concretions and tonsilloliths. Otolaryngol Clin North Am 1987;20:305 9. [27] Bailey BJ. Foul breath. JAMA 1988;259:3051. [28] Durham TM, Malloy T, Hodges ED. Halitosis: knowing when bad breath signals systemic disease. Geriatrics 1993;48:55 9. [29] Greenberger NJ. Gastrointestinal disorders: a pathophysiologic approach. Chicago: Year Book; 1981. p. 14 5. [30] Lu DP. Halitosis: an etiologic classification, a treatment approach and prevention. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1984;54:521 6. [31] Scully C, El-Maaytah M, Porter SR, Greenman J. Breath odor: etiopathogenesis, assessment and management. Eur J Oral Sci 1997;105:287 93. [32] Yaegaki K, Coil JM. Clinical application of a questionnaire for diagnosis and treatment of halitosis. Quintessence Int 1999;30:302 6. [33] Ben-Aryeh H, Horowitz G, Nir D, Laufer D. Halitosis: an interdisciplinary approach. Am J Otolaryngol 1998; 19:8 11. [34] Delanghe G, Ghyselen J, Bollen C, Streenberghe DV, Vanderkerckhove BNA, Feenstra L. An inventory of patients response to treatment at a multidisciplinary breath odor clinic. Quintessence Int 1999;30:307 10. [35] Tonzetich J. Direct gas chromatographic analysis of sulphur compounds in mouth air in man. Arch Oral Biol 1971;16:587 97. [36] Yaegaki K, Suetaka T. The effect of zinc chloride mouthwash on the production of oral malodour, the degradations of salivary cellular elements and proteins. J Dent Health 1989;9:377 86.
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[37] Shaw M, Thacher I, Electronic sensing cell. US Patent 4,017,373,1997. [38] Yaegaki K, Coil JM. Diagnosis of halitosis by utilizing questionnaire and organoleptic measurement. Quintessence 1999;18:745 53. [39] Yaegaki K. Oral malodor and periodontal disease. In: Rosenberg M, editor. Bad breath research perspectives. 2nd edition. Tel-Aviv: Ramos Publishing; 1997. p. 227 31. [40] Mirdza N, Ramos B. Operation of bad breath clinics. Quintessence Int 1999;30:295 301. [41] Yaegaki K, Coil JM. Examination, classification, and treatment of halitosis: clinical perspectives. J Can Dent Assoc 2000;66:257 61. [42] Morita M, Wang HL. Relationship between sulcular sulfide level and oral malodor in subjects with periodontal disease. J Periodontol 2001;72:79 84. [43] Loesche WJ. The effects of antimicrobial mouthrinses on oral malodor and their status relative to U.S. Food and Drug Administration regulations. Quintessence Int 1999;30:311 8. [44] Silwood CJL, Grootveld MC, Lynch E. A multifactorial investigation of the ability of oral health care products (OHCPs) to alleviate oral malodor. J Clin Periodontol 2001;28:634 41. [45] Steenberghe DV, Avontroodt P, Peeters W, Pauwels M, Coucke W, Lijnen A, et al. Effect of different mouthrinses on morning breath. J Periodontol 2001;72: 1183 91. [46] Kozlovsky A, Goldberg S, Natour I, Rogatky-Gat A, Gelernter I, Rosenberg M. Efficacy of a 2-phase oil:water mouthrinse in controlling oral malodor, gingivitis and plaque. J Periodontol 1996;67:577 82. [47] Rosenberg M, Gelernter I, Barki M, Bar-Ness R. Daylong reduction of oral malodor by a 2-phase mouthrinse as compared to chlorohexidine and placebo rinses. J Periodontol 1992;63:39 43. [48] Ieraradi E, Amoruso A, La Notte T, Francavilla A. Halitosis and Helicobacter pylori: a possible relationship. Dig Dis Sci 1998;43:2733 7. [49] Lovewell R. An unexpected cause of halitosis. Br Dent J 1984;134:151 2. [50] Preti G, Cowart BJ, Lawley HJ, Horman C, Feldman RS, Young I-M, et al. Trimethyaminuria: a metabolic disorder presenting with primary complaints of dysosmia/dysgeusia. Chem Senses 1993;18:616 7. [51] Simenhoff ML, Burke JF, Doty R. Biochemical profile of uremic breath. N Engl J Med 1977;297:132 5. [52] Thomas DF. Bad breath. JAMA 1988;260:2665.
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Pediatric oral medicine

Patricia M. Witman, MD*, Roy S. Rogers III, MD
A large number of diseases seen in children involve the oral mucosa. Many of these disorders are limited to the oral cavity; however, some are dermatologic or systemic conditions in which oral lesions are one of a constellation of findings. A strong knowledge of these diseases can be essential to make an accurate diagnosis, particularly when oral involvement is the presenting feature. A complete oral examination is an essential part of any dermatologic examination. Unfortunately, the oral cavity is frequently examined in a fleeting manner, particularly in the context of an uncooperative child. Enlisting the assistance of a parent to restrain the child gently and use of a tongue blade can be helpful in obtaining a useful examination. Moistening the tongue blade with tap water can also help to limit the discomfort of gagging. A thorough oral examination can sometimes provide the essential clues needed to make a diagnosis and should not be overlooked. The organization of the diseases discussed here is based on their clinical presentation. The article starts with congenital oral lesions. Subsequently, entities localized to the tongue are reviewed. The remaining diseases discussed are divided based on the morphology of the presenting lesion and include papules and nodules, stomatitis and mucosal ulcers, white lesions, and pigmented lesions. Congenital diseases of the oral mucosa
the alveolar or palatal mucosa of approximately 80% of neonates [1]. The term Epsteins pearls is applied most accurately to those that occur at the junction of the hard and soft palates. These likely represent remnants of epithelial tissue entrapped during palatal fusion. Bohns nodules develop from heterotopic salivary glands and are found on the facial and lingual surfaces of the alveolar ridges and on the palate away from the midline. Lesions on the crest of the alveolar ridge are known as dental lamina cysts, alveolar cysts, or gingival cysts of the newborn. They are derived from dental lamina, the ectodermal portion of the tooth bud. Clinically, all of these cysts appear similarly as small, white papules or translucent cysts. There may be one or multiple lesions. No treatment is indicated because they resolve spontaneously [2,3]. Fordyces spots Fordyces spots are collections of normal sebaceous glands within the oral cavity. Although present at birth, they often do not become clinically apparent until puberty. They present as 1- to 3-mm, white to yellow maculae and papules most commonly on the mucosa of the lips but can occur on any mucosal surface. They are of no medical significance and require no intervention [4]. Natal and neonatal teeth
Cysts of the oral mucosa Epsteins pearls, Bohns nodules, and dental lamina cysts are all variations of a cystic lesion seen on
* Corresponding author. E-mail address: witman.patricia@mayo.edu (P.M. Witman).
Natal teeth are present at birth. Neonatal teeth are less common and erupt during the first month of life. A positive family history is noted in 8% to 46% of patients with natal and neonatal teeth [3]. The teeth are frequently mobile because of poor root development and often have poorly calcified enamel secondary to their premature eruption. They frequently
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occur in pairs, most commonly in the mandibular incisor region [3]. Ulceration of the sublingual aspect of the tongue, also known as Riga-Fede disease, can result from trauma from these teeth [5]. Because most of these teeth are part of the normal complement of the primary dentition, it is helpful for normal dental development to maintain them if possible. Extraction is recommended, however, if the tooth is extremely loose and poses an aspiration risk or if the crown is poorly developed [3]. Natal and neonatal teeth have been associated with a number of syndromes including chondroectodermal dysplasia, pachyonychia congenita, and oculomandibulodyscephaly with hypotrichosis [2]. Congenital epulis of the newborn Also known as gingival granular cell tumor of the newborn, a congenital epulis is a rare, benign tumor most commonly seen in female neonates. Clinically, the lesions appear as pedunculated, firm growths arising from the alveolar ridge. The maxillary anterior alveolar ridge is the most common location. Histologically, one sees tightly packed granular cells surrounded by a fibrovascular stroma. Although these tumors can resolve spontaneously, they may interfere with feeding and respiration and can create anxiety for parents. Surgical excision is often preferred and is curative [3,6,7]. Melanotic neuroectodermal tumor of infancy This is a rare tumor usually occurring within the first 6 months of life. It appears as a smooth surfaced, rapidly enlarging, blue to black tumor most commonly located on the maxillary alveolar ridge. The tumor is most likely of neural crest origin suggested by high levels of vanillylmandelic acid in some patients urine. On histology, one sees characteristic alveolar spaces lined by cuboidal cells filled with dark staining, neural-like cells. Surgical excision is the therapy of choice. Recurrences can occur but are unlikely [2,3]. Hemangioma Hemangiomas are the most common benign tumor of the oral mucosa in children [8]. In the oral cavity, they typically appear as red to blue, poorly circumscribed, spongy tumors most commonly involving the lips, tongue, buccal mucosa, and palate. They characteristically undergo a period of rapid growth over the first several months of life, followed by stabilization and gradual spontaneous involution
over a period of years. Complications include cosmetic deformity and ulceration (Fig. 1), which can be associated with bleeding, pain, and risk of secondary infection. Hemangiomas may also interfere with respiration, ability to suck, and speech. Management is determined by the size and location of the lesion, complications, and cosmetic concerns of the patient and family. Because many spontaneously regress without sequelae, close observation with parental reassurance is a frequent plan of action. Thin or ulcerated hemangiomas may respond to pulsed dye laser. Lesions that interfere with vital functions require aggressive therapy with intralesional or systemic corticosteroids or interferon [9]. Lymphangioma The lymphangioma, or lymphatic malformation, is a relatively uncommon tumor of the mouth usually presenting at birth. It is a malformation of lymphatic vessels, and in contrast to hemangiomas, does not spontaneously regress. They most commonly occur on the tongue but may also arise on the lips, buccal mucosa, soft palate, and floor of the mouth. Superficial lesions have a papillated surface that can appear vesicular in nature (Fig. 2). Deeper lesions are nodular and can result in macroglossia when the tongue is involved. Although often asymptomatic, lymphangiomas may enlarge leading to increased difficulty and pain with speech and feeding. They also can become secondarily infected. Circumscribed, smaller lesions can be surgically excised [2]. Alveolar lymphangioma As opposed to the uncommon lymphangioma noted previously, alveolar lymphangiomas occur in
Fig. 1. Ulcerated hemangioma. Note the fibromembranous slough covering this ulceration of the lower lip in a 2-monthold infant.
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correction of the pits is only undertaken if there is a visible deformity or if there is significant salivation from them [11].
Congenital ranula The congenital ranula presents as a soft tissue swelling in the anterior floor of the mouth lateral to the lingual frenulum. The overlying mucosa may have a blue discoloration or be normal in appearance. The ranula results from obstruction, perforation, or atresia of the sublingual or submandibular salivary gland duct. Although it resembles the mucocele clinically, a ranula is actually a pseudocyst as opposed to the mucocele, which is a true cyst. Treatment with marsupialization of the obstructed duct should be performed early to prevent the possibility of sialadenitis [11].
Fig. 2. Lymphangioma of the tongue. Note the papillated or pseudovesicular surface of the tongue.
3.7% of black neonates. Clinically, the lesions appear as blue, domed, fluid-filled papules located posteriorly on the crest of the maxillary ridge or the lingual aspect of the mandibular alveolar ridge. They range in size from 1 to 9 mm. Up to four lesions may be noted in one patient but there is only one lesion per posterior quadrant. The cause is unknown. Although they share a similar location, their appearance distinguishes them from the dental lamina cyst. Their clinical appearance resembles that of a mucous retention cyst, yet they are localized to areas devoid of salivary gland tissue. Histologically, one sees vascular spaces consistent with a lymphangioma. Most of the lesions resolve spontaneously. Excision is reasonable if symptomatic [10].
Sucking pads Sucking pads, also known as sucking calluses, are not congenital but are mentioned here because they are so frequent in the neonatal period. In fact, it seems to occur in all neonates in varying degrees of severity. Clinically, one sees a hyperkeratotic thickening at the closure line of the upper and lower lips that extends inward to involve the mucosal surface (Fig. 3). The lesions may be white or pigmented. They may be smooth or may become a hyperkeratotic, square pad that cracks and peels. These are clearly an adaptive response to the mechanical effects of sucking. They usually disappear after 3 to 6 months of age [12].
Congenital pits Congenital pits, also known as congenital fistulae of the lower lip, are rare developmental anomalies inherited as an autosomal-dominant trait. Clinically, one typically sees a pair of bilateral symmetric indentations on the vermilion aspect of the lower lip. A single pit may also occur as an incomplete expression of the trait. The depth of these vary but some have been noted to extend through the depth of the orbicularis oris muscle. The lumen of the fistula is lined by stratified squamous epithelium similar to lip mucosa with scattered ducts and acini of mucinous glands noted at the opening. Saliva may be excreted spontaneously from the pits or may occur with mastication. Congenital pits, even the single variety, are strongly associated with cleft lip or cleft palate; further evaluation for such anomalies must be undertaken in any patient with congenital pits. Surgical
Fig. 3. Sucking pads in a neonate. Note the white hyperkeratotic thickening of the lip at the closure lines.
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Diseases of the tongue Developmental diseases of the tongue Macroglossia Macroglossia is defined as a resting tongue that protrudes beyond the teeth or alveolar ridge and can be caused by a number of conditions. Most cases in children are congenital and represent hypertrophy or hyperplasia of the muscles of the tongue. Syndromes associated with macroglossia include Down syndrome, Beckwith-Wiedemann syndrome, Hurlers syndrome, cretinism, and Rubenstein-Taybi syndrome [4]. Secondary macroglossia may result from hypothyroidism; amyloidosis; sarcoidosis; and neoplasms, such as lymphangiomas and hemangiomas. Macroglossia can lead to psychologic distress, other maxillofacial abnormalities, impaired swallowing and speech, and even airway obstruction. Medical management may be beneficial if the macroglossia is caused by an underlying systemic disease as in hypothyroidism. Surgical removal of a causative neoplasm or reduction glossectomy is another therapeutic option [13]. Ankyloglossia Ankyloglossia, also known as tongue-tie, results from an abnormally short lingual frenulum. This congenital anomaly is relatively common affecting up to 4.8% of newborns [14]. Although many believe ankyloglossia is rarely of medical significance, others report breast-feeding difficulties and advocate neonatal frenulectomy [14]. Lingual tonsil The lingual tonsil is a developmental anomaly found on the posterior third of the tongue between the epiglottis posteriorly and the circumvallate papillae anteriorly. It is a mass of lymphoid tissue usually divided through the midline by a ligament. Although often small and asymptomatic, lingual tonsils can become enlarged creating dyspnea, dysphonia, and the sensation of a lump in the throat. Lingual tonsillitis can result in a painful swollen tongue and fever. The diagnosis can be confirmed by histopathology, which reveals lymphoid tissue [4]. Treatment of symptomatic lesions is possible by lingual tonsillectomy [15]. Lingual thyroid Another developmental malformation is the lingual thyroid, a smooth-surfaced mass of ectopic thyroid tissue found at the foramen cecum. Although usually asymptomatic, dysphagia, coughing, or pain
may occur. Other benign or malignant tumors should be excluded by biopsy. Surgical removal can be performed for symptomatic lesions, but one first needs to confirm normal thyroid activity in the neck [16,17]. Acquired diseases of the tongue Benign migratory glossitis Also known as geographic tongue, benign migratory glossitis is a benign tongue condition affecting 2% of the population [4]. In children, it is one of the most common conditions of the oral mucosa clinically observed [18,19]. The cause is unknown. The condition may be hereditary. An association with atopy, fissured tongue, and psoriasis has also been noted [4,20]. Clinically, the dorsum of the tongue has well-defined erythematous regions of depapillation, each surrounded by a raised white edge (Fig. 4). This can lead to a geographic configuration or map-like appearance, hence the name geographic tongue. The appearance may change daily. Although usually asymptomatic, soreness sometimes occurs, especially with salty or spicy foods [21]. Reassurance is usually all that is needed. Strawberry tongue Both scarlet fever and Kawasakis disease have been associated with a strawberry tongue. The strawberry tongue is a red inflamed tongue with a white exudate that covers the entire dorsum of the tongue with the exception of prominent fungiform papillae. In scarlet fever, this white coating quickly resolves
Fig. 4. Geographic tongue. Note the alternating bald (red) and hyperplastic (white) patches on the dorsum of the tongue. (From Drage LA, Rogers III RS. Clinical assessment and outcome in 70 patients with complaints of burning or sore mouth symptoms. Mayo Clin Proc 1999;74:223 8; with permission.)
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leaving a smooth, deep red tongue. Dramatic hyperemia of other oral mucosal surfaces and the oropharynx is also characteristic of both diseases [22,23]. Furred tongue and hairy tongue A furred tongue is the result of accumulation of keratin and hypertrophy of the filiform papillae. In children, it is most commonly seen with a febrile systemic illness and is caused by lack of mechanical debridement and changes in the oral flora. The furred tongue has also been associated with smoking and a diet low in fiber. In contrast, a hairy tongue is the result of excessive elongation of the filiform papillae. This may be idiopathic or caused by chronic irritation. Regular brushing of the tongue may be beneficial in improving the appearance of both conditions [4]. A brown or black discoloration may also occur with both the furred and the hairy tongue. Antibiotic use leading to a local excess of chromogenic bacteria may be responsible. It also may result from iron supplementation, coffee consumption, or tobacco use. If aesthetically displeasing, brushing with a 1% to 2% hydrogen peroxide solution can be tried [24]. Smooth tongue Atrophy of the filiform papillae leads to a smooth or bald tongue. Although seen in unusual genetic conditions, such as Riley-Day syndrome, the most common cause is nutritional deficiency. In children of the western world, nutritional deficiencies are usually caused by malabsorption, seen in such diseases as celiac sprue and Crohns disease. Most commonly, atrophic glossitis results from deficiencies in folate, iron, or vitamin B12 [4].
Fig. 5. Mucocele of the lower lip. Note the translucent nodule of the mucosal lip surface.
Intraoral abscess and parulis In the oral cavity, abscesses are almost always the result of a nonvital tooth. This may be the result of dental caries, trauma, or periodontitis. Abscesses present as painful, fluctuant soft tissue swellings of the gingiva, palate, or buccal sulci. Parulis is a term used to describe an abscess of the gingiva adjacent to a nonvital tooth. Dental abscesses may be complicated by cellulitis, facial swelling, fever, and systemic complaints. Use of systemic antibiotics is helpful, but definitive treatment requires therapy of the devitalized tooth (root canal or extraction) or gingival surgery when periodontitis exists [3]. Squamous papilloma The squamous papilloma is a benign, common intraoral neoplasm that presents as a pink to white verrucous papule (Fig. 6). The most common location is the junction of the hard and soft palate, although lesions may occur anywhere. Treatment options include destruction modalities, such as cryotherapy, electrodessication, and surgical excision. They are caused by human papilloma virus infection [4,22]. Eruption cyst and eruption hematoma An eruption cyst may precede the eruption of either a primary or a permanent tooth. It appears as a transparent, fluctuant swelling of the alveolar mucosa overlying an erupting tooth. This results from fluid accumulating within the dental follicle that surrounds the tooth. Trauma may result in an eruption hematoma (Fig. 7), a blue to purple swelling that results from accumulation of blood in the follicular
Papules and nodules of the oral mucosa Mucocele The mucocele (Fig. 5) represents a mucous extravasation cyst resulting from trauma to salivary glands [3]. They are common in childhood, reported as the most common surgically excised oral lesion in children aged 1 to 19 [25]. Girls are more commonly affected than boys. The lower lip is the most frequent site, but mucoceles may occur on the palate, upper lip, and on the buccal mucosa. Mucoceles typically present as localized fluid-filled papules or nodules often translucent or with a blue discoloration. The lesion may rupture and usually recurs leading to fibrosis of the lesion. If simply unroofed, the lesion typically recurs; surgical excision is usually required [3].
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the pyogenic granuloma, (2) the peripheral ossifying fibroma, (3) the peripheral giant cell granuloma, and (4) the fibroepithelial polyp (Fig. 8) [29,30]. Intraoral malignancy Although extremely uncommon in the pediatric population, oral growths can be the result of malignancy. Lymphoma may very rarely present as an intraoral soft tissue enlargement, a nonhealing ulcer, or with loosening of the teeth. A radiograph may reveal bone resorption [31]. Histiocytosis X may cause lytic lesions of the skull and mandible with associated oral soft tissue swelling, ulceration, or disruption of teeth [32]. Sarcomas, such as rhabdomyosarcoma, may also present in the oral cavity, as may salivary gland malignancies. It is imperative that any growth or enlargement of soft tissue of unclear cause undergo biopsy for a definitive diagnosis [4].
Multiple papules and nodules of the oral mucosa Focal epithelial hyperplasia (Hecks disease) Focal epithelial hyperplasia, otherwise known as Hecks disease, is a condition most commonly seen among Native Americans and Eskimos of Greenland and Alaska where the prevalence is as high as 30% [22]. Children are most commonly affected and present with multiple, soft, smooth-surfaced, welldemarcated, irregular papules on the mucosa of the lips, the buccal mucosa, the tongue, and hard palate. They can be white, gray, or the color of normal surrounding mucosa. The disease has been associated specifically with human papilloma virus 13 and 31 [33]; however, genetic factors likely play a role in
Fig. 6. Squamous papilloma. Note the filiform papule just above the commissure.
space. Resolution occurs with eruption of the tooth. Lancing the cyst may be required if it becomes painful or if the tooth fails to erupt [2,26]. Retrocuspid papilla This is a common, benign, soft tissue enlargement affecting 72% of children under the age of 10 [3]. It affects girls more commonly than boys. Clinically, one sees a 2- to 3-mm, soft, sessile papule posterior to the mandibular canine tooth, frequently bilateral. A biopsy specimen reveals normal mucosa and connective tissue. Most lesions regress spontaneously with age [27,28]. Epulis The term epulis is used to refer to a localized overgrowth that is not a neoplasm, but instead a nonspecific hyperplastic inflammatory reaction. Local excision is the preferred treatment, and recurrence is possible. The four types, detailed in Table 1, can appear similar on clinical examination but are distinguishable by histologic study. They include (1)
Fig. 7. Eruption hematoma. Note the blue-domed cyst of the alveolar ridge.
P.M. Witman, R.S. Rogers III / Dermatol Clin 21 (2003) 157170 Table 1 Forms of oral epulis Condition Pyogenic granuloma Clinical features Painless, red, sessile or pedunculated vascular growth that bleeds with minor trauma. Firm, sessile or pedunculated growth arising from interdental papilla. Easily bleeding red-brown, livercolored growth arising from gingiva anterior to the first mandibular molar. Pink pedunculated or sessile painless papule. Histopathology Lobular collection of endothelial-lined vascular spaces resembling granulation tissue. Dense stroma of collagen fibers in various orientations with calcification or osseous lamellae. Nonencapsulated tumor with foci of multinucleated giant cells separated by fibrous septa. Dense bundles of collagen with overlying keratinized epithelium. Management Surgical excision.
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Peripheral ossifying fibroma Peripheral giant cell granuloma
Surgical excision.
Surgical excision. Check for associated hyperparathyroidism Surgical excision.
Fibroepithelial polyp
determining susceptibility to these viruses [22]. Although spontaneous remissions have been reported, CO2 laser and cryotherapy have also been used to treat this condition [33]. Genodermatoses with multiple oral papules Multiple oral papules can be observed as a clinical feature in a number of genodermatoses as outlined in Table 2 [34]. See the contribution on genodermatoses elsewhere in this issue by Hand and Rogers.
Trauma Although any type of trauma can lead to ulceration, the most common cause is generally selfinduced, such as involuntary chewing or biting on the oral mucosa. Accidental traumatic ulcers can also occur including punctures induced by pencils or pens, toothpicks, and fish bones. Trauma from braces, other dental appliances, and jagged teeth is also possible. Unless complicated by secondary infection, traumatic erosions and ulcers should heal in a period of days to a few weeks [4]. Infections Bacterial Acute necrotizing ulcerative gingivitis mainly affects adolescents and young adults but can rarely also be seen in children. It is characterized by the abrupt onset of extremely painful, hyperemic gingivae with sharply demarcated ulcerations of the interdental papillae. Severe oral pain, profuse salivation with a distinct metallic taste, headache, malaise, and low-grade fever may also occur. A gram-negative spirochete Borrelia vincentii and a gram-positive bacillus Fusobacterium dentium are found on smears from the gingiva and grow on anaerobic culture. Poor oral hygiene, inadequate nutrition, and dental caries are predisposing factors in this condition. Children with leukemia or other blood dyscrasias are also more likely to develop acute necrotizing ulcerative gingivitis. Treatment includes antibiotic therapy and the care of a dentist [4,22]. Viral enanthems A number of viral infections are characterized by an acute stomatitis with oral ulcerations of the oral
Stomatitis and ulcerations of the oral mucosa Stomatitis is an inflammation of the oral mucosa. It is frequently associated with oral ulcerations and significant pain. There are a multitude of disorders that may cause stomatitis and oral ulcers in children.
Fig. 8. Fibroepithelial polyp. Note the white sessile polyp of the posterior buccal mucosa.
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Table 2 Genodermatoses with multiple oral papules Genodermatosis Cowden disease Inheritance Oral findings AD Multiple 1 3 mm mucosal papules; fissured tongue. Multiple 1 3 mm mucosal papules. Other cutaneous feature Tricholemmomas; acral keratoses; keratoderma. Extracutaneous features Fibrocystic breast disease; breast cancer; thyroid adenoma; thyroid cancer; gastrointestinal polyps. Rare mental retardation; epilepsy; small stature.
Dariers disease
AD
Goltzs syndrome
XLD
Lipoid proteinosis
AR
Multiple endocrine AD neuplasia type IIb Neurofibromatosis AD
Papillomatous growths of mucosal surfaces (especially lips); lip pits; gingival hyperplasia; hemihypoplasia of tongue. Yellow to white indurated papules, plaques, and nodules of mucosal surfaces; thickened, indurated lips. Multiple mucosal neuromas; enlarged lips. Mucosal neurofibromas.
Yellow-brown greasy papules in seborrheic distribution; acral keratoses; longitudinal streaks of nail plates with distal notching. Atrophic plaques; fat herniation; congenital absence of skin; hyperpigmentation and hypopigmentation. Indurated plaques of face, axillae, extremities; string of pearls appearance of eyelids.
Mental retardation; craniofacial, ocular, dental and musculoskeletal abnormalities.
Infiltration of larynx (hoarseness), esophagus (dysphagia), and other organs.
Tuberous sclerosis
AD
Mucosal fibromas; pits in enamel of teeth.
Rare cutaneous neuromas; Medullary thyroid cancer; au lait maculea pheochromocytoma; occasional cafe marfanoid habitus. au lait maculea; Cafe Optic gliomas; Lisch neurofibromas; axillary and nodules; skeletal inguinal freckling. abnormalities; intracranial and spinal tumors; increased malignancies; seizures. Mental deficiencies; Ash-leaf maculea; seizures; hamartomas of angiofibromas; connective almost any internal organ. tissue nevi; confetti hypopigmentation; subungual and periungual fibromas.
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; XLD, X-linked dominant.
mucosa. A careful examination of the oral mucosa in the acutely ill child can sometimes provide helpful clues toward making a diagnosis (Table 3) [22,35]. This topic is addressed in detail by Hairston et al elsewhere in this issue [22,35]. Fungal Although rare in immunocompetent children, fungal infections always need to be considered when evaluating oral ulcerations in immunocompromised children. The possibilities in the differential include disseminated candidiasis, histoplasmosis, blastomycosis, paracoccidioidomycosis, cryptococcosis, aspergillosis, and mucormycosis. A biopsy is often needed for definitive diagnosis because the oral lesions tend not to be distinctive [36].
Genetic diseases Epidermolysis bullosa Epidermolysis bullosa represents a large group of inherited disorders in which the skin is unable to withstand friction. The various subtypes of epidermolysis bullosa result from a variety of defects in the proteins responsible for adherence of the epidermis to the dermis. Mucosal blistering can occur in all subtypes of epidermolysis bullosa, although to varying degrees of severity (Fig. 9). Bullae and ulcerations of the mucosae usually present in infancy secondary to suckling and can be quite painful [11]. Patients with epidermolysis bullosa who have oral blistering are also at risk for dental problems. The painful erosions make dental hygiene more difficult
P.M. Witman, R.S. Rogers III / Dermatol Clin 21 (2003) 157170 Table 3 Viral enanthems Viral enanthem Herpetic gingivostomatitis Varicella Virus Herpes simplex virus Varicella zoster virus Mucosal findings Painful, grouped vesicles or erosions Grouped vesicles or erosions, typically larger than herpes simplex Grouped vesicles or erosions Grouped vesicles or erosions Gingivitis, ulcers, white-to-gray tonsillar membranous exudate, palatal petechial hemorrhage Location of mucosal lesions Tongue, gingiva, buccal mucosa, lips Tongue, gingiva, buccal mucosa, lips Other findings
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Pain, dysphagia, lymphadenitis Cutaneous lesions of varicella, anorexia, malaise, fever Vesicles on palms and soles, anorexia, malaise, fever High fever, vomiting, sore throat, anorexia, dysphagia Marked cervical lymphadenopathy, malaise, anorexia
Hand, foot, and mouth disease Herpangina
Coxsackievirus A16; other Coxsackievirus subtypes Coxsackie A and B virus subtypes Epstein-Barr virus
Tends to spare gingiva
Infectious mononucleosis
Soft palate, anterior tonsillar pillars, tonsils, and pharynx Gingiva,tonsils, tonsillar pillars, soft palate
leading to gingivitis and decay. Teeth also may be irregular in shape and have enamel hypoplasia, also leading to more caries [11]. Unfortunately, at this time, no cure exists for patients who suffer with epidermolysis bullosa. Management of patients with intraoral involvement should include regular visits to a dental specialist. Special high-flow nipples, such as the Habermann nipple and Mead-Johnson cleft lip and palate nurser, also can be helpful in patients where intraoral blisters interfere with feedings [11,37]. Diseases with altered immune reactivity Within this category are erythema multiforme; graft-versus-host disease; lichen planus; lichenoid
drug reactions; and the autoimmune blistering diseases including pemphigus, cicatricial pemphigoid, linear IgA disease, and dermatitis herpetiformis. Because the other conditions are relatively rare causes of mucosal ulcerations in childhood, the discussion here is limited to erythema multiforme. Note also the discussion of erythema multiforme by Ayangco and Rogers elsewhere in this issue. Erythema multiforme Erythema multiforme is frequently associated with mucosal ulcerations (Fig. 10). In erythema multiforme minor, the oral mucosa may be the only mucosal membrane involved, as opposed to erythema multiforme major or the Stevens-Johnson syndrome,
Fig. 9. Junctional epidermolysis bullosa. Note the large blister on the tongue of an infant.
Fig. 10. Erythema multiforme. Oral mucosa and lips of a patient with erythema multiforme. Note the erosions, ulcerations, and hemorrhagic crusting.
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where by definition two or more mucous membranes are involved. The typical target lesions of erythema multiforme may or may not be present elsewhere on the skin. Lesions on the oral mucosa initially present as enlarging zones of ill-defined erythema that develop central zones of vesiculation that rupture to form painful erosions. These erosions can extend into deep ulcerations with bright red halos. The lips may become red, swollen, crusted, fissured, and bloody. Intense pain can lead to drooling and inability to swallow with risk of dehydration [35]. Severe oral involvement with erythema multiforme warrants hospitalization with intensive nursing care and analgesics. Careful attention to oral hygiene is essential as is the frequent application of a topical antibiotic ointment or petrolatum to prevent fissuring of the lips. An ophthalmologist should be consulted with ocular involvement [35]. The use of systemic corticosteroids is controversial because no prospective study has shown a definite improvement with their use, and retrospective studies suggest a higher infection rate and longer hospital stays with their use [38]. Erythema multiforme may result from exposure to medications (sulfonamides, barbiturates, or phenytoin) or infections, such as herpes simplex virus, hepatitis B, Epstein-Barr virus, streptococcus bacteria, and mycoplasma pneumonia. In one third of cases, however, a cause cannot be found [39]. Recurrent erythema multiforme can result with herpes simplex virus recurrences, in which instance prophylactic acyclovir can be of benefit [40]. Recurrent aphthous stomatitis Recurrent aphthous stomatitis is the most common inflammatory ulcerative condition of the oral mucosa in North American patients. It is frequently encountered in the pediatric patient population. It is estimated that 20% of the general population has recurrent aphthous stomatitis during their childhood or early adult life [41]. This topic is discussed in detail elsewhere in this issue by Zunt. Recurrent aphthous stomatitis can be classified according to the morphology of the lesions into types: (1) minor aphthous ulcers, (2) major aphthous ulcers, and (3) herpetiform ulcers. Seventy-five percent to 85% of patients who suffer from recurrent aphthous stomatitis have minor aphthous ulcers. This form is characterized by the infrequent development of one or more small (< 1 cm) oval or round shallow ulcers with a gray to tan fibromembranous slough surrounded by a peripheral zone of erythema. They are moderately painful and usually heal without scarring
in 1 to 2 weeks. Most patients suffer two to four episodes a year. Major aphthous ulcers account for 10% to 15% of sufferers of recurrent aphthous stomatitis. The ulcers are larger ( > 1 cm) and deeper. They also heal slowly and characteristically scar. The lesions of major aphthous ulcers cause significant discomfort, oral pain, fever, and malaise. Herpetiform ulcers account for the remaining 5% to 10% of patients with recurrent aphthous stomatitis. This variant presents with multiple, grouped 1- to 2-mm papules that evolve into papulovesicles and subsequently into ulcers, which can coalesce. Lesions heal in 7 to 30 days sometimes with scarring [41]. Another helpful classification of recurrent aphthous stomatitis is based on the clinical course and includes simple aphthosis and complex aphthosis [41]. Most pediatric patients with recurrent aphthous stomatitis suffer from simple aphthosis. This term refers to the common presentation of a few lesions that heal in 1 to 2 weeks and recur infrequently. Complex aphthosis describes severe recurrent aphthous stomatitis complicated by numerous, large or deep lesions with new lesions developing before the old lesions heal leading to continuous ulcerations, and leads to marked pain and morbidity [41]. Complex aphthosis occupies a position on the continuum from limited disease (simple aphthosis) to systemic disease, because a number of systemic diseases are characterized by complex aphthosis, as follows [4,41]: Hematologic disorders Cyclic neutropenia Aplastic anemia Severe combined immunodeficiency disease Chronic granulomatous disease diak-Higashi syndrome Che Gastrointestinal disorders Gluten-sensitive enteropathy Inflammatory bowel disease Connective tissue disorders Behc ets syndrome Mouth and genital ulcers with inflamed cartilage Systemic lupus erythematous Juvenile rheumatoid arthritis HIV Nutritional deficiencies Iron Vitamin B12 Folate Zinc Iatrogenic Trimethoprim-sulfamethoxole Chemotherapy medications Radiation mucositis
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In those patients where an underlying nutritional deficiency or gluten sensitivity is found, treatment of the underlying associated disease can sometimes lead to remission or lessening of disease activity [41].
intracellular edema of keratinocytes. Leukoedema has been related to poor dental hygiene and topical irritants but the cause remains unknown. No treatment is usually necessary [33,42]. Kopliks spots Kopliks spots, an oral manifestation of measles, appear as small white lesions resembling grains of salt on the buccal mucosa. Because they often occur during the prodrome of measles, they frequently go unnoticed. Measles is relatively uncommon now because of active immunization [4]. Congenital white lesions White sponge nevus The white sponge nevus is a rare autosomal dominant trait often first noted in childhood. In this distinctive lesion, the oral mucosa is thickened, folded, and white and merges imperceptibly with surrounding normal mucosa. This is most commonly found on the buccal mucosa, but the entire mucosa may be involved with the exception of the attached gingiva. Histologically, there is epidermal hyperplasia, hyperkeratosis, parakeratosis, and cellular vacuolization in the granular and squamous layers caused by intracellular edema. Isolated cells may show an eosinophilic perinuclear condensation of cytoplasm, which on electron microscopy is noted to be dense aggregates of tonofilaments. The condition is benign and requires no treatment [33,43,44]. Pachyonychia congenita Pachyonychia congenita is an autosomal dominant condition characterized by hyperkeratotic white striations or multiple white plaques on the buccal mucosa, labial mucosa, tongue, and gingiva. On histopathologic examination, one sees changes resembling white sponge nevus. The oral lesions do not have an increased propensity for malignancy. Other features include severe hyperkeratosis of the nail beds and palmoplantar keratotic plaques [45]. Dyskeratosis congenita Dyskeratosis congenita is a rare disease that initially presents as oral lesions between ages 5 and 10. Mucosal blisters that rupture and leave painful ulcers are the first sign of disease. Repeated recurrences lead to the development of intraoral atrophy and leukoplakia. As opposed to pachyonychia congenita, malignant transformation of these white lesions into squamous cell carcinoma may occur. Other common characteristics include dystrophic
White lesions Acquired white lesions Leukoplakia Leukoplakia is a term used to describe a chronic white lesion that cannot be rubbed off and for which there is no known cause. Leukoplakia is a common finding in users of chewing tobacco, a habit that is unfortunately common in children and teenagers [19]. Leukoplakia most commonly is found in the buccal and labial sulcus where the tobacco is held. Smokeless tobacco users of all ages are at risk of dysplastic change and squamous cell carcinoma; biopsies of leukoplakia should be obtained [3]. Trauma Trauma in the form of self-induced habitual chewing of the buccal mucosa can lead to diffuse white, thickened linear plaques on the buccal mucosa. This is most common in teenagers aged 15 to 19 [3]. Candidiasis Candidiasis, or thrush, is an opportunistic fungal infection of the oral mucosa caused by Candida albicans. This is frequent in infants and children and can be precipitated by broad-spectrum antibiotic therapy, oral corticosteroids, or a compromised immune system. The condition presents with superficial white curd-like plaques on the mucous membranes, which can be wiped off. For infants, nystatin suspension applied to a gauze and held on the affected surfaces can be an effective treatment. A child may be able to swish and expectorate a nystatin solution or use a clotrimazole lozenge [3,35]. Leukoedema Leukoedema is an acquired dermatosis characterized by the presence of edematous, opalescent, whitish gray lesions forming plaques diffusely over the oral mucosa with the exception of the floor of the mouth and palate. Characteristically, the lesions become less white and less perceptible when stretched helping to distinguish it from other processes. The exact cause is unknown. The condition is most prevalent in blacks but does also occur in other ethnic groups. On histopathology, one sees epithelial hyperplasia with broad, irregular rete ridges and
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nails and reticulate gray-brown pigmentation on the face, neck, chest, and flexures. An X-linked recessive mode of inheritance is most frequently noted [34]. Early mortality may result from bone marrow failure. Other serious extracutaneous features include pulmonary disease and a predisposition to malignancy [46]. Dariers disease Dariers disease or dyskeratosis follicularis is an uncommon autosomal dominant genodermatosis that first becomes noted during childhood or adolescence. Oral lesions, when they occur, typically follow the other cutaneous features of Dariers disease but can be helpful in making the diagnosis. One sees minute, red papules that turn whitish and coalesce into hypertrophic plaques with a cobblestone appearance involving the gingiva, palate, buccal mucosa, and tongue. This can result in a characteristic lacy white network on the oral mucosa. Other cutaneous manifestations include greasy, hyperkeratotic, yellowbrown papules in a seborrheic distribution and characteristic nail changes with longitudinal red streaks and distal notching of the nail plate. The typical histologic findings of acantholysis and dyskeratosis along with the clinical features are helpful in making the diagnosis [34].
intraoral melanoma is extremely rare in childhood, many advocate prophylactic excision of all intraoral pigmented nevi because of their infrequent occurrence [48].
Peutz-Jeghers syndrome Peutz-Jeghers syndrome is an autosomal-dominant condition with gastrointestinal polyposis and mucocutaneous hyperpigmented maculae. More than 95% of patients have distinctive hyperpigmented maculae involving the lips and buccal mucosa (Fig. 11). Pigmented maculae may be noted in infancy, long before polyps are diagnosed. Hyperpigmented maculae may also be noted on the digits, or on periorbital, perianal, or vulvar skin. Benign, hamartomatous polyps involving the small intestine, colon, and stomach result in colicky abdominal pain, melena, hematemesis, anemia, and prolapsed rectal polyps. Patients are also at an increased risk of both gastrointestinal and nongastrointestinal carcinomas [34,49].
Generalized hyperpigmentation Generalized hyperpigmentation of the oral mucosa can be seen in a number of settings. It can be drug-induced related to use of anticonvulsants, adrenocorticotropic hormone therapy, cytotoxic agents, oral contraceptives, antimalarial drugs, and minocycline. Other rare causes include systemic diseases, such as hemochromatosis; neurofibromatosis; incontinentia pigmenti; Addisons disease; and Albrights syndrome [4].
Pigmented lesions of the oral mucosa Macular hyperpigmentation Macular hyperpigmentation of the oral mucosa describes a normal variant seen in patients with darker skin. This can occur anywhere intraorally, but a common pattern is a pigmented band at the junction of the free and attached alveolar mucosa [11]. Amalgam tattoo The most common cause of localized oral hyperpigmentation is the amalgam tattoo, which results from trauma to the oral mucosa during placement of an amalgam filling or extraction of a tooth containing amalgam. It presents as asymptomatic blue to black maculae of various sizes. Biopsy should be obtained if there is difficulty in distinguishing it from a melanocytic process [47]. Melanocytic nevi Melanocytic nevi of the oral mucosa are relatively uncommon in children but can occur. Although
Fig. 11. Peutz-Jehgers syndrome. Note the typical hyperpigmented maculae of the lips.
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Summary A thorough examination of the oral mucosa can provide helpful clues toward making a diagnosis in a number of developmental, neoplastic, inflammatory, and infectious conditions. A number of oral lesions seen in infants and children are benign and of no medical significance. In these instances, the ability of the physician to confidently identify the diagnosis, and reassure parents that a lesion is not worrisome, carries significant value. Likewise, the ability to recognize an underlying systemic illness or genetic disease based on an oral examination can also be of tremendous value, particularly when oral involvement is the presenting feature.
References
[1] Cataldo E, Berkman MD. Cysts of the oral mucosa in newborns. Am J Dis Child 1968;116:44 8. [2] Dilley DH, Blozis GG. Common oral lesions and oral manifestations of systemic illnesses and therapies. Pediatr Clin North Am 1982;29:585 611. [3] Dilley DH, Siegel MA, Budnick S. Diagnosing and treating common oral pathologies. Pediatr Clin North Am 1991;38:1227 64. [4] Luker J. Diseases of the oral mucosa and tongue. In: Harper J, Oranje A, Prose N, editors. Textbook of pediatric dermatology. 1st edition. Oxford: Blackwell Science; 2000. p. 1435 59. [5] Buchanan S, Jenkins CR. Riga-Fedes syndrome: natal or neonatal teeth associated with tongue ulceration. Aust Dent J 1997;42:225 7. [6] Dela Monte SM, Radowsky M, Hood AF. Congenital granular cell neoplasms: an unusual case report with ultrastructural findings and a review of the literature. Am J Dermatopathol 1986;8:57 63. [7] Tucker MC, Rusnock EJ, Azumi N, et al. Gingival granular cell tumors of the newborn: an ultrastructural and immunohistochemical study. Arch Pathol Lab Med 1990;114:895 8. [8] Sato M, Tanaka N, Sato T, et al. Oral and maxillofacial tumors in children: a review. Br J Oral Maxillofac Surg 1997;35:92 5. [9] Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med 1999;341:1173 81. [10] Levin LS, Jorgenson RJ, Jarvey BA. Lymphangiomas of the alveolar ridges in neonates. Pediatrics 1976; 58:881 4. [11] Metry DW, Hebert AA. Neonatal mucous membrane disorders. In: Eichenfield LF, Frieden IJ, Esterly NB, editors. Textbook of neonatal dermatology. 1st edition. Philadelphia: WB Saunders; 2001. p. 473 86. [12] Heyl T, Raubenheimer EJ. Sucking pads (sucking calluses) of the lips in neonates: a manifestation of transient leukoedema. Pediatr Dermatol 1987;4:123 8.
[13] Murthy P, Laing MR. Macroglossia. BMJ 1994;309: 1386 7. [14] Messner AH, Lalakea ML, Aby J, et al. Ankyloglossia: incidence and associated feeding difficulties. Arch Otolaryngol Head Neck Surg 2000;126:36 9. [15] Guarisco JL, Littlewood SC, Butcher RB. Sever upper airway obstruction in children secondary to lingual tonsil hypertrophy. Ann Otol Rhinol Laryngol 1990; 99:621 4. [16] Arancibia P, Veliz J, Barrai M, et al. Lingual thyroid: report of three cases. Thyroid 1998;8:1044 57. [17] Gallo A, Leonetti F, Torri E, et al. Ectopic lingual thyroid as an unusual cause of severe dysphagia. Dysphagia 2001;16:220 3. [18] Bezena S, Costa I. Oral conditions in children from birth to 5 years: the findings of a childrens dental program. J Clin Pediatr Dent 2001;25:79 81. [19] Kleinman DV, Swango PA, Pindborg JJ. Epidemiology of oral mucosal lesions in United States schoolchildren. Community Dent Oral Epidemiol 1994;22: 243 53. [20] Hubler WR. Lingual lesions of generalized pustular psoriasis: report of 5 cases and a review of the literature. J Am Acad Dermatol 1984;11:1069 76. [21] Sigal MJ, Mock D. Symptomatic benign migratory glossitis: report of two cases and literature review. Pediatr Dent 1992;14:392 6. [22] La Placa M, Ghersetich I. Infections of the oral cavity. In: Lotti TM, Parish LC, Rogers RS, editors. Oral diseases textbook and atlas. 1st edition. Berlin: Springer; 1999. p. 78 128. [23] Park AH, Batchra N, Rowley A, et al. Patterns of Kawasaki syndrome presentation. Int J Pediatr Otorhinolaryngol 1997;40:41 50. [24] Newman CC, Wagner RF. Black hairy tongue. N Engl J Med 1997;337:897. [25] Skinner RL, Davenport WD, Weir JC, et al. A survey of biopsied oral lesions in pediatric dental patients. Pediatr Dent 1986;8:163 7. [26] Aguilo L, Cibrian R, Bagan JV, et al. Eruption cysts: retrospective clinical study of 36 cases. ASDC J Dent Child 1998;65:102 6. [27] Berman FR, Fay JT. The retrocuspid papilla. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1976;42:80. [28] Buchner A, Merrell PW, Hansen LS. The retrocuspid papilla of the mandibular lingual gingiva. J Periodontol 1990;61:585 9. [29] Prato GP, Cortellini P, Lorusso B, et al. Periodontal diseases. In: Lotti TM, Parish LC, Rogers RS, editors. Oral diseases textbook and atlas. 1st edition. Berlin: Springer; 1999. p. 239 46. [30] Willies-Jacobo LJ, Isaacs HJ, Stein MT. Pyogenic granuloma presenting as a congenital epulis. Arch Pediatr Adolesc Med 2000;154:603 5. [31] Crine JD, Tilson HB. Malignant lymphomas of the oral soft tissues. J Oral Surg 1998;36:971 4. [32] Fitzpatrick R, Rapaprot MJ, Silva DG. Histiocytosis X. Arch Dermatol 1981;117:253 7. [33] Hernandez-Martin A, Fernandez-Lopex E, de Unamuno
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P.M. Witman, R.S. Rogers III / Dermatol Clin 21 (2003) 157170 P, et al. Diffuse whitening of the oral mucosa in a child. Pediatr Dermatol 1997;14:316 20. Katsambas AD, Feliciani C, Jordan R, et al. Genetic diseases of oral mucosa. In: Lotti TM, Parish LC, Rogers RS, editors. Oral diseases textbook and atlas. 1st edition. Berlin: Springer; 1999. p. 39 75. Silverman RA. Diseases of the mucous membranes in children. Clin Dermatol 1987;5:137 56. Meyer RD. Cutaneous and mucosal manifestations of the deep mycotic infections. Acta Derm Venereol 1986;121:57 72. Nowak AJ. Oropharyngeal lesions and their management in epidermolysis bullosa. Arch Dermatol 1988; 124:742 5. Renfro L, Grant-Kels JM, Feder HM. Controversy: are systemic steroids indicated in the treatment of erythema multiforme? Pediatr Dermatol 1989;6:43 50. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria and causes. J Am Acad Dermatol 1983;8: 763 5. Green JA, Sprianci SL, Wenerstrom G, et al. Post-herpetic erythema multiforme prevented with prophylactic oral acyclovir. Ann Intern Med 1985;102:632 8. Rogers RS. Recurrent aphthous stomatitis: clinical characteristics and associated systemic disorders. Semin Cutan Med Surg 1997;16:278 83. [42] Duncan SC, Su WP. Leukoedema of the oral mucosa: possibly an acquired white sponge nevus. Arch Dermatol 1980;116:906 8. [43] Richard G, De Laurenzi V, Didona B, et al. Keratin 13 point mutation underlies the hereditary mucosal epithelial disorder white sponge nevus. Nat Genet 1995; 11:453 5. [44] Rugg EL, Mclean WH, Allison WE. A mutation in the mucosal keratin K4 is associated with oral white sponge nevus. Nat Genet 1995;11:450 2. [45] Feinstein A, Friedman J, Schewach-Millet M. Pachyonychia congenita. J Am Acad Dermatol 1988; 19:705 11. [46] Dokal I. Dyskeratosis congenita. Br J Haematol 1999;105(suppl 1):11 5. [47] Owens BM, Johnson WW, Schuman JJ. Oral amalgam pigmentations (tattoos): a retrospective study. Quintessence Int 1992;23:805 10. [48] Buchner A, Leider AS, Merrell PW, et al. Melanocytic nevi of the oral mucosa: a clinicopathologic study of 130 cases from northern California. J Oral Pathol Med 1990;19:197 201. [49] Corridor J, Wambach J, Barnard J. Gastrointestinal polyps in children: advances in molecular genetics, diagnosis, and management. J Pediatr 2001;138: 621 8.
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Dermatol Clin 21 (2003) 171 182
Oral manifestations of systemic disease

Edwin T. Parks, DMD, MS*, Henry Lancaster, DMD
Department of Oral Pathology, Medicine, and Radiology, Indiana University School of Dentistry, West Michigan Street, Indianapolis, IN 46202, USA
Most systemic diseases can affect the oral cavity. Some oral changes are nonspecific, whereas others directly lead to the diagnosis of a particular disorder. A systems approach is used here to catalog these oral changes. In some instances it is difficult to separate the oral manifestations of pharmacotherapy for a particular disease from that entity. The oral manifestations of pharmacotherapy are presented for selected disease processes. This article introduces the most common oral manifestations of systemic disease.
Cardiovascular system There are no specific oral changes that can be attributed to diseases that affect the cardiovascular system. The oral changes associated with disease of the cardiovascular system can be grouped into two distinct areas: risk factors and manifestations of pharmacotherapy. Risk factors Numerous articles have chronicled the relationship between periodontal disease and cardiovascular disease in the scientific literature [1]. Although it cannot be said that a direct relationship exists between periodontal disease and cardiovascular disease, several longitudinal studies have indicated that the presence of alveolar bone loss (as a result of periodontal disease) increases the risk of death from cardiovascular disease from 1.9 to 3 times the death rate of the
sample population without periodontal disease [2 4]. Albandar et al [5,6] report that 35% of the adult US population have some form of bony periodontal destruction and over half of the population have some soft tissue component of periodontal disease. The common oral findings associated with periodontal disease are gingival erythema, gingival enlargement, and ultimately loss of attachment (Fig. 1). Research is ongoing to identify the exact relationship between periodontal and cardiovascular disease. Another recent dental finding related to cardiovascular disease is the presence of calcifications within the carotid arteries. These calcifications can be identified in dental panoramic images (Fig. 2). The presence of these calcifications is indicative of an increased risk for a cerebrovascular accident. Carter et al [7,8] identified carotid calcifications in approximately 5% of the panoramic radiographs of a dental school population. Most of these patients reported additional risk factors for stroke. Doris et al [9] reported a high correlation between the findings of carotid calcifications in plain film imaging and in more sophisticated imaging techniques (eg, angiography or ultrasound). Care must be taken not to confuse hyoid bone calcifications with carotid artery calcifications. The significant morbidity associated with cerebrovascular accidents makes it imperative that patients with radiographic findings of carotid calcifications be referred to their physician for additional work-up. Oral manifestations of cardiovascular pharmacotherapy Many of the medications used to treat cardiovascular diseases have effects on the oral cavity. The
* Corresponding author. E-mail address: edparks@iupui.edi (E.T. Parks).
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E.T. Parks, H. Lancaster / Dermatol Clin 21 (2003) 171182
Fig. 1. Moderate periodontal disease. Heavy deposits of dental plaque and calculus are present at the cervical regions of the teeth. (From Mayo Clin Proc 1999;74: 223 8: with permission.)
Fig. 3. Abnormal pigmented lesions on the lips of a patient diagnosed with a lung malignancy. (Courtesy of D-J. Summerlin, DMD, MS, Indianapolis, IN.)
most significant adverse effect is xerostomia [10]. Xerostomia is the subjective feeling of dryness of the oral cavity. Xerostomia is very common in patients taking diuretics to control either hypertension or edema. The lack of saliva can have profound effects on the oral health of the patient. Patients with xerostomia usually demonstrate a high caries rate. Additionally, oral candidal infections are seen more frequently in patients with a dry mouth. Although several medications (eg, pilocarpine hydrochloride [Salagen] and civemeline hydrochloride [Evoxac]) exist to treat dry mouth, by and large they are contraindicated for use in patients with a history of cardiovascular disease. Calcium channel blockers can produce significant gingival enlargement in both dentate and edentulous patients [11]. Finally, multiple cardiovascular medications, such as angiotensin-con-
verting enzyme inhibitors, b-blockers, and loop diuretics, can produce oral lichenoid reactions [12].
Respiratory system Because of the oral cavitys proximity to the respiratory tract it often becomes the location of clinical manifestations of illnesses affecting the respiratory system. Merchant [13] showed that nearly 25% of patients with malignant lung disease (eg, bronchogenic carcinoma) presented with abnormal pigmentation of the soft palate. The pigmented lesions are usually on the lateral surface of the soft palate, but can occur anywhere on the oral mucosa. Oral lesions can vary from a unilateral macule 4 mm in size to considerably larger areas (Fig. 3) [14]. One may hypothesize that the pigmentation is a result of the
Fig. 2. Panoramic radiograph demonstrating calcifications within the carotid artery. Two calcifications are identified by the white arrows.
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high incidence of smoking in this population; however, Merchant showed a much lower incidence of abnormal pigmentation in a population with similar rates of smoking but with no lung malignancies [14]. Although tuberculosis is still rare, it is on the rise. In 1991 there were a total of 26,283 cases in the United States [15]. Tuberculosis is a chronic bacterial infection that usually forms granulomas in the lungs. An untreated patient with significant lung involvement can present with oral lesions. Up to 3.5% of tuberculosis sufferers can have oral ulcers similar in appearance to major aphthous ulcers, or a discrete granular mass [16]. The most common areas affected are the gingiva and the base of the tongue. It is thought that seeding of the oral tissue with tuberculosis bacilli when the patient repeatedly coughs up infected sputum produces the lesions. Sarcoidosis can occasionally involve the oral cavity with lesions that can affect various oral structures including the lips, tongue, buccal mucosa, floor of mouth, palate, gingiva, and the salivary glands (Fig. 4) [17]. Sarcoidosis affects 10 to 40 per 100,000 people in the United States, and to date there have been 47 documented cases of oral involvement [17]. It can affect people of any age, sex, and race. The typical oral lesions can include firm, asymptomatic, submucosal masses of the tongue or buccal mucosa. Gingival tissue can appear erythematous and enlarged with occasional ulceration. These patients may exhibit Heerfordts syndrome, which is a triad of bilateral parotid gland enlargement, uveitis, and a low-grade fever. Associated palsy of the facial and mandibular nerves also has been reported [18 20]. A respiratory illness that may escape diagnosis for much of its course is Wegeners granulomatosis. Wegeners is an inflammatory condition of unknown cause that usually manifests as a triad of respiratory, kidney, and vascular inflammation. One must be aware
Fig. 5. Photograph of a patient with Wegeners granulomatosis. The erythematous, granular appearance of the gingiva is referred to as strawberry gingivitis. (Courtesy of G.W. Mirowski, DMD, MMSc, MD, Indianapolis, IN.)
that the initial presentation of Wegeners can be one of intraoral lesions [21]. The oral lesions commonly involve the gingiva and appear as red, granular, and sometimes ulcerative lesions (Fig. 5). This is referred to as strawberry gingivitis because of its similar appearance in texture and color to a strawberry.
Gastrointestinal system Because digestion starts in the oral cavity, oral manifestations of gastrointestinal diseases are quite common. At least 15% of the adult US population reports some symptoms of gastroesophageal reflux disease [22]. The pediatric population is not immune to the symptoms of gastroesophageal reflux disease. Although the prevalence of symptoms is lower, reported regurgitation displays a similar prevalence with the adult population [23,24]. Although many of these individuals have mild symptoms, a fair proportion has significant esophageal reflux that can find its way into the oral cavity [25,26]. The pH of stomach contents is low enough to dissolve the enamel of the teeth. Immediate brushing of the teeth after reflux into the oral cavity can accelerate the loss of tooth structure. Patients with persistent gastroesophageal reflux disease should be instructed to rinse the mouth with water or a dilute baking soda solution to neutralize the oral pH before brushing the teeth. The dentin becomes more visible as the enamel dissolves and the teeth exhibit a more yellow color (Fig. 6). The teeth most commonly affected are the upper incisors and the lower molars and premolars. Loss of enamel structure produces many dental problems, such as
Fig. 4. Sarcoid lesions affecting the gingival tissues. The erythematous areas indicated by the arrows are granulomas of the gingiva.
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with inflammatory bowel disease [32]. The oral lesions present as numerous punctate pustular eruptions on the labial and buccal mucosa and the palate. Lesions are rarely found on the tongue or on the floor of the mouth. The pustules often coalesce and break leaving superficial erosions. Pyostomatitis vegetans is usually treated with corticosteroids, but also responds to the management of the inflammatory bowel disease.
Endocrine system A variety of soft tissue lesions have been associated with diabetes. Those most commonly reported include candidal infections, fissured tongue, irritation fibroma, and traumatic ulcers. Additionally there seems to be a higher incidence of periodontal disease and complaints of dry mouth. The complaints of xerostomia may be related to the adverse effects of medications with this group of patients [33]. Candidosis manifesting as angular cheilitis, atrophy of tongue papillae, median rhomboid glossitis, and denture stomatitis were found in greater than 15% of diabetic patients according to Guggenheimer et al [34]. The combined prevalence of the previously mentioned noncandidal lesions was determined to be 44.4% among insulin-dependent diabetics [33]. Oral findings seem to be related to the type of diabetes, history of smoking, and poor glycemic control [34]. Diffuse oral pigmentation may be suggestive of Addisons disease. Addisons, a primary deficiency of adrenocorticotropic hormone, is characterized by weakness, fatigue, and abnormal bronzing of the skin and pigmentation of the oral mucosa [35]. Although rare, Addisons disease is increasingly being seen in AIDS patients as a result of damage from opportunistic infections of the adrenal glands. Clinically this disease can present as light brown to black pigmented
Fig. 6. Enamel erosion in a patient with gastroesophageal reflux disease. The slightly darker line that follows the contour of the dental crowns is the junction between enamel and dentin. This region is not visible in the normal dentition.
restoration failure and dentinal sensitivity. Continued reflux has a significant impact on the methods used to restore teeth that have lost enamel structure. Definitive restoration of the teeth may be deferred until reflux is controlled in patients with severe gastroesophageal reflux disease with attendant reflux into the oral cavity. Recurrent aphthous ulcerations are very common oral mucosal findings. The prevalence of recurrent aphthous ulcerations ranges from 10% to 50% depending on the study population [27 29]. Aphthous ulcers appear as a shallow, round ulcer with a band of erythema surrounding the ulcer (Fig. 7). Most aphthous ulcers heal without scarring in 10 to 14 days. Many different etiologic agents and conditions have been identified with regard to aphthous ulcers, the most common of which is local trauma. Recurrent aphthous ulceration has been implicated with ulcerative colitis, Crohns disease, coeliac disease, and numerous vitamin deficiencies that may or may not be associated with a malabsorption disorder [29 31]. Numerous nongastrointestinal disorders have also been implicated in the etiology of recurrent aphthous ulcerations. It is apparent that not all aphthous ulcerations are related to gastrointestinal disorders. Gastrointestinal disorders, however, should be considered as a possible etiologic agent in patients with persistent aphthae or recurrent aphthous ulcerations with a high rate of recurrence. Pyostomatitis vegetans is a rare oral condition but is presented here because of its association with ulcerative colitis and, to a lesser extent, Crohns disease [31,32]. A recent review of pyostomatitis vegetans found that 78% of all reported cases had an association
Fig. 7. Aphthous ulcer. This patient has Crohns disease.
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Fig. 8. Addisons disease can present with pigmented lesions of the buccal mucosa as seen in this patient. (Courtesy of DJ. Summerlin, DMD, MS, Indianapolis, IN.)
maculae on the lips, gingival, buccal mucosa, or tongue (Fig. 8) [36].
Skeletal system Quite often illnesses of the skeletal system result in clinically obvious oral manifestations. One such disturbance is Pagets disease of bone. Pagets disease of bone is seldom found in patients younger than 40. Because of uncontrolled osteoclastic and osteoblastic activity, there is excessive bone formation resulting in increased bone volume with a concurrent decrease in bone strength. Advanced cases of Pagets disease of bone can cause compression of cranial nerves leading to loss of hearing and even sight. The first oral sign may be an increased space between the teeth as the maxillary bone increases in size (Fig. 9). Often edentulous patients may be diagnosed because of complaints about their denture becoming too tight after years of normal wear [16]. A severe complication is
development of osteosarcomas, which occurs in 60% of patients over 50 years of age [37]. Surgical removal of bone is contraindicated in this population because of the high rate of complicated osteomyelitis [16]. Osteogenesis imperfecta, also known as brittle bone disease, is an autosomal-dominant disease of collagen formation that is characterized by blue sclera, hearing loss, growth deficiency, and multiple long bone fractures. Osteogenesis imperfecta is currently classified into four types based on the particular genetic mutation and severity. Among the type III and IV patients one study shows that greater than 80% also exhibit dentinogenesis imperfecta [38]. Dentinogenesis imperfecta is a condition that results in a dentition that may be markedly discolored. The discoloration can be yellow-brown or blue-gray. The involved teeth are very susceptible to chipping of the enamel and excessive wear of the incisal and occlusal surfaces (Fig. 10). Up to 80% of osteogenesis imperfecta patients also exhibit class III malocclusion (prognathic mandible) [38].
Nervous system The oral cavity is highly innervated. Consequently, many oral components of neurogenous disease processes, such as tic douloureux and medicationinduced oral dyskinesias, have been described. Tic douloureux is a form of trigeminal neuralgia that presents with a trigger zone. Light contact with the trigger zone causes an intense lancinating pain that follows the affected branch of the trigeminal nerve. The patients response to this pain is most likely responsible for the involuntary grimace or movement of the head (tic). The involuntary movements of the facial and oral musculature seen in many of the oral
Fig. 9. Photograph of patient suffering from Pagets disease of bone. Note the spaces (diastemas) between the maxillary teeth caused by the large deposition of bone in the maxilla. (Courtesy of D-J. Summerlin, DMD, MS, Indianapolis, IN.)
Fig. 10. Dentinogenesis imperfecta in the presence of osteogenesis imperfecta type IV. The arrows indicate dark discoloration of teeth and chipped enamel surfaces.
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Fig. 11. Gingival hyperplasia. Phenytoin-induced gingival hyperplasia in a black man.
Fig. 12. Multiple oral mucosal neuromas. Multiple neuromas in a 13-year-old white man with multiple endocrine neoplasia type IIB. Two neuromas are identified with white arrows.
dyskinesias are associated with the chronic use of neuroleptic medications [39,40]. These involuntary movements do not diminish when the medications are diminished. Taste alterations have long been associated with mineral or vitamin deficiencies or the aging process [41]. These alterations usually have an insidious onset and tend to affect the classic taste sensations equally (sweet, sour, salt, and bitter). Rapid onset alteration of taste sensation or alteration of one specific taste sensation may indicate an intracranial space-occupying lesion or central neurologic disorder [42,43]. Phenytoin is commonly used to manage certain forms of epilepsy. Gingival hyperplasia is a very common side effect of the phenytoins (Fig. 11). Good oral hygiene practices can minimize the impact of phenytoin on the gingival tissues. Neurofibromatosis types I and II are common disorders (approximately 1 in 3000 live births) that often demonstrate oral manifestations [44]. The most common oral manifestation of neurofibromatosis is the presence of mucosal neurofibromas. These intraoral neurofibromas occur in approximately 25% of patients with neurofibromatosis. The rate of malignant transformation of mucosal neurofibromas is similar to that of cutaneous neurofibromas. Additional oral manifestations include enlarged fungiform papillae and bony erosion adjacent to a soft tissue tumor (eg, widening of the mandibular canal space caused by a neurofibroma involving the inferior alveolar nerve). Multiple endocrine neoplasia type IIB is an autosomal-dominant disorder that consists of medullary thyroid carcinoma, pheochromocytoma, marfanoid habitus, and mucosal neuromas [45,46]. Mucosal neuromas are commonly found in the oral cavities of individuals with multiple endocrine neoplasia type IIB (Fig. 12). The significance of these oral mucosal neuromas is that their presence may precede the onset of the potentially devastating neoplasms associated
with this syndrome and accelerates diagnosis and management of the syndrome. Metastatic thyroid carcinoma has been reported in an infant with multiple endocrine neoplasia type IIB less than 1 year old [47].
Hematologic system Many clinicians may be unaware that cases of leukemia can first present in the mouth. Leukemia, a cancer of the white blood cells, results from uncontrolled proliferation of an abnormal hematopoietic cell and leads to marrow failure. It is classified according to the primary hematopoietic cell affected and as to the acute or chronic course of the disease [48]. It is estimated that 10% of cases exhibit oral signs of leukemic infiltrate. Oral manifestations may occur as generalized hyperplasia of the gingiva. The gingival tissues are swollen and soft and easily bleed (Fig. 13). As a result of the anemia associated with leukemia, one may also present with mucosal pallor, multiple petechia, and ecchymoses of the oral tissues. Treat-
Fig. 13. Severe, generalized hyperplasia of gingival caused by leukemia infiltrate in a patient with leukemia. (Courtesy of D-J. Summerlin, DMD, MS, Indianapolis, IN.)
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Fig. 14. The lichenoid lesions of chronic graft-versus-host disease present in the palate of a patient 2 years status post bone marrow transplant.
ment for leukemia can also be responsible for further oral lesions. Chemotherapy can cause mucositis of the oral cavity and bone marrow transplant may lead to graft-versus-host disease. When present in the mouth, graft-versus-host disease is both clinically and histologically identical to oral lichen planus (Fig. 14). Extranodal lymphomas account for approximately 24% of total lymphomas, and involvement of the oral cavity is relatively rare [49]. Tomich and Shafer [50] reported oral involvement in 0.1% to 0.2% of cases of non-Hodgkins lymphoma. When the oral region is the site of non-Hodgkins lymphoma, it can involve several areas including the gingiva, floor of mouth, palate, buccal vestibule, and the bone of the maxilla or mandible. It has also been reported that patients with Sjo grens syndrome are 44 times more likely to develop a primary lymphoma than healthy patients [51]. The parotid gland is the usual location and presents clinically as a unilateral swelling in the parotid region. According to Fukuda et al [52], a painless soft tissue swelling commonly is the initial presentation in cases of intraoral lymphoma (Fig. 15). In the case of bony involvement, numbness, paresthesia, or loose teeth may accompany the swelling [52]. Treatment for oral lymphoma is local radiation in stage I cases and combination chemotherapy in advanced cases [49]. Many cases of aphthous ulceration are of unknown cause or are somehow linked to gastrointestinal disorders or to infectious processes. One type, however, may be attributed to a decrease in circulating neutrophils. Cyclic neutropenia is a condition characterized by an episodic defect in development of neutrophils in the marrow leading to periodic decreases in mature neutrophils in the circulation. In many cases the patients white cell count falls to approximately 3000 each month for a period of 5 days [16]. It is shortly
Fig. 15. Oral lymphoma. The lesion presented as a soft swelling in the patients palate (arrows). (Courtesy of D-J. Summerlin, DMD, MS, Indianapolis, IN.)
after this phase that oral ulcers can arise (Fig. 16). The ulcers may last for 3 to 5 days. In addition to the ulcers, the patient may have fever, malaise, and cervical lymphadenopathy [53]. Serial white cell counts are indicated to make a diagnosis in these cases because of the cyclic nature of the neutropenia. A deficiency of vitamin B12, also called pernicious anemia, is primarily a disease of the elderly with the average patient presenting at age 60 [54]. Pernicious anemia is caused by the inability to absorb vitamin B12 across the intestinal wall because of the lack of intrinsic factor. This deficiency results in megaloblastic or macrocytic anemia and oral conditions. The classic oral manifestation of pernicious anemia is
Fig. 16. Cyclic neutropenia. The arrow indicates a large area of ulcerated mucosa on the palate. These ulcers resemble recurrent aphthous ulcers.
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bald tongue. The tongue appears smooth with an erythematous cast because of the depapillation of the dorsal surface [16]. Commonly these patients complain of pain and burning of the tongue and oral cavity. Monthly parenteral administration of vitamin B12 is curative for these patients.
Immune system A vast number of disease processes have an immunologic component. Many of these diseases present with oral signs. HIV infection has been extensively studied. A large array of oral manifestations has been reported in the literature [55,56]. The most commonly encountered oral lesions or conditions are oral candidiasis, oral hairy leukoplakia, Kaposis sarcoma, and ulceration [55,56]. Several different presentations of oral candidiasis can be encountered (Fig. 17). Pseudomembranous candidiasis presents as a whitish plaque that, when removed, leaves a superficially denuded mucosal surface. Erythematous candidiasis appears as a subtle smooth red patch. This change is often difficult to detect on a mucosal surface that is already somewhat red. Attendant complaints of taste alteration or oral burning are suggestive of candidiasis. Hyperplastic candidiasis presents as a thickened white patch that cannot be removed. The prevalence of oral candidiasis increases as the CD4 count falls. Several other fungal infections have been associated with HIV infection but are not seen with the frequency of candidiasis. Several forms of antifungal therapy are available. The efficacy of systemic antifungal agents can be diminished by lack of compliance, poor absorption, or the interaction of other medications. Topical antifungal agents can also be affected by compliance and, if the patient suffers from xerosto-
Fig. 18. Oral hairy leukoplakia. Oral hairy leukoplakia on the lateral borders of the tongue of a HIV-positive man. (Courtesy of G.W. Mirowski, DMD, MMSc, MD, Indianapolis, IN.)
mia, they have great difficulty dissolving a troche in their mouth. The sugar content of topical agents can impact the caries experience of the patient. The patients toothbrush, oral appliances, inhalers, and lipstick should be considered as fungal reservoirs and need to be treated to eliminate the infection and diminish reinfection successfully. Oral hairy leukoplakia is commonly seen on the lateral border of the tongue but can appear in other parts of the oral cavity. It appears as a corrugated or hairy white patch (Fig. 18). Oral hairy leukoplakia has also been reported in kidney transplant patients and other groups of immunosuppressed individuals [55]. Oral hairy leukoplakia is present in approximately 20% of asymptomatic HIV-infected individuals. The prevalence of oral hairy leukoplakia increases with decreasing CD4 cell counts [55]. Kaposis sarcoma presents as a purple or red plaque that can become papular and ulcerated. The most common intraoral location of Kaposis sarcoma is the palate followed by the gingiva and tongue (Fig. 19) [57]. Hermans [58] has reported a decrease in incidence of Kaposis sarcoma with the advent of protease inhibitor therapy.
Fig. 17. Oral candidiasis. Pseudomembranous candidiasis on the palate of a HIV-positive man.
Fig. 19. Kaposis sarcoma. Kaposis sarcoma on the palate of a HIV-positive man.
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The diagnosis of specific types of oral ulceration can be challenging in the HIV-infected patient. The typical distribution of both herpes simplex lesions and recurrent aphthae is disrupted as the degree of immunosuppression increases. Additionally, the level of immunosuppression diminishes the striking inflammatory response associated with recurrent aphthous ulcerations. Consequently, a herpetic lesion can appear where an aphthous ulcer is anticipated and vice versa. Biopsies should be obtained from any oral ulcer before initiating therapy. Systemic lupus erythematosus is an autoimmune disease process that can affect virtually every organ system [59]. Oral lesions are frequently encountered in patients with systemic lupus erythematosus with reported prevalence ranging from 9% to 45% [60 62]. Oral ulcerations are the most commonly reported oral lesions [63,64]. The appearance of the ulcer can be confused with erosive lichen planus and should undergo biopsy (Fig. 20). White plaques have also been associated with systemic lupus erythematosus. These white lesions are nonspecific and also should undergo biopsy. Schidt [62] reported that oral lesions were the first manifestation of systemic lupus erythematosus in 40% of his study group. Sjo grens syndrome is the second most common autoimmune disease (after rheumatoid arthritis) and is comprised of dry eyes (keratoconjunctivitis sicca) and xerostomia [65,66]. Thomas et al [67] reported a 3% to 4% prevalence of Sjo grens syndrome in the adult population. Because dry eyes and dry mouth are fairly common complaints in the adult population, the diagnosis should be confirmed through laboratory tests or labial salivary gland biopsy. Dry mouth or xerostomia has a serious effect on the health of the oral cavity (Fig. 21). Diminished salivary flow leads to an increased caries rate and potential for candidal
Fig. 21. Xerostomia. Note the dry appearance of the tongue and lips in this Sjo grens syndrome patient.
Fig. 20. Oral ulceration in a patient with systemic lupus erythematosus. The lesion has many similarities with erosive lichen planus. These similarities make biopsy a necessity.
infections. Additionally, the patients nutritional intake can be altered significantly because of the difficulty in chewing and swallowing many foods. Parasympathomimetics, such as pilocarpine hydrochloride and civemeline hydrochloride, can increase both salivary and lacrimal output as long as functional glandular parenchyma is still present [68]. Enlargement of major salivary glands is often seen in Sjo grens syndrome patients. Although dry eyes and dry mouth can have a significant impact on the quality of life, they are not life threatening and may not be pursued with much diagnostic rigor. The concern with a diagnosis of Sjo grens syndrome is the association with non-Hodgkins lymphoma. Voulgarelis et al [69] reported a 4.3% prevalence of non-Hodgkins lymphoma in a fairly large population of patients with Sjo grens syndrome. These findings are similar to those reported by Jordan and Speight [51]. This high prevalence of non-Hodgkins lymphoma in Sjo grens syndrome patients necessitates a complete diagnostic work-up for patients who complain of dry mouth and dry eyes. Many systemic disorders have oral manifestations. The oral component may precede the systemic pre-
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E.T. Parks, H. Lancaster / Dermatol Clin 21 (2003) 171182 wald E, Wilson JD, Martin JB, Fauci AS, Kasper DL, editors. Harrisons principles of internal medicine. 13th edition. New York: McGraw-Hill; 1994. p. 710 8. Sapp JP, Eversole LR, Wysocki GP. Contemporary oral and maxillofacial pathology. St. Louis: Mosby; 1997. Batal H, Chou LL, Cottrell DA. Sarcoidosis: medical and dental implications. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:386 90. Chisholm DM, Lyell A, Haroon TS, Mason DK, Beeley JA. Salivary gland function in sarcoidosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1971;31:766 71. Cohen DM, Reinhardt RA. Systemic sarcoidosis presenting with Horners syndrome and mandibular paresthesia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1982;53:577 81. Delaney P. Neurologic manifestations in sarcoidosis. Ann Intern Med 1977;87:336 45. Lilly J, Juhlin T, Lew D, Vincent S, Lilly G. Wegeners granulomatosis presenting as oral lesions: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:153 7. Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux disease and the health-related quality of life. Arch Intern Med 2001;161:45 52. Locke GR, Talley NJ, Felt SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997;112:1448 56. Nelson SP, Chen EH, Syniar GM, et al. Prevalence of symptoms of gastroesophageal reflux during childhood: a pediatric practice-based survey. Arch Pediatr Adolesc Med 2000;154:150 4. Locke GR, Talley NJ, Felt SL, et al. Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 1999;106:642 9. Schroeder PL, Filler SJ, Ramirez B, et al. Dental erosion and acid reflux disease. Ann Intern Med 1995; 122:809 15. Embil JA, Stephens RG, Manuel FR. Prevalence of recurrent herpes labialis and aphthous ulcers among young adults on six continents. Can Med Assoc J 1975;113:627 30. Miller MF, Ship II, Ram C. A retrospective study of the prevalence and incidence of recurrent aphthous ulcers in a professional population: 1958 1971. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;43:532 7. Ship JA. Recurrent aphthous stomatitis: An update. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:141 7. Biel K, Bohm M, Luger TA, et al. Long-standing aphthae-a clue to the diagnosis of coeliac disease. Dermatology 2000;200:340. Ficarra G, Cicchi P, Amorosi A, et al. Oral Crohns disease and pyostomatitis vegetans. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1993;75:220 4. Soriano ML, Martinez N, Grilli R, et al. Pyodermatitis-
sentation of a particular disease. Early diagnosis and management can often diminish the morbidity associated with a systemic disease. Careful examination of the oral cavity is a necessary component of the diagnostic work-up for any patient.
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Oral manifestations of genodermatoses

Jennifer L. Hand, MDa,b,*, Roy S. Rogers III, MDa
b a Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Department of Medical Genetics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Hundreds of known genetic disorders affect the mouth and oral mucous membranes. Many of these conditions are associated with late-onset complications that affect a patients overall life expectancy. For example, almost all patients with multiple endocrine neoplasia (MEN) type IIB develop an aggressive form of medullary thyroid cancer [1]. With recent advances in technology and improved screening techniques, the opportunity to prevent life-threatening complications in patients with genetic disorders is greater than ever before. Optimal prevention of secondary complications, however, is dependent on an early, correct initial diagnosis. This article provides a focused review of specific genetic disorders that affect the mouth and also have prominent associated dermatologic features. In several conditions presented here, the oral findings are distinct and may provide the first clue of an underlying genetic diagnosis. In each discussion, clinical features that help confirm a genetic diagnosis are discussed. For these genetic disorders, family members may be at risk. Molecular genetic testing, when available as an aid for diagnosis and genetic counseling, is included in the discussion.
Multiple endocrine neoplasia type IIB Multiple endocrine neoplasia refers to a group of genetic disorders named for their association with
* Corresponding author. Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail address: hand.jennifer@mayo.edu (J.L. Hand).
neoplasm and malignancy of endocrine glands. In MEN type I, the parathyroid gland is most frequently affected by malignancy [2]. In MEN type II, the thyroid gland is most frequently affected [3]. One subtype, MEN IIB, is of particular interest because of its association with oral mucosal neuromas. MEN IIB represents about 5% of cases of MEN II and is also known as mucosal neuroma syndrome or Wagenmann-Froboese syndrome [1,3]. Oral mucosal neuromas may be the first feature to present in infancy or early childhood [3,4]. Mucosal neuromas may be found on the dorsal surface of the tongue, the palate, or pharynx. When found on the tongue, they are considered to be almost pathognomonic of medullary thyroid carcinoma (Fig. 1) [1]. The tongue may appear crenated or notched [4]. Pedunculated symmetric nodules on the buccal mucosa behind each lip commissure have been described [4]. When mucosal neuromas appear as submucosal nodules on the vermilion border of the lips, the resultant thickening of the lips (Fig. 2) is described as pebbly or blubbery [3]. The palate may be high and arched. The jaw may be prominent [1]. All of the oral findings in MEN IIB are generally thought of as asymptomatic and benign [4]. Multiple endocrine neoplasia IIB is distinguished from other MEN syndromes because it alone has associated physical characteristics other than the endocrine findings [4]. Distinct features of MEN IIB include thickened corneal nerves visible by slit lamp examination, a wide-eyed facies (Figs. 3 and 4), a Marfanoid body habitus with joint laxity, and medullary thyroid carcinoma [1,3]. Virtually all patients with MEN IIB develop aggressive medullary thyroid cancer. Early thyroidectomy (eg, at less than 1 year of age) is imperative to prevent metastasis [3].
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Fig. 1. Multiple endocrine neoplasia (MEN) IIB. Mucosal neuromas of the tongue.
Continued monitoring is recommended after thyroidectomy for residual or recurrent cancer. About 50% of patients develop pheochromocytoma [3]. Gastrointestinal problems may be associated because of hamartomatous ganglioneuromatosis of the gastrointestinal tract [1]. Molecular genetics Multiple endocrine neoplasia IIB is inherited in an autosomal-dominant manner. The disease-causing mutation is found in the RET gene at the chromosomal locus 10q11. The American Society of Clinical Oncologists denotes MEN II as a welldefined hereditary cancer syndrome for which genetic testing is considered standard of care for affected probands and at-risk family members [3]. A clinical genetic test is available that detects a disease-causing mutation in 95% of patients with MEN IIB. Interestingly, more than 95% of patients with MEN IIB have
Fig. 3. MEN IIB. Characteristic facies. Neuromas cause thickening and eversion of the upper eyelids and a wide-eyed appearance. Eyebrows appear prominent.
the same mutation caused by substitution of a single methionine to threonine in the affected protein [1]. Linkage testing is available when no mutation is found and multiple family members are affected. RET mutation analysis should be performed soon after birth in all children known to be at risk [3]. About half of affected individuals with MEN IIB have a de novo or new mutation [3], usually paternally inherited [1]. In patients without a family history,
Fig. 2. MEN IIB. Note thick lips with pebbly nodules at the vermilion border.
Fig. 4. MEN IIB. Mucosal neuroma of the eyelid.
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RET mutation analysis should be performed as soon as the diagnosis is being considered [3].
Carney syndrome (NAME or LAMB syndrome) Carney syndrome is also called NAME syndrome (Nevi, Atrial myxomas, Myxoid neurofibromas, Ephelides) and LAMB syndrome (Lentigines, Atrial myxomas, Mucocutaneous myxomas, Blue nevi). Carney syndrome is considered to be an MEN syndrome. Cardiac myxomas are an associated complication that may, unfortunately, present as an embolic stroke if not detected or removed. Myxomas may also appear in the skin or breasts [5]. Endocrine abnormalities include Cushings syndrome caused by primary pigmented nodular adrenocortical disease, elevated growth hormone and acromegaly caused by pituitary adenomas, and prolactinemia thought to be caused by hyperplasia of cells within the pituitary gland [6]. In affected men, tumors of the testicular Sertolis and Leydigs cells are associated [6]. Oral features of Carney syndrome include pigmented maculae over the lips and oral mucosa (Fig. 5). Mucosal pigmented maculae may also be found on the conjunctiva (Fig. 6). Associated skin pigmented maculae may appear on all body surfaces and include ephelides or freckles, darkly pigmented au lait maculae, and as blue nevi. nevi, cafe Molecular genetics Carney syndrome is inherited in an autosomaldominant manner. A causative mutation in the gene called PRKAR1A on chromosome 17 has been identified and clinical genetic testing is available for this alteration. Many affected patients, however, may have an alteration at a separate site. A second
Fig. 6. Carneys syndrome. Pigmented maculae affect the conjunctiva and periorbital skin.
gene is suspected on chromosome 2p, but has not yet been identified.
Cowden disease (multiple hamartoma syndrome) Cowden disease, also known as multiple hamartoma syndrome, is characterized by facial and oral papules and hamartomas. The hamartomas may appear in any body organ [7]. Lifetime risk of malignancy is increased. Affected women have a 20% to 50% risk of breast cancer and increased risk of endometrial cancer. All patients have a 10% risk of nonmedullary cancers of the thyroid [8]. The incidence of malignant melanoma and renal cell cancer is also suspected to be increased [8]. Diagnostic criteria have been developed and published [7] by the International Cowden Consortium (Box 1). These are expected to be updated as further information about the disorder becomes known. Oral findings are present in 80% of patients [9,10] and may aid early identification of the diagnosis. In most cases, the oral findings are found in multiple locations, such as the gingival mucosa (Figs. 7 and 8) and buccal mucosa [10]. The oropharynx, larynx, tongue (Fig. 9), nasal mucosa, and anogenital region may be involved [10]. The typical appearance of multiple, coalescent mucosal papillomas has been described as cobblestone-like and is seen in 40% of patients [10]. Skin findings are included among the current major and minor criteria for diagnosis [8,10]. The finding of multiple facial trichilemmomas is considered pathognomonic for the disorder. Other characteristic skin findings include lichenoid papules, acral keratoses, palmoplantar keratoses, and lipomas. Acral keratoses are skin colored to slightly pigmented flat, warty papules on the backs of the hands and feet and
Fig. 5. Carneys syndrome. Pigmented maculae, also called lentigines, affect the lips and facial skin.
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Box 1. Diagnostic criteria for Cowden disease* Pathognomonic criteria Facial trichilemmomas Acral keratoses Papillomatous lesions Mucosal lesions Major criteria Thyroid carcinoma Macrocephaly Lhermitte-Duclos diseasey Minor criteria Other thyroid lesions Mental retardation Gastrointestinal hamartomas Fibrocystic breast disease Lipomas Fibromas Genitourinary tumors Operational Diagnosis if: Pathognomonic lesions alone including at least six facial papules with at least three trichilemmomas or facial papules and oral papillomatosis or oral papillomatosis and acral keratoses or at lease six palmoplantar keratoses Two major criteria including macrocephaly or LhermitteDuclos disease One major and three minor criteria Four minor criteria * Criteria are considered operational and expected to evolve as further information becomes available. y Hamartomatous change of cerebellar cells with characteristic appearance on MRI or CT.
Fig. 7. Cowden disease. Oral mucosal papillomatosis may affect the gingival mucosa.
been found in the PTEN gene in 80% of patients who meet established diagnostic criteria [7]. The chromosomal locus of the PTEN gene is 10q23.3 [8]. Clinical genetic testing is currently available.
Tuberous sclerosis complex Tuberous sclerosis complex (TSC) has been described and studied for more than 160 years [12,13]. As a result, diagnostic criteria have been well defined [12,14] and are available in updated format at www.geneclinics.org (Box 2). Abnormalities of the skin, central nervous system, kidney, and heart are prominent features of this disorder. TSC shows a great deal of variability in the degree of severity even among affected family members. Central nervous system abnormalities, such as mental retardation and seizures, affect long-term prognosis most. Up to 14% of patients with TSC develop subependymal giant cell astrocytoma. Associated skin findings, such as hypomelanotic maculae, facial
palmoplantar keratoses are translucent and punctate keratoses on the palms and soles. Vitiligo, neuromas, au lait spots are additional skin xanthomas, and cafe findings that have a reported infrequent association with Cowden disease [11]. Facial papules usually show a periorificial distribution (Fig. 10) [10]. Molecular genetics Cowden disease is inherited in an autosomaldominant manner. A disease-causing mutation has
Fig. 8. Cowden disease. Verrucous or papular fibrous overgrowths are typical on the gingiva.
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Box 2. Diagnostic criteria for TSC* Major features Facial angiofibromas or forehead plaque Periungual fibromas Hypomelanotic macules (greater than three) Shagreen patch or connective tissue nevus Nodular retinal hamartomas Cortical tubery Subependymal nodule Subependymal giant cell astrocytoma Cardaic rhabdomyomas Lymphangiomatosisz Renal agiomyolipomaz Minor features Multiple dental enamel pits Hamartomatous rectal polyps Bone cysts Cerebral white matter radial migration linesy Gingival fibromas Nonrenal hamartoma Retinal achromic patch Confetti skin macules Multiple renal cysts Definite TSC if two major or one major and two minor features Probable TSC if one major and one minor feature Possible TSC if one major or two or more minor features * Criteria are available in updated form at www.geneclinics.org. y Cortical tuber and white matter migration lines count as only one feature when diagnosed together. z Lymphangiomatosis and renal aniomyolipoma, when found together, are insufficient to make the diagnosis of TSC.
Fig. 9. Cowden disease. Oral papillomatosis affects the tongue causing a cobblestone appearance.
angiofibromas, and ungual fibromas, have been reviewed in detail [15]. Current diagnostic criteria include the oral finding of gingival fibromas (Fig. 11). These are described as small, fibrous nodules on the gingiva. Oral fibromas in TSC have also been described on the buccal mucosa and dorsum of the tongue [16]. Gingival fibromas are found in some patients with TSC, but
Fig. 10. Cowden disease. A periorificial distribution of facial trichilemmomas is characteristic.
not others and are not essential to make the diagnosis. Also, gingival hyperplasia caused by antiseizure medication, such as phenytoin, may obscure gingival fibromas in these patients [17]. Lack of oral hygiene has been associated with TSC, but this is thought to be caused by mental subnormality rather than a growth or neoplastic change [12].
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Molecular genetics The TSC complex is inherited in an autosomaldominant manner and considered to be a heterogeneous disorder. About two thirds of cases represent new mutations in patients with no family history of the disorder. Most cases are caused by a mutation of the TSC1 gene on chromosome 9q34 or the TSC2 gene on chromosome 16p13. An identifiable mutation has not yet been found to explain the remainder of cases. In addition, TSC has a high rate of somatic mosaicism among affected individuals estimated to be 10% to 25% [14]. Because of these and other complexities, the diagnosis of TSC is currently based on clinical findings. Genetic testing is available on a research basis only.
Fig. 11. Tuberous sclerosis. Gingival fibromas.
Multiple randomly distributed pits in dental enamel (Fig. 12) provide another diagnostic feature of TSC. Enamel pitting may be seen by direct inspection and usually affects the labial surfaces of the front and lateral incisor and canine teeth [12]. The prevalence of dental pits in patients with TSC is thought to range from 48% to 100% [12,18]. Smaller pits can be appreciated better using dental plaquedisclosing stain on the surfaces of the teeth. Electron microscopy can also be used once a tooth has been removed. Dental enamel pits may be found on the teeth of normal patients, but are usually fewer and less obvious. A study by Flanagan et al [18] found that most patients with TSC had great than 14 pits per person, whereas most normal controls had less than 6 pits per person.
Peutz-Jeghers syndrome Peutz-Jeghers syndrome is a genetic condition characterized by gastrointestinal polyposis and tan to dark brown or blue maculae on the skin and oral mucosa (Fig. 13) [19]. Diagnosis is based on these clinical findings. Polyps may cause intussusception or bowel obstruction. A study by Boardman et al [20] determined that patients with Peutz-Jeghers syndrome had a relative risk for cancer increased to 9.9 times normal. The incidence of gastrointestinal cancers and breast cancer is particularly increased [20,21]. Cancer
Fig. 12. Tuberous sclerosis. Example of enamel pitting made more prominent by use of dental plaque-disclosing stain. (From Gomez MR, Sampson JR, Whittemore VH. Tuberous sclerosis complex: developmental perspectives in psychiatry. 3rd Ed. Oxford University Press; 1999. p. 178; with permission.)
Fig. 13. Peutz-Jeghers syndrome. Characteristic pigmented maculae of the lips and buccal mucosa.
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predisposition to hematologic abnormalities and bone marrow failure [23,24]. Failure of the bone marrow is the chief cause of early death. New treatments are under development, but no treatment has been found to be effective uniformly in all patients [23]. Patients with dyskeratosis congenita are also predisposed to pulmonary complications and malignancy. Oral leukoplakia is a diagnostic feature of this disorder and usually appears early in life in association with skin hyperpigmentation [24]. Leukoplakia is generally only seen in the mucous membranes of the mouth, but may also be found in the esophagus and anal and genital mucosa. The leukoplakia tends to progress with time and may undergo malignant transformation [24]. Extensive dental caries and loss of teeth is reported in 18% of patients with dyskeratosis congenita [23]. Molecular genetics
Fig. 14. Peutz-Jeghers syndrome. Characteristic perianal pigmented maculae.
surveillance comprises an important part of management for these patients. The pigmented maculae usually are present at birth or are first noted in early childhood [19]. The maculae are usually found on the lips, on the buccal mucosa and on the skin around the mouth. In the mouth, they may also be found on the palate and tongue. On the skin, distribution may include the face, dorsum of the hands, feet, fingers, eyes, umbilicus, and anus (Fig. 14). Maculae may be found in a periorificial distribution around the eyes in some patients [22]. Skin maculae are reported to fade with age, but the maculae on the oral mucosa remain [19]. Molecular genetics Peutz-Jeghers syndrome is inherited in an autosomal-dominant manner. It is estimated that in 50% of cases, the condition is inherited from a parent and in 50% of cases, the condition is the result of a new or de novo mutation [21]. The causative gene in 30% to 70% of cases is the STK11 gene located at chromosomal locus 19p13 [21]. A clinical genetic test is currently available for Peutz-Jeghers syndrome.
Most affected family members are males with pedigrees that show no male-to-male transmission. Most cases are thought to be X-linked. Female cases
Dyskeratosis congenita Dyskeratosis congenita is a genetic disease characterized by reticulated hyperpigmentation of the skin, dystrophy of the nails, oral leukoplakia, and a
Fig. 15. Pachyonychia congenita. Leukokeratosis affects the tongue.
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Fig. 16. Pachyonychia congenita. Leukokeratosis affects the buccal mucosa.
have been reported. These are thought to be caused by an autosomal-recessive form of the disorder [23]. A causative gene, DKC1, has been localized to Xq28. A clinical genetic test for a mutation in this gene is available.
Fig. 17. Hypohidrotic ectodermal dysplasia. Female carrier. Note sparse, fine, blond hair and mild flattening of the nasal bridge.
Pachyonychia congenita Pachyonychia congenital (PC) is a group of disorders unified by characteristic, distinct nail changes with distal onycholysis, subungual hyperkeratosis that causes transverse arching of the distal nail plate, and yellow-brown discoloration [25,26]. In PC type I (also called Jadassohn-Lewandowsky syndrome), hyperkeratosis of the palms, soles, knees, and elbows and follicular hyperkeratosis are associated features. Oral leukokeratosis separates PC type I from PC type II (or Jackson-Lawler syndrome). In PC type II, natal teeth, epidermal cysts, and steatocysts are associated. Oral leukokeratosis may be found, but is less marked than in PC type I [26]. Oral lesions are white, opaque thickenings in areas of the tongue or buccal mucosa (Figs. 15 and 16), or may present as white plaques that cover the entire surface of the tongue, lips, and cheeks [25]. Superinfection with Candida albicans has been reported [25,26]. In a patient reported by Hannaford and Stapleton [26], lesions did not respond to anticandidal treatment despite a positive culture. Malignant transformation of the leukokeratosis has not been reported [25].
Molecular genetics Pachyonychia congenital is an autosomal-dominant disorder. Keratins are structural proteins usually expressed in pairs [27]. The keratin pair K6b-K17 is expressed in nails and the palmoplantar surface.
Fig. 18. Hypohidrotic ectodermal dysplasia. Hypodontia and conical teeth in a female carrier.
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dentition usually requires extensive dental treatment at an early age with prosthetic teeth. This intervention is considered critical for development of positive selfimage and overall oral health [28,29]. Molecular genetics Hypohidrotic ectodermal dysplasia is X-linked and affects mostly males. Female carriers may also express the disorder, however, usually in a less severe form. Clinical genetic testing is available for the disease causing EDA mutation on the X chromosome [30].
` vre syndrome. Well-circumscribed Fig. 19. Papillon-Lefe hyperkeratosis of the elbows and knees in an affected patient.
` vre syndrome Papillon-Lefe ` vre syndrome is a very rare genetic Papillon-Lefe condition characterized by well-demarcated palmoplantar hyperkeratosis (Fig. 19). Periodontitis sepa` vre syndrome from other inherited rates Papillon-Lefe palmoplantar keratodermas [31]. The features of the condition usually first become apparent about ages 2
Mutations in either of these keratins cause PC type II. Mutations in either K16 or K6a cause PC type I [27]. The genes for keratin 6a and 6b are on chromosome 12 and the genes for keratin 16 and 17 are on chromosome 17. A clinical genetic test is available.
Hypohidrotic ectodermal dysplasia Hypohidrotic ectodermal dysplasia is an inherited condition that affects ectodermal structures, specifically hair, teeth, and sweat glands. Hair is often fine, sparse, and blond (Fig. 17). Lack of sweating may result in heat intolerance and frequent fevers of seemingly unknown cause [28]. Variable associated facial features include a prominent forehead, thick lips, and a depressed nasal bridge (see Fig. 17) [28]. Because features of this disorder may be subtle and unrecognized, the oral findings may first reveal the diagnosis [28]. These include hypodontia and conical teeth (Fig. 18). Feeding may be difficult because of lack of teeth and saliva [28]. Lack of
` vre syndrome. Inflammatory perioFig. 20. Papillon-Lefe dontitis and tooth loss.
Fig. 21. Hereditary hemorrhagic telangiectasia. Characteristic papular telangiectasia affecting the skin.
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Molecular genetics Box 3. Diagnostic criteria for HHT* Diagnostic criteria Spontaneous and recurrent nosebleeds Telangiectasias Internal arteriovenous malformations (pulmonary, cerebral, hepatic, spinal, or gastrointestinal) Positive family history of HHT in firstdegree relative Definite HHT if three or more criteria Possible or suspected HHT if two criteria Unlikely HHT if less than two criteria * Criteria are available in updated form at www.geneclinics.org. ` vre syndrome is a rare autosomalPapillon-Lefe recessive disorder with an increased rate of consanguinity in parents of affected patients [31]. Most cases are caused by mutations of the cathespin C gene on chromosome 11q14 [31]. A clinical genetic test is not yet currently available.
Hereditary hemorrhagic telangiectasia Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is characterized by multiple small and large arteriovenous malformations that become more prominent with age. The most common areas of involvement include the mucous membranes, skin (Fig. 21), gastrointestinal tract, brain, and lung. Bleeding may cause sudden and devastating consequences. Diagnostic criteria are available for this disorder in updated form at www.geneclinics.org (Box 3). Oral lesions may be punctate, spider-like, or nodular and be found on the buccal mucosa, tongue, lips, palate, and gingiva [33]. Color may vary from bright red to purple [34], but in the oral mucosa is usually cherry-red [33]. Presentation of HHT as hemorrhagic vesicles and ulcers of the gingival and oral mucosa has also been reported [34]. Use of a
to 4 [32]. Palmoplantar hyperkeratosis has been reported to improve with time [32]. Severe, inflammatory periodontitis results in complete loss of deciduous teeth by 4 years (Fig. 20). The same process results in complete loss of the adult teeth when they appear. The wisdom teeth, however, are spared [32]. The specific mechanism that causes the periodontitis is not yet known.
Table 1 Summary findings Genetic condition Multiple endocrine neoplasia IIB Carney syndrome Cowden disease Tuberous sclerosis complex Peutz-Jeghers syndrome Dyskeratosis congenita Pachyonychia congenita type 1 Hypohidrotic ectodermal dysplasia vre syndrome Papillon-Lefe Hereditary hemorrhagic telangiectasia Oral findings Mucosal neuromas; high, arched palate; prominent jaw Pigmented macules on lips and oral mucosa; dental enamel pits Mucosal papillomatosis Gingival fibromas; oral fibromas Pigmented macules on lips, buccal mucosa Oral leukoplakia; dental caries and tooth loss Oral leukokeratosis Hypodontia; conical teeth Inflammatory periodontitis; tooth loss Oral telangiectasias Gene and locus RET gene 10q11 PRKAR1A 17 PTEN 10q23.3 TSC1, TSC2 9q34, 16p13 STK11 19p13 DKC1 Xq28 K6a/K16 17q12,12q13 EDA Xq12 Cathespin C 11q14 ENG, ACVRL1 9q34.1,12q1 Genetic test Yes Yes Yes Research only Yes Yes Yes Yes No Research only
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very soft toothbrush may help prevent trauma from routine oral hygiene [34]. Molecular genetics Hereditary hemorrhagic telangiectasia is an autosomal-dominant disorder. Two main genetic subtypes of HHT have been described: HHT1 and HHT2 [35]. The disease causing mutation in HHT1 is in the endoglin (ENG) gene on chromosome 9q34.1. For HHT2, the mutation is in the activin receptor gene on chromosome 12q1 [35]. Currently, only researchbased genetic testing is available.
[7]
[8]
[9]
[10]
[11]
Summary Many genodermatoses have distinct oral features that may help identify or confirm a genetic diagnosis. Oral features of the disorders described here are summarized in Table 1. These conditions provide clear examples of rapid progress in the field of genetic technology relevant to patient care. Less than a decade ago, the exact genetic locus of most of these disorders was unknown. Today, for many of these disorders, the exact location of the disease-causing mutation is known and clinical genetic testing is available for patients. This information has impact not only for genetic counseling and anticipatory medical care, but also provides insight into the mechanisms of disease. How this rapid progress will impact care, and ultimately treatment of patients, remains to be seen.
[12]
[13] [14]
[15]
[16]
[17]
References
[18] [1] Morrison PJ, Nevin NC. Multiple endocrine neoplasia type IIB (mucosal neuroma syndrome, WagenmannFroboese syndrome). J Med Genet 1996;33:779 82. [2] Rimoin DL, Connor JM, Pyeritz RE. Emery and Rimoins principles and practices of medical genetics. 3rd edition. New York: Churchill Livingstone; 1996. p. 1383 5. [3] Wiesner GL, Snow K. Multiple endocrine neoplasia type 2. Available at: www.geneclinics.org. Accessed September 20, 1999. [4] Schenberg ME, Zajac JD, Lim-Tio S, et al. Multiple endocrine neoplasia syndrome-type 2b. Int J Oral Maxillofac Surg 1992;21:110 4. [5] Quintal MC, Tabet JC, Oligny L, et al. Oral soft tissue myxoma: report of a case and review of the literature. J Otolaryngol 1994;23:42 5. [6] Raff SB, Carney JA, Krugman D, et al. Prolactin secretion abnormalities in patients with the syndrome of
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[21]
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[24]
spotty skin pigmentation, myxomas, endocrine overactivity and Schwannomas (Carney complex). J Pediatr Endocrinol Metab 2000;13:373 9. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000;37: 828 30. Eng C, Hampel H, de la Chapelle A. Genetic testing for cancer predisposition. Annu Rev Med 2001;52: 371 400. Chaudhry SI, Shirlaw PJ, Morgan PR, Challacombe SJ. Cowdens syndrome (multiple hamartoma and neoplasia syndrome): diagnostic dilemmas in three cases. Oral Dis 2000;6:248 52. Hildebrand C, Burgdorf WHC, Lautenschlager S. Cowden syndrome: diagnostic skin signs. Dermatology 2001;202:362 6. Thyresson HN, Doyle JA. Cowdens disease (multiple hamartoma syndrome). Mayo Clin Proc 1981;56: 179 84. Cutando A, Gil JA, Lopez J. Oral health management implications in patients with tuberous sclerosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000; 90:430 5. Gomez MR. History of the tuberous sclerosis complex. Brain Dev 1995;17:55 7. Northrup H, Kit-Sing A. Tuberous sclerosis complex. Available at: www.geneclinics.org. Accessed April 13, 2002. Rogers RS, OConnor WJ. Dermatologic manifestations. In: Gomez MR, Sampson JR, Whittemore VH, editors. Tuberous sclerosis complex. 3rd edition. Oxford: Oxford University Press; 1999. p. 160 80. Tillman HH, DeCaro F. Tuberous sclerosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1991;71: 301 2. Gomez MR. Liver, digestive tract, spleen, arteries, thymus, and lymphatics. In: Gomez MR, Sampson JR, Whittemore VH, editors. Tuberous sclerosis complex. 3rd edition. Oxford: Oxford University Press; 1999. p. 228 39. Flanagan N, OConnor WJ, McCartan B, et al. Developmental enamel defects in tuberous sclerosis: a clinical genetic marker? J Med Genet 1997;34:637 9. Kitagawa S, Townsend BL, Hebert AA. Peutz-Jeghers syndrome. Dermatol Clin 1995;13:127 31. Boardman LA, Thibodeau SN, Schaid DJ, et al. Increased risk for cancer in patients with Peutz-Jeghers syndrome. Ann Intern Med 1998;128:896 9. Amos CI, Frazier ML, McGarrity TJ. Peutz-Jeghers syndrome. Available at: www.geneclinics.org. Accessed February 23, 2001. Mallory SB, Stough DB. Genodermatoses with malignant potential. Dermatol Clin 1987;5:221 30. Andrews NC, Fleming MD. Dyskeratosis congenita: recent advances and future directions. J Pediatr Hematol Oncol 1999;21:344 55. Solder B, Weiss M, Jager A, et al. Dyskeratosis congenita: multisystemic disorder with special consideration of immunologic aspects. Clin Pediatr 1998;37:521 30.
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J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183194 [31] Zhang Y, Lundgren T, Renvert S, et al. Evidence of a founder effect for four cathepsin C gene mutations in ` vre syndrome patients. J Med Genet Papillon-Lefe 2001;38:96 101. [32] Wiebe CB, Hakkinen L, Putnins EE, et al. Successful periodontal maintenance of a case with Papillon` vre syndrome:12-year follow-up and review of the Lefe literature. J Periodontol 2001;72:824 30. [33] Austin GB, Quart AM, Nvak B. HHT with oral manifestations. Oral Med 1981;51:245 51. [34] Bartolucci EG, Swan RH, Hurt WC. Oral manifestations of hereditary hemorrhagic telangiectasia (Osler-WeberRendu disease). Review and case reports. J Periodontol 1982;53:163 7. [35] McDonald J, Guttmacher AE. Hereditary hemorrhagic telangiectasia. Available at: www.geneclinics.org. Accessed June 26, 2000.
[25] Dahl PR, Daoud MS, Su WPD. Jadassohn-Lewandowsky syndrome (pachyonychia congenita). Semin Dermatol 1995;14:129 34. [26] Hannaford RS, Stapleton K. Pachyonychia congenital tarda. Australas J Dermatol 2000;41:175 7. [27] Smith FJD, Coleman CM, Bayoumy NM, et al. Novel keratin 17 mutations in pachyonychia congenita type 2. J Invest Derm 2001;116:806 8. [28] Kupietzky A, Houpt M. Hypohidrotic ectodermal dysplasia: characteristics and treatment. Oral Pathol 1995; 26:285 91. [29] Ohno K, Ohmori I. Anondontia with hypohidrotic ectodermal dysplasia in a young female: a case report. Pediatr Dent 2000;22:49 52. [30] Kobielak K, Kobeilak A, Roszkiewicz J, et al. Mutations in the EDA gene in three unrelated families reveal no correlation between phenotype and genotype in the patients with an X-linked anhydrotic ectodermal dysplasia. Am J Med Genet 2001;100:191 7.
Dermatol Clin 21 (2003) 195 205
Oral manifestations of erythema multiforme

Lilibeth Ayangco, DMDa, Roy S. Rogers III, MDb,*
a
Division of Periodontics, Department of Dental Specialties, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA b Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Erythema multiforme (EM) is a reactive mucocutaneous disorder in a disease spectrum that comprises a group of acute self-limited exanthematic reactions, which are occasionally chronic and recurrent eruptions. EM includes a wide range of clinical expression from mild (EM minor) to fulminatingly severe (Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]). EM is a reaction pattern of the skin and mucous membranes. This pattern occurs as a result of an allergic host response to an antigenic challenge. Many patients react to infectious diseases, the most common of which is recurrent herpes simplex virus infection (Box 1). Other patients with more severe mucocutaneous disease react to pharmacologic agents, particularly antibiotics and nonsteroidal anti-inflammatory drugs (Box 2). This article describes the spectrum of the vascular reactivity from mild to severe variants of EM, discusses causes, and describes the oral manifestations of the variants and the histopathology and immunopathology of EM. The article concludes with recommendations on the evaluation and treatment of EM and its variants.
The spectrum of EM Erythema multiforme was first described by Hebra [1] in 1866 as a relatively benign condition characterized by skin lesions with concentric color changes, which were symmetrically distributed. Lesions of EM are located primarily on the extremities and have a tendency to recur. The disease tends
* Corresponding author. E-mail address: rogers.roy@mayo.edu (R.S. Rogers).
to have an episodic course with duration of 1 to 4 weeks. It usually occurs in young healthy individuals. The entity described by Hebra [1] did not mention mucosal involvement, but most authors have accepted occasional erythematous or erosive oral lesions as part of EM. Stevens and Johnson [2] in 1922 reported two children who had fever, conjunctivitis, stomatitis, and a generalized exanthem with skin lesions of purplish cutaneous maculae and necrotic centers that were distinct from EM. In 1950, Thomas [3] suggested that EM and SJS were variants of the same pathologic process. He proposed that the mild cutaneous form of Hebra be called EM minor, and the more severe mucocutaneous varieties, as described by Stevens and Johnson and others, be called EM major. In 1956, Lyell [4] reported a series of patients with a lifethreatening, rapidly evolving mucocutaneous reaction characterized by widespread erythema, necrosis, and bullous detachment of the epidermis resembling scalding, a condition currently known as TEN [5]. In 1968, Kennett [6] described an inflammatory oral disorder with lesions typical of the oral lesions of EM as EM affecting the oral cavity. In 1978, Lozada and Silverman [7] reported 50 patients with oral EM lesions dominating the clinical picture. Similar patients were reported by Bean and Quezada [8] in 1983. Some authors including Huff et al [9] aver that . . . diagnosis as EM of illnesses characterized by only acute mucosal inflammation without skin lesions is unjustified: the typical skin lesion is sine qua non for the diagnosis of EM. Significant differences exist among EM minor, EM major, SJS, and TEN with regards to severity and clinical expression. All variants, however, share two common features: typical or less typical cutaneous target lesions and satellite-cell or more wide-
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Box 1. Infectious causes of

erythema multiforme Viral infections AIDS Adenovirus Coxsackie virus Epstein-Barr virus Hepatitis A, B, and C Herpes simplex 1 and 2 Herpes zoster Influenza, type A Lymphogranuloma inguinale Lymphogranuloma venereum Mumps Poliomyelitis Psittacosis Rickettsiae Vaccinia Variola Bacterial infections B-hemolytic streptococci Brucellosis Diphtheria Mycobacteria Mycoplasma pneumoniae Tularemia Typhoid fever Fungal infections Coccidioidomycosis Dermatophytosis Histoplasmosis Protozoal infections Malaria Trichomonasis
Box 2. Drug therapy causes of

erythema multiforme Allopurinol Amino penicillins Antipyrene Arsenic Barbiturates Bromides Busulfan Butazone Carbamazepine Cephalosporins Co-trimazole Chlorpropamide Cyclophosphamide Diclofenac Digitalis Ethambutol Fenbufen Fluoquinolones Furadantoin Gold salts Hydralazine Hydantoins Ibuprofen Iodides Ketoprofen Mercurials Naproxen Nitrogen mustard Oxicam Penicillin Piroxicam Phenobarbital Phenolphthalein Phenylbutazone Phenytoin Rifampin Salicylates Sulindac Sulfadiazine Sulfadoxine Sulfasalazine Tenoxicam Thiabendazole Trimethadione Tolbutamide Vancomycin
spread necrosis of the epithelium. These features are considered to be sequelae of a cytotoxic immunologic attack on keratinocytes expressing non selfantigens. These antigens are primarily microbial (viruses) or drugs and in rare instances histocompatibility antigens [5]. Although the precise pathogenesis is unknown, there is a tendency to consider both EM minor and major as part of one spectrum that is most often triggered by viral infections, and SJS and
L. Ayangco, R.S. Rogers / Dermatol Clin 21 (2003) 195205 Table 1 Classification of the spectrum of erythema multiforme Variant Erythema multiforme minor Erythema multiforme major Stevens-Johnson syndrome Toxic epidermal necrolysis Oral erythema multiforme Author Hebra [1] Thomas [3] Stevens and Johnson [2] Lyell [4] Kennett [6]
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Stevens-Johnson syndrome Skin involvement of SJS consists of widespread small blisters, developing on purple maculae or on flat atypical target lesions (Fig. 3). The lesions occur predominantly on the torso rather than the extremities. Nikolskys sign is positive with detachment of epidermal sheets in localized areas, but total detachment remains below 10% of the BSA. Lesions usually last for 2 to 6 weeks. Involvement of one or more mucous membranes is noted with scarring as sequelae. The vermilion of the lips is typically involved [5,11 14]. Extensive mucosal disease with the involvement of oral, ocular, nasal, and genital mucosae is characteristic (Fig. 4). There is a 10% mortality rate for patients with extensive disease. Toxic epidermal necrolysis Skin and mucosal involvement of TEN is similar to SJS but more extensive. Epidermal detachment involves 30% or more of the BSA [13,15]. Mucosal involvement is severe with scarring sequelae commonly encountered. There is a 30% mortality rate for patients with extensive disease. Oral EM Oral EM is a distinct but less well-recognized variant of the EM spectrum of diseases. The concept of oral EM is controversial and is not universally accepted [9]; however, it is widely considered as a distinct entity by many authors [5 8,16 19]. It is characterized by episodic, recurrent, or chronic intraoral bullae and erosions over a protracted period of time interfering with speech, mastication, and swallowing producing considerable morbidity (Fig. 5). The diagnosis is often difficult because the clinical picture mimics other oral inflammatory and vesiculobullous diseases. Involvement of the lip vermilion occurs in some patients. Cutaneous involvement typical for EM minor may be seen in 25% of patients.
TEN as a separate spectrum most often elicited by drugs with EM major and SJS representing a bridge in the continuum of EM [10 13].
Classification of EM The spectrum of disease discussed under the rubric of EM includes (1) EM minor, (2) EM major, (3) SJS, (4) TEN, and (5) oral EM (Tables 1 and 2). EM minor Erythema multiforme minor is an acute, selflimited reaction pattern that may be episodic or recurrent. Skin involvement consists of typical target lesions that are individual lesions less than 3 cm in diameter with a regular round shape; well-defined border; and at least three different zones (ie, two concentric rings around a central disk, one ring consisting of palpable edema paler than the center disk [11]) or raised atypical targets characterized by round, edematous, palpable lesions with only two zones or a poorly defined border located on the acral extremities or the face [14]. Blisters may be present (Fig. 1). Skin lesions are usually present on the acral extensor surfaces. The cutaneous lesions of EM minor involve less than 10% of the body surface area (BSA). Nikolskys sign is negative. Lesions last for 1 to 3 weeks and heal without scarring, but may leave postinflammatory hyperpigmented maculae. Characteristically, EM minor has minimal to nil mucous membrane involvement [9,11,13]. EM major
Causes of EM Erythema multiforme major is also an acute, selflimited reaction pattern that may be episodic or recurrent. EM major has a mucocutaneous pattern. Skin involvement is similar to EM minor but may be more extensive. Involvement of one or more mucous membranes [14] almost exclusively limited to the oral cavity is typical [5]. Mucosal disease may be the most prominent element of the disease (Fig. 2). EM minor and major Erythema multiforme minor and major may occur in patients of all ages, but it is most often seen in adolescents and young adults. It is often recurrent. The cause of both EM minor and major is usually related to an infectious agent. Herpes simplex virus
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Table 2 Spectrum of erythema multiforme Course EM minor Acute, self-limited, occasionally recurrent Cutaneous involvement Typical symmetric target lesions/ raised atypical targets acrally distributed. Blisters when present involve < 10% of BSA, () Nikolskys sign Typical symmetric target lesions/ raised atypical targets acrally distributed. Blisters when present involve < 10% of BSA, () Nikolskys sign Widespread small blisters, purple macules or flat atypical target lesions predominantly occuring on the torso. (+) Nikolskys sign Epidermal detachment < 10% of BSA Widespread small blisters, purple macules or flat atypical target lesions predominantly occuring on the torso. (+) Nikolskys sign Epidermal detachment 30% or more of BSA Nails maybe shed. Typical symmetric target lesions acrally distributed in 25% of patients Mucosal involvement Absent or limited to one mucosal site, usually oral. Duration 1 3 wk Prognosis Recovery; may be episodic L. Ayangco, R.S. Rogers / Dermatol Clin 21 (2003) 195205
EM major
Acute, self-limited or episodic
SJS
Acute, progressive systemic illness
Involvement almost exclusively limited to the oral cavity; may be the most prominent element of the disease. Involvement of one or more mucous membrane with possibilty of scarring; extensive mucosal involvement is characteristic. Involvement of one or more mucous membrane with possibility of scarring; extensive mucosal involvement.
1 6 wk
Mortality may occur; may be episodic
2 6 wk
10% mortality
TEN
Prodromal mucosal inflammation followed by acute systemic illness
2 6 wk
30% mortality
Oral EM
Acute, self-limited, occasionally recurrent or chronic
Limited to the oral cavity and the lips
Cyclic episodes last from 10 d- 6 wk. Frequency of episodes occur from every 3 wk to annually.
Chronic with recurrent episodes over protracted period of time.
Abbreviations: BSA, body surface area; EM, erythema multiforme; SJS, Stevens-Johnson Syndrome; TEN, toxic epidermal necrolysis.
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Fig. 1. Cutaneous target lesions of erythema multiforme. These vesiculobullous lesions are typical for the target or iris lesions of erythema multiforme. The center is the site of greatest damage with the concentric rings of lesser damage noted by color and morphologic changes. These lesions are believed by some authors to represent the sine qua non lesions of erythema multiforme.
Fig. 3. Cutaneous lesions of Steven-Johnson syndrome. The target lesions are atypical with a hemorrhagic or purpuric component reflecting necrosis of the epidermis. Concentric color changes are noted.
(HSV) infections are implicated in 50% of patients with EM. Both HSV-1 and HSV-2 infections may trigger EM. Half of the acute episodes of EM and about 80% of the recurrent episodes have been associated with HSV infections [5,13,20]. Other infections may trigger the EM reaction (see Box 1). SJS and TEN Stevens-Johnson syndrome and TEN usually occur in adults but may also be seen in children [21]. Stevens and Johnson [2] originally described the severe EM variant in children. In most cases it occurs as a single event. It is a reaction pattern with many
possible causes. The major causes of SJS and TEN have been attributed to drugs. The most common are sulfa drugs, particularly the long-acting sulfonamides and co-trimoxazole; anticonvulsive drugs, such as phenytoin, carbamazepine, and phenobarbital; and the nonsteroidal anti-inflammatory drugs, such as butazone and oxicam (see Box 2) [15]. Few patients conditions have been linked to an infectious agent. The well-documented cases have been those triggered by Mycoplasma pneumoniae [14]. The incidence of SJS and TEN is increased dramatically in patients with AIDS [22]. Oral EM Oral EM occurs most frequently in adolescents and young adults but may occur at any age. Different series have reported a slight preponderance both for
Fig. 2. Oral lesions of erythema multiforme major. Oral lesions are diffuse, causing a generalized stomatitis. The gingivae and buccal mucosae are involved by a confluent inflammatory reaction with erosions and a covering fibromembranous slough.
Fig. 4. Oral lesions of Steven-Johnson syndrome. The generalized stomatitis is severe with hemorrhagic plaques, which erode and desquamate leaving a raw bleeding surface. The vermilion of the lips typically is involved.
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Fig. 5. Oral lesions of oral erythema multiforme. The oral lesions of this variant characteristically involve the gingival, buccal, and labial mucosae. Some patients have lesions of the vermilion of the lips.
Fig. 7. Oral lesions of erythema multiforme major. Lesions of the vermilion of the lip are characteristic of erythema multiforme. Vesiculobullous lesions erode, are covered by a fibromembranous slough, and may become hemorrhagic with deeper, more necrotic involvement.
females [18] and males [8]. Episodes may be cyclic. The frequency of episodes varied from every 3 weeks to once yearly. For the cyclic episodes, the duration varied from 10 days to 6 weeks [7]. Oral EM may be a chronically recurrent condition. The etiology is largely unknown; however, a wide variety of causative factors have been implicated including bacterial, viral, and fungal infections; drugs; radiation therapy; malignancies; and emotional stress [5 8,17 20, 23,24].
authors accept mild erythematous patches or superficial erosions of the oral mucosa or lips as part of the EM minor spectrum. EM major Oral involvement is common because 40% to 60% of patients have oral lesions [9,11,13]. Lesions are typically seen in the anterior part of the mouth, on nonkeratinized mucosa and less frequently on the gingivae [25]. The lesions appear clinically as erythematous maculae that evolve into numerous small-grouped papulovesicles that rupture, leaving superficial erosions covered by a fibrinous pseudomembrane (Fig. 6). Target lesions may be formed on the lips; otherwise, characteristic bloodstained crusted
Oral lesions of EM EM minor By definition, some authors state that EM minor patients do not have oral lesions [9,11,13]. Most
Fig. 6. Oral lesions of erythema multiforme major. Erosive vesiculobullous lesions of the tongue and anterior oral mucosal surfaces are typical.
Fig. 8. Oral lesions of Stevens-Johnson syndrome. The deep necrotic involvement of the vermilion of the lips produces hemorrhagic crusts.
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erosions of the swollen lips may be seen (Fig. 7) [26,27]. Cervical lymphadenopathy may be present. Oral lesions usually occur simultaneously with skin lesions but may precede or follow the onset of cutaneous lesions by several days [28]. Lesions typically heal without scarring unless they are deep and necrotic. SJS and TEN The oral cavity is almost always involved in SJS and TEN. The sites of predilection are the buccal mucosa, the palate, and the vermilion borders of the lips. Initial signs and symptoms are sore and burning sensations, followed by edema and erythema, then by deep blisters that rupture to form extensive hemorrhagic dull-red erosions with grayish white pseudomembranes or shallow aphthous-like ulcers. Characteristic massive hemorrhagic crusts cover the lips (Fig. 8). Oral lesions are extremely painful causing eating and breathing difficulties and hypersalivation. In more severe cases, lesions may extend to involve the gingiva, tongue, pharynx, nasal cavity, larynx, esophagus, and the respiratory tree [15]. In about 40% of cases, in addition to the oral mucosa, bulbar and palpebral conjunctivae and anogenital mucosa are also involved (Fig. 9) [15]. Mucosal lesions characteristically heal with scarring, the most serious of which occurs in the eyes, which may result in symblephara or blindness. Oral and lip lesions usually heal without complications but strictures may develop in the throat, esophagus, bronchi, and anogenital areas [15].
Fig. 10. Oral lesions of oral erythema multiforme. The buccal mucosa is involved with erythematous plaques interspersed with hyperkeratotic white plaques.
Oral EM In some patients, EM lesions are limited mainly to the oral cavity. Lesions may be chronically present or may be self-limiting and recur periodically. The clinical appearance of the lesions is variable and may present as diffuse areas of mucosal erythema (see Fig. 5), bullae and erosions, ulceration with or without a pseudomembrane, or nonspecific hyperkeratotic plaques interspersed with erythematous changes (Fig. 10). The sites of the lesions are also variable. Extraoral lesions may be present. In a study involving 95 patients with recurrent oral EM, 43% had oral lesions only; 32% had oral and lip lesions; and 25% had oral, lip, and skin lesions [18].
Histopathology and immunopathology of EM Erythema multiforme In early classic EM with target lesions, a prominent dermal inflammatory reaction with edema, vasodilation, and a lymphohistiocytic infiltrate around blood vessels is noted (Fig. 11). There is little epidermal change. There may be some vacuolar degeneration of the lower epidermis or individually necrotic epidermal cells. Dramatic necrosis of the whole dermis is seen in more severe bullous cases [16,22]. Accumulation of mononuclear cells around the upper dermal blood vessels is the pathologic change seen in the earliest skin lesions of EM. A second characteristic finding of EM is epidermal damage in the form of hydropic degeneration of basal cells and necrosis of individual keratinocytes. This is particularly prominent in the
Fig. 9. Ocular lesions of Steven-Johnson syndrome. The bulbar and palpebral conjunctivae are involved. Symplephara or scar bands between the conjunctival surfaces may follow such severe involvement.
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membrane pemphigoid, and lichen planus. The immunofluorescent findings are nonspecific [8,29].
Evaluation of EM Erythema multiforme In typical cases, the skin lesions of EM should not be confused with other conditions because of the characteristic symmetric acral distribution of the targetoid or bullous lesions. EM is a relapsing condition that is most often etiologically related to HSV infection. Extracutaneous involvement occurs in EM major and is most often limited to the oral mucosa. Laboratory test results are usually normal. Patients with severe EM major may have an elevated erythrocyte sedimentation rate, moderate leukocytosis, elevated acute phase proteins, and mildly elevated liver transaminases. The prognosis is excellent [5,22], although the rare patient with extensive EM major may succumb to the disease. EM is one of the serious diseases diagnosed primarily based on the clinical manifestations. SJS and TEN The fully established SJS and TEN presentations are distinctive; however, they may be confused with generalized morbilliform drug eruptions before the confluence and vesiculation of the skin lesions. Skin tenderness of early macular lesions and a positive Nikolskys sign are important clinical characteristics. SJS and TEN are usually acute episodic events with a drug eruption background. Skin lesions are found on
Fig. 11. Histopathology of erythema multiforme. The dermal perivascular inflammatory infiltrate is noted along with acanthosis and hyperkeratosis of the epithelium with a hemorrhagic crust (hematoxylin and eosin, original magnification 25).
center of the classic target lesions of EM and in more established lesions [9]. Immunofluorescence findings are nonspecific and have been of value primarily to rule out other diseases with diagnostic immunofluorescent findings [5,29]. Stevens-Johnson syndrome Prominent epidermal necrosis with minimal inflammation in the epidermis and dermis is noted in SJS and TEN. Injury of the epidermis may present in the early stages as satellite-cell necrosis and progress to a more extensive eosinophilic necrosis of the basal and suprabasal layers with subepidermal separation. In TEN, full-thickness necrosis and sloughing of the epidermis is seen (Fig. 12) [15]. Oral EM The pathologic changes of oral EM are classified as nonspecific inflammatory changes. Microscopic findings are consistent with EM, however, including a perivascular mononuclear cell infiltrate and degenerative changes in the epithelium. There is intercellular or intracellular edema and acanthosis of the spinous layer with occasional irregular elongation of the rete ridges. Vascular dilatation, congestion, a perivascular infiltrate of mononuclear cells, and edema of the upper portion of the lamina propria may be observed in the connective tissue [16]. Immunofluorescent studies of tissue and serum are important to exclude immunobullous diseases, such as pemphigus, paraneoplastic pemphigus, mucous
Fig. 12. Histopathology of toxic epidermal necrolysis. A subepidermal blister has developed with necrosis of the epidermal roof of the blister cavity. A full-thickness sheet of epidermis peels away as the disease progresses (hematoxylin and eosin, original magnification 40).
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the face and the trunk. Extensive mucosal involvement is seen. Constitutional signs of fever and internal organ involvement are common. The prognosis is associated with significant morbidity and mortality [15]. Paraneoplastic pemphigus may be confused with SJS and TEN and must be excluded. Oral EM The diagnosis of oral EM has always been a challenge particularly when the disease is limited primarily to the oral tissues because it may show extremely variable features that can mimic other diseases [7,8,18]. A number of other diseases, such as pemphigus, paraneoplastic pemphigus, mucous membrane pemphigoid, and oral lichen planus, also produce chronic erosions of the oral cavity and at times may initially be confused with recurrent oral EM. The rapid onset, the spontaneous recovery, the pattern of recurrences, the lip involvement, and the typical associated skin lesions, when present, however, are clinical aids in the diagnosis. Frequently, the diagnosis of recurrent oral EM cannot be confirmed until other conditions are ruled out. The major value of biopsy is to exclude other inflammatory and vesiculobullous and dysplastic diseases. Immunofluorescent testing of mucosa and serum is important to exclude pemphigus, paraneoplastic pemphigus, mucous membrane pemphigoid, and lichen planus [8,29].
Box 3. Oral care regimen

Analgesics for oral pain Soothing mouth rinses Viscous lidocaine rinse Topical anesthetics Lidocaine gel Benzocaine in orabase Bland soft diet Avoid acidic or spicy foods Antibiotics for secondarily infected lesions systemic topical
[5]. Some authors believe that they may cause worsening of the condition [22]. In recurrent cases of EM, especially with a history of HSV infection, antiviral therapy may prove beneficial in preventing recurrences [5,9,19]. SJS and TEN There is no specific treatment for SJS and TEN. Identification of the causative agent must be attempted. Suspected drugs must be withdrawn and infections appropriately treated. Mild cases may be treated on an outpatient basis but for the more severe cases, hospital admissions to the dermatology or intensive care burn units are necessary. Early, aggressive therapy of SJS and TEN with cyclophosphamide, hemodialysis, plasmapheresis, and intravenous immunoglobulin G has been proposed. The ideal treatment regimen remains to be determined. Prophylactic antibiotics should be started from the beginning to prevent a common fatal complication of overwhelming infection. Good nursing care, a high-calorie and high-protein diet, and maintenance of fluid and electrolyte balance are essential. Supportive pulmonary care, such as suctioning and postural drainage, and ophthalmologic preventive measures with ocular lubricants, sweeping of conjunctival fornices, and removal of fresh adhesions are of great importance [15]. Patients with ocular involvement should be managed with an ophthalmologist. Oral EM Therapy for oral EM is mainly palliative consisting of oral analgesics and viscous lidocaine rinse (see Box 3). Emphasis on adequate nutrition and fluid intake should be made. In patients with a history of
Treatment of EM Erythema multiforme In most cases, once the disease is established, EM minor causes minimal discomfort and regresses spontaneously in 2 to 4 weeks. Therapy is similar for EM minor and major with the addition of oral care for oral mucous membrane involvement in EM major. In general, treatment depends on the severity of the condition. If manifestations are mild, symptomatic, conservative care is usually adequate. This may include systemic or topical analgesics, and antibiotic treatment for secondarily infected lesions. Oral care consists of soothing mouth rinses, such as viscous lidocaine rinse; topical anesthetics, such as lidocaine gel; soft liquid diet; and avoidance of acidic and spicy food (Box 3). Good nursing with high-calorie and high-protein diet and sufficient fluid intake is essential. These treatments have little impact on the course of the disease but may reduce subjective symptoms. Systemic glucocorticoids are considered unnecessary
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HSV infection or recurrent episodes with possible viral etiology, antiviral therapy is recommended and may prevent recurrences [18]. Some patients have recurrent or continuous oral EM disease activity causing a great deal of morbidity. Treatment with prednisone and systemic corticosteroids has been recommended [18]. Corticosteroidsparing drugs, such as dapsone [30], azathioprine [18], methotrexate, and mycophenolate mofetil, may be considered for these challenging patients.
membrane pemphigoid, and lichen planus, is a necessary component of the diagnosis. The value of a biopsy specimen studied by both routine histopathologic and immunopathologic methods is fundamental to excluding the other causes for this variant of EM [29].
Acknowledgments The authors are grateful to Dr. Francesco Boin for his assistance.
Summary Erythema multiforme is a reactive mucocutaneous disorder in a disease spectrum that comprises a selflimited, mild, exanthematic, cutaneous variant with minimal oral involvement (EM minor) to a progressive, fulminating, severe variant with extensive mucocutaneous epithelial necrosis (SJS and TEN). Significant differences exist among EM minor, EM major, SJS, and TEN with regards to severity and clinical expression; however, all variants share two common features: typical or less typical cutaneous target lesions and satellite-cell or more widespread necrosis of the epithelium. These features are considered to be sequelae of a cytotoxic immunologic attack on keratinocytes expressing non self-antigens. These antigens are primarily microbial (viruses) or drugs and in rare instances histocompatibility antigens [5]. Although the precise pathogenesis is unknown, there is a tendency to consider EM both minor and major as part of one spectrum that is most often triggered by viral infections, and SJS and TEN as a separate one most often elicited by drugs with EM major and SJS representing a bridge in the continuum of EM [10 13]. The oral manifestations of the spectrum of EM range from tender superficial erythematous and hyperkeratotic plaques to painful deep hemorrhagic bullae and erosions. Other mucosal surfaces including ocular, nasal, pharyngeal, laryngeal, upper respiratory, and anogenital may be involved. Scarring sequelae from ocular and pharyngeal involvement cause morbidity. The oral EM variant is an underrecognized form of EM. Most patients have chronic or recurrent oral lesions only, but one third have oral and lip lesions and one quarter have oral, lip, and skin lesions. This variant is a reaction pattern similar to EM minor, EM major, SJS, and TEN. The diagnosis of oral EM is one of exclusion. Careful clinical evaluation for other chronic mucocutaneous diseases, such as pemphigus, paraneoplastic pemphigus, mucous
References
[1] von Hebra F. Atlas der hautkrankheiten. Vienna: Kaiserliche Akademie der Wissenchaften Wien; 1866. [2] Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia. Am J Dis Child 1922;24:526 33. [3] Thomas BA. The so-called Stevens-Johnson syndrome. BMJ 1950;1:1393 7. [4] Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol 1956; 68:355 61. [5] Fritsch PO, Maldonado RR. Erythema multiforme. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in General Medicine, vol. 2. 4th edition. New York: McGraw-Hill; 1993; p. 636 43. [6] Kennett S. Erythema multiforme affecting the oral cavity. Oral Surg 1968;25:366 73. [7] Lozada F, Silverman Jr S. Erythema multiforme: clinical and natural history in fifty patients. Oral Surg 1978;46:628 36. [8] Bean SR, Quezada RK. Recurrent oral erythema multiforme: clinical experience with 11 patients. JAMA 1983;249:2810 2. [9] Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol 1983;8: 763 75. [10] Assier H, Bastuji-Garin S, Revuz J, et al. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol 1995;131: 539 43. [11] Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993;129:92 6. [12] Cote B, Wechsler J, Bastuji-Garin S, et al. Clinicopathologic correlation in erythema multiforme and Stevens-Johnson syndrome. Arch Dermatol 1995;131: 1268 72. [13] Roujeau JC. Stevens-Johnson syndrome and toxic epi-
L. Ayangco, R.S. Rogers / Dermatol Clin 21 (2003) 195205 dermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol 1997;24:726 9. Labreze CL, Lamireau T, Chawki D, et al. Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome. Arch Dis Child 2000;83:347 52. Fritsch PO, Maldonado RR. Stevens-Johnson syndrome-toxic epidermal necrolysis. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in General Medicine, vol. 2. 4th edition. New York: McGraw-Hill; 1993; p. 644 54. Buchner A, Lozada F, Silverman Jr S. Histopathologic spectrum of oral erythema multiforme. Oral Surg Oral Med Oral Path Oral Radiol Endod 1980;49:221 8. Gebel K, Hornstein OP. Drug-induced oral erythema multiforme: results of a long-term retrospective study. Dermatologica 1984;168:35 40. Lozada-Nur F, Gorsky M, Silverman Jr S. Oral erythema multiforme: clinical observations and treatment of 95 patients. Oral Surg Oral Med Oral Path Oral Radiol Endod 1989;67:36 40. Nesbitt SP, Gobetti JP. Multiple recurrence of oral erythema multiforme after secondary herpes simplex: report of case and review of literature. J Am Dent Assoc 1986;112:348 52. Ayangco L, Sheridan PJ, Rogers III RS. Erythema multiforme secondary to herpes simplex infection: a case report. J Periodontol 2001;72:953 7. Maldonado RR. Acute disseminated epidermal necro-
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lysis types 1, 2, and 3: a study of 60 cases. J Am Acad Dermatol 1985;13:623 35. Dowd PM, Champion RH. Erythema Multiforme. In: Burton JL, Burns DA, Breathnach SM, editors. Rook/ Wilkinson/Ebling Textbook of Dermatology, vol. 4. 6th edition. Oxford, UK: Blackwell Science; 1998; p. 2081 7. Davis J, Pack GT. Erythema multiforme following deep x-ray therapy. Arch Dermatol Syph 1952;66:41 8. Koltze V. Stevens-Johnson syndrome associated with mycoplasma pneumoniae infection. J Laryngol Otol 1973;87:35 40. Shklar G, McCarthy PL. Oral manifestations of erythema multiforme in children. Oral Surg 1966;21:713 23. Alcalay J, David M, Ingber A, et al. Bullous pemphigoid mimicking bullous erythema multiforme. J Am Acad Dermatol 1988;18:345 9. Laskaris G, Satriano RA. Drug-induced blistering oral lesions. Clin Dermatol 1993;11:545 50. Jensen JL, Rhyne RR, Correll RW, Craig RM. Acute episodic inflammatory lesions of the mucous membrane and skin. J Am Dent Assoc 1980;100:896 8. Helander SD, Rogers III RS. The sensitivity and specificity of direct immunofluorescence testing in disorders of mucous membranes. J Am Acad Dermatol 1994;30:65 75. Schofield JK, Tatnall FM, Leigh IM. Recurrent erythema multiforme: clinical features and treatment in a large series of patients. Br J Dermatol 1993;128: 542 5.
Dermatol Clin 21 (2003) 207 215
Current therapy
Important drug interactions and reactions in dermatology

Nancy Aria, MD, C. Lisa Kauffman, MD*
Georgetown University Medical Center, 3800 Reservoir Road NW, 5-PHC Dermatology, Washington, DC 20007, USA
A constantly expanding pharmacologic armamentarium increases the concern for serious drug interactions. It is impossible to know every possible prescription drug interaction, let alone all the overthe-counter drug and dietary supplement interactions. It is possible, however, to predict potential interactions by having a basic knowledge of drug metabolism. A potential drug interaction occurs when one drug may alter the intensity of pharmacologic effects of another drug that is given concurrently. This may result in enhanced or diminished activity of the affected drug and can lead to toxicity or therapeutic failure [1].
polar compound that usually has decreased pharmacologic activity and toxicity [2].
Cytochrome P-450 family The name of these enzymes is derived from the spectral absorbance maximum produced at or near 450 nm when carbon monoxide binds to the enzyme in its reduced state [2]. Since its origin, the cytochrome P-450 gene family has diversified to accommodate the metabolism of a growing number of environmental chemicals, foods, toxins, and drugs. At least 12 cytochrome P-450 gene families and 31 functional cytochrome P-450 gene products have been described in humans [2]. The cytochrome P-450 family is a group of heme proteins that catalyze the oxidation and reduction of a wide variety of structurally diverse compounds, from medications to food. The cytochrome P-450 enzymes are localized in the smooth endoplasmic reticulum of numerous tissues, most importantly the liver. The specific cytochrome P-450 family involved is identified by a number representing the enzyme family. The letter following the number refers to the subfamily of the enzyme. The cytochrome P-450 multigene family is classified according to the sequence similarity of the individual protein. Members of a given gene family have at least 40% amino acid identity and are designated by a roman numeral. A given cytochrome P-450 family is further divided into subfamilies, such that the protein sequences within the same subfamily are more than 55% similar [3]. Cytochrome P-450 genes that are involved with drug metabolism are cytochrome P-450 I, II, III, and IV, whereas the enzymes of the remaining cytochrome
Drug metabolism Enzymes metabolize drugs primarily by converting lipophilic drugs into water-soluble metabolites, which are excreted more readily. The kidney cannot efficiently eliminate lipophilic drugs; these drugs must first be metabolized in the liver. Significant drug interactions involve the liver during the biotransformation process, which has been subdivided into phases I and II (Fig. 1) [2]. Phase I consists of intramolecular changes including hydroxylation, oxidation, and reduction catalyzed by the cytochrome P-450 family, which is involved in the conversion of an active to inactive drug [2]. During phase II, extramolecular changes occur, including glucuronide, glycine, and sulfate conjugation, which create a more
* Corresponding author. E-mail address: kauffmac@georgetown.edu (C.L. Kauffman).
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Fig. 1. The biotransformation process.
P-450 families are important in the metabolism of endogenous compounds, such as steroids and fatty acids. An individuals P-450 system determines the rate and degree to which both endogenous substances, such as glucocorticoids and androgens, and exogenous agents, such as drugs and toxins, are metabolized [3].
Drug-drug interactions Understanding how drugs are metabolized is helpful in understanding which mechanisms are involved in drug interactions. Drug interactions occur when one drug alters the clearance of another drug by one of four mechanisms: 1. 2. 3. 4. Rate or degree of absorption Renal excretion Distribution from binding sites Hepatic metabolism of drugs involving the cytochrome P-450 system
The first mechanism involves alteration of the rate of drug absorption. An example of this drug interaction is seen in the gastrointestinal tract when
ingestion of a second medication can result in decreased absorption of the initial drug by a change in drug binding, altered gastric pH, or altered gastrointestinal motility. Absorption can also depend on the surface area to which a drug is exposed. Other factors involved include whether there are other agents that could result in binding or chelating the drug [4]. The second mechanism that can lead to a drug interaction involves a change in drug metabolism because of altered renal clearance. An example of this mechanism is the interaction of nonsteroidal antiinflammatory drugs (NSAIDs) with methotrexate. This drug interaction occurs by displacing methotrexate from its protein-binding sites and by inhibiting renal elimination of the drug. The third mechanism involves impairment of another drugs metabolism because of changes in the distribution of binding sites. An example is when two drugs are competing for the same plasma proteinbinding sites or one drug displaces another from tissue-binding sites resulting in higher serum levels of the displaced drug. This includes competition for plasma protein-binding sites and displacement from tissue-binding sites. The fourth mechanism, which is by far the most important, involves changes in drug clearance be-
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Fig. 2. Enzyme induction.
cause of changes in the hepatic metabolism involving the cytochrome P-450 enzyme system [5]. The cytochrome P-450 enzyme system is one of the most important hepatic mechanisms of drug interactions. Recent studies have shown that potentially severe interactions involve drug biotransformation pathways catalyzed by the cytochrome P-450 enzyme family. Drug interactions generally occur as either a pharmacodynamic or pharmacokinetic interaction. Pharmacodynamic interactions occur when one drug induces a change in another without altering its own plasma level. There is usually an additive effect of the two drugs. Examples are the additive effects of alcohol and antianxiety drugs, or the additive anticoagulation effects resulting from simultaneous ingestion of aspirin and warfarin [6]. In dermatology, most of the drug interactions are of the pharmacokinetic type and usually involve
altered hepatic metabolism mediated by the cytochrome P-450 3A isoenzyme system. Two of the most significant mechanisms of drug interactions involve induction and inhibition. Induction consists of an increase in synthesis of de novo cytochrome P-450 proteins because of exposure to certain drugs or environmental pollutants. The time it takes for induction to occur depends on the half-life of the inducer, which can vary from 24 hours to approximately 1 week [1]. Enzyme induction leads to an increased rate of biotransformation and a corresponding decrease in the availability of the parent drug (Fig. 2). Inhibition of biotransformation enzymes result in the increase of the parent drug, prolonging its effects and an increased incidence of drug-induced toxicity in the cytochrome P-450 family. Competition between two or more drugs for the active site on the same enzyme may lead to a decrease in the
Fig. 3. Inhibition of biotransformation enzymes.
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metabolism of these agents, depending on the relative concentrations of each substrate and their affinity for the enzyme. This is one of the most important drug interaction mechanisms because it can quickly lead to an unwanted increase in drug concentrations and toxicity without the lag time observed in the cytochrome induction process (Fig. 3) [2].
Patients at risk Drug interactions may be more severe in the elderly, the immunocompromised, and patients on multiple medications. Interactions that may be of minor clinical significance in healthy patients may cause significant exacerbation of the clinical condition in patients who are chronically ill. Decreased efficacy is important in situations where reduced drug levels (eg, oral contraceptive pills [OCPs]) can result in pregnancy [5]. Elderly patients are at risk because of decreased liver mass, reduced hepatic enzyme activity, and hepatic blood flow resulting in a decrease in the overall metabolic capacity [7]. Patients with impaired renal function may also be at increased risk because of decreased ability to metabolize drugs. In HIVpositive patients, adverse drug interactions may be problematic as a result of multiple medical problems that make it difficult to determine whether a change in the patients condition is caused by a drug interaction or by progression of disease [5].
infections. These medications have a unique set of properties and interactions of which physicians need to be aware. For example, the administration of acidic beverages, such as Coca-Cola Classic and Pepsi, along with itraconazole can increase its bioavailability in patients with hypochlorhydria [1]. Beverages with a pH less than 3 enable itraconazole, which is a weak base, to be ionized. Some diet sodas, such as Diet Coca Cola, Diet Pepsi, and Diet Canada Dry Ginger Ale, may not be effective because they have a pH greater than 3 [1]. The absorption of itraconazole can be affected by drugs that can change the gastric pH and absorption. Most importantly, itraconazole can have significant drug interactions because it is an inhibitor of the cytochrome P-450 3A4 enzyme system causing increased levels of certain drugs that share the same cytochrome. Drug levels that may be increased in combination with itraconazole include the following [1,8 10]: 3-hydroxy-3methylglutaryl (HMG) coenzyme A inhibitors Simvastatin Atorvastatin Lovastatin Benzodiazepines Midazolam Triazolam Other drugs Digoxin Warfarin Sildenafil Itraconazole (Sporonax) and HMG coenzyme A inhibitors Inhibition of the P-450 3A4 enzyme by itraconazole (or ketoconazole) can produce serious problems when given with lovastatin, simvastatin, and atorvastatin, which also use the P-450 3A system. This combination may result in higher concentrations of the cholesterol-reducing drugs that can lead to liver toxicity. Itraconazole inhibits the metabolism of lovastatin, resulting in significantly elevated plasma concentrations of lovastatin associated with rhabdomyolysis [1]. Itraconazole and triazolam (Halcion) or midazolam (Versed)
Significant drug interactions This article now focuses on the most common dermatologic drug interactions and in particular the most clinically significant reactions. This includes drug interactions that are of great potential harm to the patient, are predictable, or occur frequently and are well documented. Drug interactions are rated to indicate the severity of the adverse reaction. A score of 1 to 5 is given, with 1 denoting severe and welldocumented drug interactions and 5 being unlikely or partially documented [6]. Interactions that are clinically significant are given a rating of 1, 2, or 3, whereas drug interactions that are unlikely are rated as a 4 or 5 [6].
Antifungal drug interactions Antifungals, such as itraconazole and terbinafine, are commonly used to treat dermatophyte and yeast Administration of itraconazole, which is an inhibitor, with a benzodiazepine may result in elevated levels of the benzodiazepine because the azoles may
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decrease the metabolism by the cytochrome P-450 3A4 enzyme. Oral midazolam and oral triazolam are contraindicated with itraconazole [1]. Itraconazole and digoxin This combination can cause increased levels of digoxin leading to possible toxicity. Digoxin is a substrate of the cytochrome P-450 3A4 and itraconazole can inhibit the metabolism of digoxin. Patients should be monitored closely for bradycardia and toxicity [8]. Itraconazole and warfarin (Coumadin) Co-administration of warfarin and itraconazole may result in an increased anticoagulant effect possibly by inhibition of warfarin metabolism [1]. Itraconazole and sildenafil (Viagra) Sildenafil has been known to cause some serious adverse effects, such as priapism, myocardial infarction, shock, sudden death, and ventricular arrhythmias [9]. Given in combination with itraconazole it can lead to an increased level of sildenafil. Itraconazole (and ketoconazole) can inhibit the cytochrome P-450 3A4, which metabolizes sildenafil. It is recommended that patients be given the lowest dosage of sildenafil (25 mg) when taking a cytochrome P-450 3A4 inhibitor, such as itraconazole and ketoconazole [10]. Terbinafine in contrast with itraconazole is an allylamine that does not inhibit or induce P-450 3A4. It does, however, seem to be an inhibitor of P-450 2D6, which may lead to increased levels of drugs using the same isoenzyme. There are no absolute contraindications with the use of terbinafine as there are with the azoles [11]. Terbinafine (Lamisil) and theophylline The mechanism of this interaction is not completely known, but it has been speculated that it involves the microsomal cytochrome P-450 enzyme system. Terbinafine is believed to disrupt the P-450 reductase membranes, resulting in the inhibition of theophylline metabolism by the P-450 1A2 pathway [1]. Terbinafine and warfarin The addition of oral terbinafine to the therapy of a patient maintained on warfarin resulted in decreased
warfarin anticoagulant effect. It is postulated that because of the prolonged period of warfarin dose adjustment after the start and end of terbinafine treatment, the mechanism involves enzyme induction [1]. In another case report, however, a prolonged prothrombin time was observed. In a postmarketing surveillance study no interaction was noted [1].
Antibiotics Tetracyclines Tetracycline is one of the commonly used antibiotics in the treatment of acne, rosacea, and nongonococcal arthritis. Tetracyclines can reduce effectiveness of OCPs by interfering with the enterohepatic circulation of estrogens by reducing bacterial hydrolysis of conjugated estrogens in the intestine. By reducing the bacterial flora in the intestine, a decreased amount of contraceptive steroid is reabsorbed. Although the evidence of interactions between tetracyclines and OCPs is scarce, women who are taking OCPs should be encouraged to use additional forms of contraception. Breakthrough bleeding can also occur because of decreased estrogen levels [12]. Tetracycline can also decrease the absorption of antacids, calcium, iron, or magnesium supplements. The use of tetracycline in pregnant women and children up to 8 years of age is not recommended because it may cause permanent tooth discoloration and enamel hypoplasia [12]. Another potential drug interaction involves the use of oral retinoids or vitamin A with tetracyclines. This combination may produce an increased risk of benign intracranial hypertension (pseudotumor cerebri) that is usually seen within 4 weeks of initiating treatment [12]. Erythromycin Erythromycin is an inhibitor of cytochrome P-450 1A2 and P-450 3A4. As a result, erythromycin causes decreased metabolic clearance of carbamazepine, warfarin, theophylline, phenytoin, digoxin, terfenadine, and methylprednisone [13]. Some important drug interactions include the following examples. Erythromycin (or clarithromycin) and theophylline This combination results in decreased metabolism of theophylline and an increase in plasma levels. This is a potentially problematic combination because an increase in theophylline levels can result in seizures and arrhythmias [13].
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Erythromycin and phenytoin (Dilantin) or phenobarbital An increase in the levels of phenytoin and phenobarbital may be seen in combination with erythromycin in about 1 week. Monitoring blood levels is recommended [10]. Erythromycin and warfarin An increase in plasma warfarin levels with the risk of increased anticoagulation and hemorrhage can occur [13]. Erythromycin and terfenadine This combination is contraindicated in patients receiving clarithromycin or erythromycin [13]. In contrast to clarithromycin, azithromycin and dirithromycin do not affect the cytochrome P-450 system. Erythromycin and sildenafil This combination can lead to increased levels of sildenafil for reasons mentioned previously (see the section on antifungals). Rifampin Rifampin is a potent inducer of the hepatic cytochrome P-450 2C9, 2C19, and 3A4 enzymes and has been known to lower the levels of many drugs including warfarin, cyclosporine, theophylline, digoxin, and OCPs. The combination of OCPs and rifampin is not advised because it can cause breakthrough bleeding and an increased risk of pregnancy [10]. If this combination is necessary, then the use of an OCP with higher estrogen content ( > 35 mg of ethinyl estradiol) or the use of an additional method of contraception is recommended [10,14]. Trimethoprim and sulfamethoxazole (co-trimoxazole, Bactrim) Trimethoprim and sulfamethoxazole interferes with folic acid metabolism in patients on methotrexate [13]. Trimethoprim and sulfamethoxazole may prolong the prothrombin time of patients on warfarin. Furosemide (Lasix) and celecoxib (Celebrex) are sulfonamides and can be absorbed systemically. Like other sulfonamides, they can produce severe, possibly fatal, reactions, such as toxic epidermal necrolysis and Stevens-Johnson syndrome [15]. It is not recommended to give a sulfa product to a patient with allergy to these medications.
Trimethoprim and sulfamethoxazole and methotrexate Methotrexate plasma protein binding and renal clearance can be decreased by the concurrent administration of sulfamethoxazole. This interaction may be secondary to protein displacement of methotrexate by co-trimoxazole or competition for renal tubular excretion. It has been postulated that methotrexate and co-trimoxazole act synergistically to produce significant folate deficiency, which leads to megaloblastic anemia. Co-trimoxazole rarely causes megaloblastic anemia alone. This effect, however, seems more likely to develop in patients with pre-existing folate deficiency [18]. Cephalosporins Certain cephalosporins contain an N-methylthiotetrazole ring, which inhibits the production of vitamin K dependent clotting factors that can result in a prolonged prothrombin time. Co-administration of these cephalosporins with warfarin may be potentially dangerous. Cephalosporins with the N-methylthiotetrazole ring, such as Cefobid, Mandol, and Cefotan, may also induce disulfiram reactions with alcohol ingestion [13]. Fluoroquinolones (ciprofloxacin and levofloxacin) There are several drug interactions involved with the use of ciprofloxacin. A decreased bioavailability is seen when administered with aluminum, magnesium, and alum-containing antacids. Antacids should be taken at least 2 hours after ciprofloxacin. Fluoroquinolones act as inhibitors of the cytochrome P-450 1A2 enzyme system and can decrease the metabolism and clearance of theophylline [13]. The mechanism for interaction involving fluoroquinolone and such drugs as warfarin and cyclosporine is unclear. The combination of fluoroquinolones and warfarin can lead to increased prothrombin time. Cyclosporine in combination with a fluoroquinolone can lead to nephrotoxicity [13]. Although not a drug interaction, it is important to know fluoroquinolones showed impairment of cartilage formation in animal studies and are contraindicated during pregnancy [13].
Retinoids Drug interactions with isotretinoin have been rarely reported in the literature and are limited to
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case reports. To avoid additive toxic effects, patients on isotretinoin should not take vitamin supplements containing vitamin A. Concomitant use of drugs in the tetracycline class should strongly be discouraged because of the potential for pseudotumor cerebri (benign intracranial hypertension), as mentioned previously [5].
Methotrexate and probenecid These two drugs used concurrently may increase the nephrotoxicity of methotrexate. Probenecid seems to inhibit the active renal tubular excretion of methotrexate [17]. Acitretin and methotrexate
Methotrexate Both the liver and the kidney metabolize methotrexate. Thirty-five percent is metabolized by the enterohepatic system and the remaining 60% to 80% of the drug is excreted unchanged by the kidney [5]. Any co-administered agent that interferes with methotrexate excretion in the kidney has the potential to increase serum methotrexate levels and cause toxic effects [12]. Some common examples include aspirin and NSAIDS. Methotrexate and aspirin and methotrexate and NSAIDs The concurrent administration of methotrexate and aspirin may result in elevated or prolonged serum concentration of free methotrexate by decreasing renal tubular excretion of methotrexate. This can increase the potential for methotrexate toxicity. Aspirin and NSAIDs can also displace methotrexate from albumin, increasing the serum levels of methotrexate. Methotrexate and aspirin have a common elimination pathway where aspirin competes with and inhibits methotrexate elimination through the kidney, leading to an increase in serum methotrexate concentration and half-life [16]. Methotrexate and omeprazole (Prilosec) Increased methotrexate levels may result with concurrent administration of omeprazole. It is postulated that omeprazole may inhibit the active secretion of methotrexate from the kidney [17]. Methotrexate and NSAIDs Methotrexate has been shown to increase the serum levels of some NSAIDs, such as naproxen. There are NSAIDs that can be given safely with methotrexate, however, because they have been shown not to affect serum levels of methotrexate. These drugs are ketoprofen, fluorobiprofen, and piroxicam [18].
The use of this combination reportedly has an increased risk of hepatotoxicity [17].
Cyclosporine Any drug that induces or inhibits the P-450 3A4 enzyme system easily alters the metabolism of cyclosporine. Cyclosporine has a narrow therapeutic range with decreased efficacy in the subtherapeutic range and renal toxicity when given in excess [5]. Cyclosporine concentrations can become elevated when given with medications that inhibit the cytochrome P-450 3A4. These medications include antibiotics (erythromycin, norfloxacin, and doxycycline); antifungals (ketoconazole, itraconazole, and fluconazole); hormones (androgens, steroids, and estrogens); antivirals (protease inhibitors); calcium channel blockers (diltiazem); and grapefruit juice (only affects oral cyclosporine levels) (Table 1) [19]. Decreases in the concentration of cyclosporine are seen when induction of the cytochrome P-450 3A occurs. Some common inducers include anticonvulsants (carbamazepine, phenytoin, and phenobarbital); antibiotics (rifampin and trimethoprim-sulfamethoxazole); and dexamethasone (Table 1) [19]. Cyclosporine and ketoconazole Ketoconazole has a high affinity binding to P-450 3A4 and causes marked inhibition of cyclosporine metabolism leading to increased serum levels. [19] Cyclosporine and diltiazem Concurrent administration of cyclosporine and diltiazem results in increased cyclosporine levels. Diltiazem interferes with hepatic metabolism (P-450 3A4) of cyclosporine and is thought to increase cyclosporine levels resulting in decreased renal function. Patients should be monitored closely for elevated cyclosporine and serum creatinine levels during concurrent therapy with diltiazem [17].
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Table 1 Drugs that may interact with cyclosporine levels Drugs that increase cyclosporine Antiobiotics Erythromycin Norfloxacin Doxycycline Antifungals Ketoconazole Itraconazole Fluconazole Hormones Androgens Steroids Estrogens Antivirals Protease inhibitors Calcium channel blockers Diltiazem Other Grapefruit juice Amiodarone Metoclopramide Data from references [6] and [18]. Drugs that decrease cyclosporine Anticonvulsants Carbamazepine Phenytoin Phenobarbitol Antibiotics Rifampin Bactrim
because of extensive metabolism by intestinal P-450 3A4. Grapefruit contains bioflavonoids (naringenin and quercetin) that can inhibit the P-450 3A4 enzymes in the gastrointestinal tract. Various brands of grapefruit juice (or even the same brand from time to time) may have different concentrations of bioflavonoids that affect the degree of inhibition of P-450 3A4. In contrast, orange juice does not contain bioflavonoids [2]. The effect of orange juice on P-450 3A4 has been assessed in several studies, but it does not seem to inhibit this enzyme.
Antifungals Terbinafine
Eutectic mixture of local anesthetics (EMLA) This is commonly used for relieving pain associated with such procedures as venipuncture, venous cannulation, biopsies, and more recently laser therapies. EMLA cream is an emulsion in which the oil phase is a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine. The major concern with EMLA is the potential risk of methemoglobinemia. Patients with glucose-6-phosphate deficiency and patients taking methemoglobin-inducing agents are more susceptible to methemoglobinemia. Some agents commonly associated with methemoglobinemia are sulfonamides, acetaminophen, nitrates, nitrites, dapsone, phenytoin, and phenobarbital. These drugs should be used with caution when in conjunction with EMLA [21]. E.M. Forsters famously simple but maddenly complex phrase only connect applies precisely to the ability to prevent drug interactions. For some, the best way to help remember and understand an interaction is to determine whether the drug combination in question causes induction or inhibition. This is not, however, always obvious. Luckily, there are websites and software that provide assistance in determining drug interactions. A popular software program called ePocrates (www.epocrates.com) has a drug reference application that requires a personal computer with Internet access and Palm OS-driven personal digital assistant (eg, Palm Pilot, Handspring, Sony, TRGPro). This software has a multicheck option, which determines if an interaction exists [9]. Similar programs are found at www.PDR.net, www.micromedex.com, and www.drug-interactions. com. These websites are offered at no charge; however, the electronic trail to the users computer supplies marketing data to the pharmaceutical companies. Other useful reference materials that are not computer mediated include the Hansten and Horns Drug Interactions Analysis and Management, The Medical Letter on Drugs and Therapeutics, and Drug
Cyclosporine and grapefruit juice Grapefruit juice is an inhibitor of the cytochrome P-450 3A4. Inhibition of P-450 3A4 can last for a number of hours after drinking grapefruit juice. Pharmacokinetic studies in both normal controls and patients on chronic cyclosporine have developed increased cyclosporine serum concentrations when it is taken with grapefruit juice [20]. Cyclosporine undergoes extensive first-pass metabolism by P-450 3A4 in the intestine and liver. Factors that seem to increase the magnitude of the interaction include taking grapefruit juice with cyclosporine repeatedly (as opposed to single-dose studies) and taking the grapefruit juice and cyclosporine simultaneously (as opposed to taking the doses separately as much as an hour apart). Certainly, sporadic drinking of grapefruit juice in a patient on cyclosporine should be discouraged because it may result in greater fluctuations in cyclosporine serum concentrations [20]. Whether grapefruit juice can be used intentionally to reduce the dosage (and potential cost) of cyclosporine therapy is open to debate [17]. Grapefruit juice inhibits intestinal P-450 3A4 and can increase bioavailability of drugs metabolized by this isozyme, especially if the drug normally has low bioavailability
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Interaction Facts. Although idiosyncratic reactions may still occur, use of these resources combined with the information in this article should help to prevent known adverse drug interactions from occurring.
References
[1] Gupta AK, Katz HI, Shear NH. Drug interactions with itraconazole, fluconazole, and terbinafine and their management. J Am Acad Dermotol 1999;41:237 49. [2] Singer MI, Shapiro LE, Shear NH. Cytochrome P-4503A: interactions with dermatologic therapies. J Am Acad Dermatol 1997;37:765 71. [3] Hardman JG, Limbird LE, Molinoff PB, Ruddin RW. Goodman and Gilmans the pharmacological basis of therapeutics. 9th edition. New York: McGraw Hill; 1996. [4] Katzung B. Basic and clinical pharmacology. 7th edition. Stamford, CT: Appleton and Lange; 1998. [5] Anderson WK, Feingold DS. Adverse drug interactions clinically important for the dermatologist. Arch Dermatol 1995;131:468 73. [6] Barranco V. Clinically significant drug interactions in dermatology. J Am Acad Dermatol 1998;38:599 612. [7] Ehrenpreis ED, Ehrenpreis S. Cytochrome P-450 role in drug-induced hepatotoxicity. Clinics in Liver Disease 1998;2:457 70. [8] Anderson JR, Nawarskas JJ. Cardiovascular drug-drug interactions. Cardiol Clin 2001;19:215 34. [9] Epocrates.com Website. Available at: http://www. epocrates.com. Accessed December 12, 2002.
[10] Ament PW, Bertolino JG, Liszewski JL. Clinically significant drug interactions: clinical pharmacology. Am Fam Physician 2000;61:1745 54. [11] Moossavi M, Baheri B, Scher R. Systemic antifungal therapy. Dermatol Clin 2001;19:35 52. [12] Le Cleach L, Bocquet H, Roujeau JC. Reactions and interactions of some commonly used systemic drugs in dermatology. Dermatol Clin 1998;16:421 9. [13] Sadick N. Systemic antibiotic agents. Dermatol Clin 2001;19:1 21. [14] Helms SE, Bredle DL, Zajic J, Jarjoura D, Brodell R, Krishnarao I. Oral contraceptive failure rates and oral antibiotics. J Am Acad Dermatol 1997;36:705 10. [15] Litt J. Drug eruption reference manual. New York: Parthenon Publishing Group; 2000. [16] Silvis NG. Antimetabolites and cytotoxic drugs. Dermatol Clin 2001;19:105 18. [17] Hansten PD, Horn JT. Drug interactions analysis and management. Facts and Comparisons. October 2000. [18] Lebwohl M, Ali S. Treatment of psoriasis. Part 2. Systemic therapies. J Am Acad Dermatol 2001;45: 649 61. [19] Cather JC, Abramounts W, Menter A. Cyclosporine and tacrolimus in dermatology. Dermatol Clin 2000; 19:119 37. [20] www. powernetdesign.com/grapefruit. Website for Grapefruit Juice-Drug Interactions Homepage. Accessed December 2002. [21] Huang W, Vidimos A. Topical anesthetics in dermatology. J Am Acad Dermatol 2000;43:286 98.
Dermatol Clin 21 (2003) 217
Erratum
Erratum to Melanoma and pigmented lesions [Dermatol Clin 20 (4) (2002) xv]$
Darrell S. Rigel, MD
35 East 35th Street, Suite 208, New York, NY 10016, USA
In the October 2002 issue, volume 20, number 4, Dr. Darrell Rigels address was listed incorrectly on
page xv. Dr. Rigels correct address is: 35 East 35th Street, Suite 208, New York, NY 10016.
PII of original article S0733-8635(02)00024-4 E-mail address: dsrigel@prodigy.net (D.S. Rigel).

2003, Vol.21, Issues 1, Oral Medicine and Oral Dermatology

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2003, Vol.21, Issues 1, Oral Medicine and Oral Dermatology

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Dermatol Clin 21 (2003) xi xii

Oral medicine/Oral dermatology

Roy S. Rogers III, MD Alison J. Bruce, MD Guest Editors

R.S. Rogers III, A.J. Bruce / Dermatol Clin 21 (2003) xixii

Dermatol Clin 21 (2003) 1 15

Acute oral ulcers

* Corresponding author. E-mail address: bruce.alison@mayo.edu (A.J. Bruce).

A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115

A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115

Fig. 3. Mucosal ulceration related to use of aspirin to relieve toothache.

Masticatory mucosa (keratinized)

A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115

Abbreviations: HSV, herpes simplex virus; RAS, recurrent aphthous stomatitis.

A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115

A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115

A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115

A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115

Fig. 11. Extensive luetic leukoplakia in a patient with secondary syphilis.

A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115

Fig. 14. Histoplasmosis infection of the tongue with diffuse involvement.

A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115

A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115

A.J. Bruce, R.S. Rogers III / Dermatol Clin 21 (2003) 115

including culture, biopsy, or serologic studies is dictated by clinical impression.

[44] [45] [46]

[47] [48] [49]

[35] [36] [37]

Dermatol Clin 21 (2003) 17 32

Viral diseases of the oral mucosa

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732

Fig. 2. Herpes pharyngitis, with erythema and erosions of posterior oropharynx.

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732

Direct immunofluorescence Culture Polymerase chain reaction In situ hybridization

Serology Tzancks smear

Serum Vesicle base scraping

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732

Abbreviations: HPV, human papillomavirus.

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732

B.R. Hairston et al / Dermatol Clin 21 (2003) 1732

[22] [23] [24]

Dermatol Clin 21 (2003) 33 39

Recurrent aphthous stomatitis

E-mail address: Szunt@iupui.edu

S.L. Zunt / Dermatol Clin 21 (2003) 3339

S.L. Zunt / Dermatol Clin 21 (2003) 3339

S.L. Zunt / Dermatol Clin 21 (2003) 3339

S.L. Zunt / Dermatol Clin 21 (2003) 3339

Dermatol Clin 21 (2003) 41 48

Complex aphthosis and Behc ets disease

* Corresponding author. E-mail address: jjorizzo@wfubmc.edu (J.L. Jorizzo).

M.A. McCarty et al / Dermatol Clin 21 (2003) 4148

Fig. 1. Pathergy lesions induced by intradermal injection of sterile saline at 24 hours.

* Findings are applicable if no other clinical explanation is present.

M.A. McCarty et al / Dermatol Clin 21 (2003) 4148

M.A. McCarty et al / Dermatol Clin 21 (2003) 4148

Fig. 5. Vulvar pyoderma gangrenosum-like major aphthous ulcer.

M.A. McCarty et al / Dermatol Clin 21 (2003) 4148

[22] [23] [24]

Dermatol Clin 21 (2003) 49 61

Pseudo-Behc ets disease