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Oral Manifestations of Immunologically Mediated Diseases
Oral Manifestations of Immunologically Mediated Diseases Lisa Johnson, DDS, MSc, FRCD(C) a,*, Kristina Perschbacher, DDS, MSc, FRCD(C) b, Iona Leong, BDS, MSc, FRCD(C) c, Grace Bradley, DDS, MSc, FRCD(C) d KEYWORDS Oral Mucosa Swelling Ulcer Erythema Stomatitis Inflammation KEY POINTS Oral mucosal swelling, ulceration or red-white lesions may be caused by an aberrant immune response. Clinical history is important to identify any trigger for the aberrant immune response; removal of the trigger will lead to resolution of the mucosal lesion. Clinical investigations may be needed to determine if the oral lesions are associated with extraoral lesions, which may indicate an underlying systemic disease. Incisional biopsy is useful for diagnosis of some conditions, whereas other conditions are diagnosed by clinical history and appearance. Symptomatic treatment may be provided if no known trigger or causative factor can be found.
Introduction
Swellings
Immune-mediated conditions represent a spectrum of diseases characterized by an individual’s immune system mounting an aberrant attack leading to tissue damage. In this article, we address immune-mediated conditions in which an inappropriate inflammatory reaction results in oral mucosal diseases that range from swelling to ulceration to red/white lesions. The inciting factor for the immune reaction is often difficult or impossible to identify. We highlight the clinical history and appearance of each condition and describe the role of laboratory tests and biopsy in diagnosis. The management of these conditions varies and may include removal of any demonstrable trigger, topical steroid, and other immunosuppressive agents. Conditions that present with self-limited oral lesions only require supportive care. In those conditions where oral lesions are associated with extraoral lesions, timely investigations are important to detect and treat systemic manifestations of disease.
Orofacial granulomatosis
The authors have nothing to disclose. Department of Oral and Maxillofacial Sciences, Faculty of Dentistry, Dalhousie University, 5981 University Avenue, Room 5124, PO Box 15000, Halifax, Nova Scotia B3H 4R2, Canada b Oral Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto, 124 Edward Street Room 308, Toronto, Ontario M5G 1G6, Canada c Oral Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto, 124 Edward Street Room 311, Toronto, Ontario M5G 1G6, Canada d Oral Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto, 124 Edward Street Room 315C, Toronto, Ontario M5G 1G6, Canada * Corresponding author. E-mail address: [email protected] a
Atlas Oral Maxillofacial Surg Clin N Am 25 (2017) 171–185 1061-3315/17/ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cxom.2017.04.009
Description Characterized by persistent swelling of one or both lips and/or intraoral swelling; biopsy shows inflammation with noncaseating granulomas. The etiology and pathogenesis are not fully understood; there may be multiple pathogenetic pathways leading to a common set of clinical manifestations. Patients who are known to have Crohn’s disease or sarcoidosis may rarely develop orofacial swelling with clinical and histologic features nearly identical to orofacial granulomatosis (OFG); it is a matter of debate whether such patients should be classified as having OFG. OFG presenting in childhood is associated with an increased probability of Crohn’s disease, although the signs and symptoms of Crohn’s disease may only appear after an interval of several years. A minority of OFG have been shown to be associated with allergy to food, food preservatives and flavoring agents and oral hygiene products; both type I (immediate, IgEmediated) hypersensitivity and type IV (delayed, cellmediated) hypersensitivity have been shown to be associated with OFG. The remainder of OFG cases are idiopathic with no associated gastrointestinal tract abnormality and no identifiable allergen. Prevalence OFG is an uncommon condition, but the exact prevalence has not been determined. Median age at onset is between 15 and 30 years of age in the majority of case series.
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172 Males and females are almost equally affected. Firm swelling of one or both lips is seen in more than 90% of cases; upper and lower lips are equally likely to be affected (Fig. 1A); the swelling varies in severity and may be symmetric or affect one side more than the other (Fig. 2A). Lip swelling may be associated with perioral erythema, angular cheilitis, and vertical fissures of the lip. The swelling is usually painless, although severe swelling with scaling and fissuring of the mucosa may cause discomfort. Lip swelling accompanied by fissured tongue and facial paralysis is known as MelkerssoneRosenthal syndrome. Intraoral lesions include diffuse or segmental swelling of the attached gingiva (see Fig. 1B), cobblestone appearance of the buccal mucosa, linear ulceration and swelling of the buccal vestibule (see Fig. 2B), and swelling of the anterior floor of mouth over Wharton’s ducts. Clinical and laboratory investigations are required to determine if there is an underlying systemic disease (Table 1) or a local cause (Table 2). Patients with Crohn’s disease who have orofacial lesions along with intestinal lesions (“oral Crohn’s disease”) may present clinically similar to OFG patients, but are more likely to have involvement of the mandibular buccal sulcus (Fig. 3A,B); it has also been shown that patients with OFG who have ulcers and swelling of the buccal sulcus are more likely to have concurrent Crohn’s disease upon investigation than OFG patients with predominantly lip swelling. Histopathology Edema in the lamina propria, chronic inflammatory infiltrate with nonnecrotizing granulomas consisting of epithelioid macrophages, and lymphocytes, often with multinucleated giant cells. Nonnecrotizing granulomas may be absent in the biopsy because of sampling problems or fluctuations in the disease process; a repeat biopsy of deeper tissues may be helpful to demonstrate the granulomatous inflammation.
Johnson et al. Special stains are negative for the presence of acid-fast bacilli and fungal organisms. No detectable foreign bodies by conventional or polarized light examination. Diagnosis Based on clinical presentation and biopsy findings. Clinically, the lip swelling of OFG can be distinguished from that of angioedema because the latter condition has a rapid onset and resolves after 24 to 72 hours. Biopsy to demonstrate nonnecrotizing granulomas is useful to support the diagnosis of OFG. Clinical and laboratory investigations are required to determine if there is an underlying systemic disease or an allergy (see Tables 1 and 2). Treatment Investigate for an underlying systemic disease (eg, Crohn’s disease); the orofacial lesions should resolve upon treatment of the systemic disease. Treatment of odontogenic infections may lead to resolution of OFG. Perform cutaneous patch tests and urticarial tests if allergy is suspected; avoid exposure to allergens, for example, by instituting an elimination diet for patients who are found to have an associated allergy. Intralesional injections of triamcinolone acetonide are effective in the majority of patients in reducing lip and oral mucosal swelling; the injections are given every 2 to 4 weeks, typically for 4 to 6 months. Topical corticosteroids or calcineurin inhibitors (tacrolimus, pimecrolimus) may be used as an adjunct to intralesional injections of corticosteroid. Immunosuppressants such as azathioprine, or tumor necrosis factor-a inhibitors such as infliximab may be used in severe cases. Pediatric patients (age < 16 years) with OFG but no gastrointestinal disease should be monitored for signs and symptoms of Crohn’s disease, because a number of
Fig. 1 (A) Diffuse, firm swelling of the lower lip and less extensive swelling of the upper lip in a 22 year-old female. The patient had a surgical reduction of the lower lip 7 years earlier but the swelling has slowly recurred. Biopsy showed nonnecrotizing granulomatous inflammation, consistent with a diagnosis of orofacial granulomatosis. (B) Same patient as A, showing diffuse swelling and erythema of the maxillary labial gingiva. Similar changes were noted in the mandibular anterior gingiva.
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Fig. 2 (A) A 14-year-old healthy female with painless swelling of the right lower lip of several months’ duration. The patient reported no gastrointestinal problems. (B) Same patient as A, showing a painless, deep fissured ulcer surrounded by raised linear folds of tissue in the right mandibular buccal vestibule. Biopsy demonstrated nonnecrotizing granulomatous inflammation, consistent with a diagnosis of orofacial granulomatosis.
studies have suggested that childhood onset of OFG is predictive of the development of Crohn’s disease. Surgical reduction of lip enlargement has been used to improve facial appearance, but there is a risk of recurrence.1e8
Ulcers Recurrent aphthous stomatitis Description Painful, self-limited, recurrent oral ulcers. Unknown cause, but a variety of triggers have been reported, including stress, hormonal effects, food allergy, trauma, and smoking cessation. May also be triggered by use of systemic medications, including nonsteroidal antiinflammatory drugs, betablockers, and nicorandil. Decrease in mucosal barrier, antigenic stimulation, and Tcellemediated immunologic reaction have been implicated in the pathogenesis.
Table 1
Three clinical forms: minor, major, and herpetiform. Predominantly on nonkeratinized mucosa. Prevalence Common, affecting 20% of the population. Usually presents in childhood or adolescence. Eighty percent of affected individuals present with minor aphthous ulcers. Clinical presentation All forms of aphthous ulcers are painful and characterized by a whitish-grey pseudomembrane and an erythematous halo. Minor aphthous ulcers (Fig. 4A, B). Round ulcers, less than 1 cm in diameter. Develop on nonkeratinized tissues; rare on dorsum of tongue, hard palate, and gingiva. Predilection for the buccal and labial mucosa, followed by ventral tongue, soft palate, and floor of mouth. Typically 1 to 5 are present at any given time. Heal in 1 to 2 weeks with no scarring. Major aphthous ulcers (Fig. 5A, B).
: Investigations of patients with orofacial granulomatosis to rule out systemic disease
Clinical presentation
Diagnostic tests
Diagnosis
Gastrointestinal problems, such as bloating, cramps, and diarrhea; perianal symptoms in children Laboratory findings of low hemoglobin, serum iron, vitamin B12, folate Elevated levels of inflammatory markers e erythrocyte sedimentation rate, C-reactive protein
Endoscopy and biopsy
Crohn’s disease
Respiratory problems such as dyspnea Salivary and lacrimal gland dysfunction Elevated levels of inflammatory markers e erythrocyte sedimentation rate, C-reactive protein Serum angiotensin-converting enzyme level
Chest radiography to look for hilar lymphadenopathy Bronchoscopy and biopsy
Sarcoidosis
174 Table 2
Johnson et al. Investigations of patients with orofacial granulomatosis to rule out local causes
Clinical presentation
Diagnostic tests
Diagnosis
Predominantly gingival involvement
Vitality test, periodontal examination, and radiographs of teeth in the vicinity of orofacial swelling
Chronic dental infection
Gingival swelling History of scaling and polishing of teeth
Identification of foreign material in gingival biopsy
Foreign body gingivitis
History of atopy e asthma, eczema, allergic rhinitis Association between exposure to suspected allergen and development/exacerbation of orofacial swelling
Skin patch test against foods, food preservatives, and additives (eg, benzoates, monosodium glutamate, cinnamaldehyde), dental materials Elevated serum IgE levels Response to elimination diet
Allergy
Fig. 3 (A) Elongated ulcer surrounded by thickened mucosa in the left mandibular buccal vestibule in a patient with Crohn’s disease. Note the similarity to Fig. 2B. (B) Diffuse swelling of the maxillary labial gingiva in a patient with Crohn’s disease.
Fig. 4 (A) Minor aphthous ulcers. A 40-year-old female with 2 aphthous ulcers of the labial mucosa. The patient has a history of recurrent oral ulcers since childhood. (B) Aphthous ulcer on the labial mucosa with the characteristic appearance of a round ulcer covered by a whitish-grey pseudomembrane and surrounded by an erythematous halo.
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Fig. 5 (A) Major aphthous ulcer. Adolescent male presented with an ulcer of the right soft palate of 4 weeks’ duration. He has a history of minor aphthous ulcers. (B) Same patient as A, 1 month later. The ulcer has healed, leaving a whitish scar.
Larger, deeper, and more irregular ulcers with a preference for tonsillar pillars, soft palate, and labial mucosa. Diameter of 1 to 3 cm. There may be 1 to 10 ulcers may be present at a time. May extend from nonkeratinized to keratinized tissues. Heal in 2 to 6 weeks, often with scarring. Herpetiform (Fig. 6A, B). Least common form, representing only 5% of recurrent aphthous stomatitis cases. Demonstrates a female predilection and may present in adulthood. Numerous pinhead-sized ulcers, 1 to 3 mm in diameter, that coalesce to form larger ulcers, giving a resemblance to herpetic stomatitis.
Despite the name, infection with herpes virus has not been convincingly demonstrated. Up to 100 ulcers may develop at 1 time, predominantly affecting nonkeratinized mucosa, but may affect keratinized mucosa as well. Heal in 1 to 2 weeks, but frequent recurrences are typical. Histopathology Nonspecific ulceration consisting of loss of surface epithelium with a mixed inflammatory infiltrate composed of neutrophils, lymphocytes, and histiocytes in the underlying connective tissue. The mucosa at the margins of the ulcer shows an inflammatory infiltrate of lymphocytes and histiocytes in the connective tissue and migration of inflammatory cells into the epithelium.
Fig. 6 (A, B) 16 year-old male with herpetiform aphthous ulcers that were reported to be associated with stress. (Courtesy of Dr John Lovas, BSC, DDS, MSc, FRCD(C), Halifax, NS.)
176 Diagnosis Based on history of self-limited, recurrent ulcers, characteristic clinical appearance and exclusion of underlying systemic disease (see below). Biopsy is not required except in rare occasions when a major aphthous ulcer has to be distinguished from malignant disease such as squamous cell carcinoma or lymphoma. Aphthous-like ulcers occur as part of several systemic diseases (Fig. 7AeD, Table 3); control of the systemic disease usually leads to improvement of the oral ulcers. A medical history should be taken to determine if the oral ulcers are associated with gastrointestinal problems including diarrhea, bloating, and signs of malabsorption, fever, lymphadenopathy, weight loss, skin lesions, ulcers
Johnson et al. on other mucosal surfaces, ocular inflammation, and joint pain. Laboratory investigation including complete blood count, red blood cell folate, serum iron, and vitamin B12 should be considered in case of onset of ulcers after adolescence or unusual number, frequency or location of ulcers. Treatment A variety of treatments have been proposed, but none has been consistently effective in preventing recurrence or promoting healing of ulcers. Elimination of suspected triggers, for example, certain fruits, nuts, flavoring agents, and preservatives. Substitution of suspected medications with other medications, if possible.
Fig. 7 (AeD) A 9-year-old male with ulcers of the maxillary and mandibular vestibules and lateral tongue. The patient has a history of ulcers starting at age 5 and experiences 1 to 2 outbreaks per month during which time he takes prednisolone. Diagnosis of periodic fever, aphthae, pharyngitis, adenitis (PFAPA) was made by a pediatric rheumatologist.
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Systemic disorders that are associated with aphthouslike oral ulcers
Systemic disorder
Clinical findings besides oral ulcers
Laboratory tests
Behc‚et syndrome
Genital ulcers, uveitis, skin lesions, joint lesions, central nervous system manifestations (see next section)
Celiac disease (gluten sensitive enteropathy)
Gluten intolerance; bloating, diarrhea, weight loss, dental defects
Small intestine biopsy; antibodies to gliadin and tissue transglutaminase
Cyclic neutropenia
Presents in childhood with cyclical occurrence of fever and infections; usually improves in second decade
Complete blood count and correlation with development of ulcers
Nutritional deficiencies (iron, folate, vitamin B12)
Fatigue, weakness, pallor; atrophic glossitis, angular cheilitis
Serum iron, vitamin B12, red blood cell folate
Immunocompromised conditions, eg, HIV infection
Candidiasis, hairy leukoplakia; Kaposi sarcoma, lymphoma
Complete blood count with immunodeficiency panel; HIV testing
Inflammatory bowel disease (ulcerative colitis and Crohn’s disease)
Diarrhea, abdominal pain, weight loss
Endoscopy, biopsy
Mucosal and genital ulcers with inflamed cartilage
More common in the 4the5th decades of life with oral and genital lesions with relapsing polychronditis
Periodic fever, aphthae, pharyngitis, adenitis
Presents in young children and occurs in 3e5 wk intervals with fever, sore throat and cervical lymphadenopathy in the absence of upper respiratory tract infection
Sweet syndrome (acute febrile neutrophilic dermatoses)
Sudden onset of fever, red papules and plaques on skin, mucosal ulcers, arthralgia/arthritis
Reactive arthritis
Urethritis, arthritis, conjunctivitis; strong male predilection
Abbreviation: HIV, human immunodeficiency virus.
Laser therapy can provide pain relief and reduce healing time. Tetracycline rinse (contents of 250 mg capsule dissolved in 1 tbsp of water); doxycycline and minocycline gel or rinse are also effective. Chlorhexidine rinses 0.12%. Topical glucocorticosteroids, particularly 0.1% triamcinolone acetonide in orabase. Zylactin (over the counter) provides a covering film for symptomatic relief. Systemic glucocorticoids and other immune modulators may be considered in major aphthous stomatitis.9e11
Behc‚et disease Description Behc‚ets disease (BD) is a multisystem inflammatory disease of unknown etiology, currently considered to be a systemic vasculitis. Characterized by recurrent episodes of active disease and remissions, with different durations, most often manifesting as a triad of oral ulcers, genital ulcers, and ocular inflammation. Prevalence BD is rare; the majority of cases are associated with HLAB51 genotype, occurring more commonly in countries along the “silk route”: Turkey, Japan, and the eastern Mediterranean countries. Usual age at onset is between the second and fourth decades. Males are more often diagnosed with BD than females and may have a worse clinical course.
Clinical presentation Oral ulcerations are similar in appearance to aphthous ulcers (both minor and major), with recurrent multifocal presentation, often lasting 1 to 4 weeks and healing without scarring. Oral ulceration is seen in nearly all patients with BD and it is also the most frequent presenting symptom (see Fig. 8AeD). Genital lesions are similar to oral lesions and are present in approximately 75% of cases. Eye lesions are serious and may lead to severe vision loss and blindness. Most commonly include posterior uveitis, conjunctivitis, conjunctival aphthosis, and scleritis. Typical skin lesions consist of erythematous papules, vesicles, or acnelike eruptions, as well as erythema nodosum. Arthritis, thrombophlebitis, gastrointestinal disease, and central nervous system involvement may be seen. Histopathology Nonspecific ulceration of the epithelium. Most frequent pattern seen for skin lesions is leukocytoclastic vasculitis, consisting of infiltration of neutrophils and fibrinoid necrosis of the walls of small blood vessels, and extravasation of red blood cells. Diagnosis Diagnosis of BD is difficult because it is based on clinical manifestations, which may be seen in other diseases as well. No other disease has had so many different classification and diagnostic criteria; there are currently 17 published sets of criteria.
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Fig. 8 (AeD) Behc‚et disease. A 26-year-old male of Turkish descent with multiple large ulcers of the dorsal and lateral tongue, labial and buccal mucosa. The patient has a history of recurrent oral ulcers since childhood associated with pustular lesions of the skin and genital ulcers.
The international criteria for BD were revised in 2014 and state that a patient must get 4 points from a list of symptoms: Oral aphthosis (2 points), Genital aphthosis (2 points), Ocular manifestations (2 points), Skin manifestations (1 point), Vascular manifestations (1 point), Neurologic manifestations (1 point), and Positive pathergy test (1 point). BD must be differentiated from other systemic conditions presenting with oral ulcerations (see Table 3 in Recurrent Aphthous Stomatitis section). Treatment Symptomatic treatment for oral ulcers, such as topical or intralesional corticosteroids. No treatment or medication has been found to be universally effective for BD; different patient groups
have responded to systemic antiinflammatory and immunosuppressive medications such as azathioprine, colchicine, corticosteroids, cyclosporine, dapsone, methotrexate, thalidomide, and tumor necrosis factor-alpha inhibitors.12e14
Erythema multiforme Description Self-limiting condition that presents with an acute onset of erythema, erosions, vesicles, and ulcers affecting the skin and mucous membranes. Clinical and microscopic features suggest that this is an immunologically mediated condition but the pathogenesis is not well-understood. Approximately 50% of cases are associated with a preceding infection, in particular herpes simplex infection;
Immunologically Mediated Diseases
Fig. 9 Hemorrhagic, crusting lesions of the lips in a patient with erythema multiforme.
mycoplasmal infection, histoplasmosis, coccidioidomycosis and EpsteineBarr virus have also been implicated. May also be triggered by use of medications, in particular sulfonamides, penicillin, barbiturates, salicylates and antimalarial drugs (see Kentaro Ikeda’s article, “DrugInduced Oral Complications,” in this issue). Controversial whether erythema multiforme (EM) is a separate condition from StevenseJohnson syndrome and toxic epidermal necrolysis; the latter 2 conditions are characterized by more severe and extensive lesions of the skin and multiple mucosal sites and displays epithelial necrosis upon biopsy; the majority of cases of StevenseJohnson syndrome and toxic epidermal necrolysis are triggered by medications (see Kentaro Ikeda’s article, “Drug-Induced Oral Complications,” in this issue). May also present in association with cancer, in particular carcinomas and lymphomas, and in patients with collagen
179 vascular diseases, such as systemic lupus erythematosus and polyarteritis nodosa. Prevalence Presents in the second to fifth decades of life, with no sex predilection. In comparison, toxic epidermal necrolysis presents in older adults with a female predilection, whereas Stevense Johnson syndrome occurs more commonly in children. Clinical presentation Acute onset with lesions appearing over a few days. Self-limiting course with resolution after 2 to 6 weeks. Flulike symptoms consisting of low-grade fever, malaise, headache, and sore throat may precede the onset of EM by 1 week. EM associated with a precipitating infection (eg, recurrent herpetic labialis) usually presents 10 to 14 days after the infection. Skin lesions typically include symmetric targetoid lesions on the hands and feet. Hemorrhagic crusting of the lips is a characteristic finding (Fig. 9). Erythematous patches and irregular shallow ulcers on any oral mucosal surface, most commonly on the labial and buccal mucosa; often sparing the gingiva and palate (Fig. 10A, B). Exclusive oral involvement is not uncommon; alternatively oral involvement may precede worsening of disease severity. Oral lesions are painful and cause difficulty with eating and drinking. More severe presentation (EM major) involves extensive skin lesions, conjunctival, nasal, and genital lesions. Recurrent episodes may occur in a minority of cases, often after recurrent herpetic labialis. Differential diagnosis includes: Pemphigus vulgaris, Paraneoplastic pemphigus,
Fig. 10 A 55-year-old female with diffuse erythema and ulcers of the lips (A) and buccal mucosa (B) of 2 weeks’ duration. The lesions had a sudden onset, with no history of use of medications or viral infection in the preceding month. There were no associated skin lesions. Topical corticosteroids and prednisone (10 mg/d) were not helpful. The clinical diagnosis of erythema multiforme was confirmed at the 4-week follow-up appointment when the lesions had completely resolved.
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Fig. 11 Oral mucosal and skin lesions of a patient with lichen planus. (A, B) Reticular white lesions associated with mucosal pigmentation in a symmetric presentation on both buccal mucosa. (C) White plaques and a small area of white reticular appearance on the dorsum of the tongue. (D) Pruritic, purplish-red papules on the skin of the forearm.
Erosive lichen planus, Fixed drug reaction, and Infections, including human immunodeficiency virus, primary herpetic gingivostomatitis, and fungal infections. Histopathology Biopsy of perilesional tissue may show subepithelial or intraepithelial vesicle formation with necrosis of the basal cell layer. A mixed inflammatory infiltrate is seen in the connective tissue, composed of lymphocytes, neutrophils, and eosinophils, often with a perivascular distribution. The histologic findings are not diagnostic, but are useful for excluding mucocutaneous diseases with a similar clinical presentation, particularly pemphigus vulgaris and paraneoplastic pemphigus. Direct immunofluorescence is negative for the presence of autoantibodies.
Diagnosis Diagnosis of EM is initially a presumptive diagnosis based on clinical history and the characteristic appearance of skin and mucosal lesions. Diagnosis of EM is confirmed by seeing complete resolution of lesions in 2 to 6 weeks. In cases where the clinical findings are nonspecific, biopsy, and direct and indirect immunofluorescence assays can be used to exclude other skin and mucosal diseases. Determine if there is a precipitating factor such as viral infection or use of systemic medication; this is particularly important for patients with recurrent EM. Treatment Supportive care including soft diet, plenty of fluids, topical anesthetics, and rest. Use of topical or systemic corticosteroids has not been shown to be highly effective.
Immunologically Mediated Diseases Discontinuation of any medication that is suspected to be the trigger. Monitor the patient until all lesions have resolved. Prophylactic antiviral medication is indicated in cases of recurrent EM triggered by herpes simplex infection.14e17
Red and white lesions Lichen planus Description Lichen planus is a chronic inflammatory disorder of skin and/or mucosa characterized by immunologically mediated reactions to basal keratinocytes. The etiology and triggering factors are poorly understood and there is currently no cure. Prevalence Oral lichen planus is common, affecting 0.1% to 2.2% of the population. Usually presents in the fifth and sixth decades. Occurs twice as commonly in women than in men. Clinical presentation Skin lesions are characterized by 4 Ps: purplish, pruritic, polygonal papules, most commonly on the arms and legs (Fig. 11D). Oral lesions are multiple, bilateral, and often symmetric (see Fig. 11AeC). Oral lichen planus often presents with a waxing and waning course. There are 2 major forms of oral lichen planus: reticular and erosive. Reticular lichen planus is more common and usually asymptomatic. Lesions of reticular lichen planus appear as white striae and as an annular and/or lacelike pattern of
181 hyperkeratosis that most commonly affects the bilateral buccal mucosa, but other oral sites may also be affected, including lateral and dorsal tongue, gingivae, palate and vermilion border (see Fig. 11AeC). Erosive lichen planus is usually symptomatic with patients complaining of pain and/or sensitivity, especially with spicy or acidic foods. Erosive lichen planus is characterized by multiple erythematous lesions, erosions and shallow irregularly shaped ulcers that may be bordered by fine radiating white striae (Fig. 12A, B). Gingival involvement may present as desquamative gingivitis. Histopathology The mucosal epithelium shows hyperkeratosis and sawtoothed rete ridges with hydropic degeneration of the basal layer. Colloid (cytoid, hyaline, or Civatte) bodies are degenerating keratinocytes near the epithelialeconnective tissue interface. The connective tissue contains a bandlike infiltrate of lymphocytes that is immediately beneath the epithelium. A fibrinogen band may be seen at the basement membrane zone with direct immunofluorescence studies. The histopathologic features of lichen planus are shared with other conditions, such as lichenoid drug reaction and lichenoid amalgam reaction (please see section on Oral Lichenoid Lesions); clinical correction is required to differentiate among them. Diagnosis Diagnosis of oral lichen planus can be made from the clinical presentation if the oral lesions are sufficiently characteristic. Biopsy may be required to confirm the diagnosis and to exclude dysplasia and malignancy.
Fig. 12 Erosive lichen planus. A 59-year-old male with a 4-year history of ulceration and erythema with peripheral white striations on the buccal mucosa (A, B) and lip mucosa. He was taking hydrochlorothiazide to control hypertension and it was not feasible to alter his medication. The lesions were partly responsive to topical corticosteroids, which provided symptomatic relief.
182 Treatment Reticular lichen planus is not treated because it is usually asymptomatic; however, periodic monitoring is recommended. Erosive lichen planus is usually managed with topical corticosteroids delivered in the form of gels, ointments, mouth rinses, or adhesive pastes. Midpotency topical corticosteroids such as triamcinolone acetonide, potent fluorinated corticosteroids such as fluocinonide, and super-potent corticosteroids such as clobetasol propionate are effective on most patients; the choice of topical steroid type and formulation depends on the distribution and clinical severity of the lesions. Although there are few adrenal suppressive effects associated with use of topical corticosteroids, secondary candidiasis may occur in up to one-third of cases and can be treated with topical antifungal agents. Maintenance of good oral hygiene and removal of local mechanical sources of trauma such as sharp dental cusps, rough dental restorations, and poorly fitting dentures will help to prevent exacerbation of lesions. Intralesional corticosteroid injections, immunomodulatory agents such as topical tacrolimus, and systemic corticosteroids may be considered in cases of erosive lichen planus refractory to treatment with topical corticosteroids, however, use of these less conventional therapies is best restricted to oral medicine specialty practice. Patients with erosive lichen planus should be periodically monitored every 3 to 6 months; a repeat biopsy may be considered for persistent and/or progressive lesions that do not respond to topical steroids.18e20
Oral lichenoid lesions Oral lichen planus is a chronic inflammatory mucosal disease that is associated with a cell-mediated immune reaction to basal keratinocytes. The etiology and pathogenesis are not well-understood (see elsewhere in this article and also Paolo G. Arduino’s article, “Oral Complications of Dermatologic Disorders,” in this issue). Lesions of the oral mucosa may also present with a clinical appearance similar to lichen planus, as white reticular patches, plaques, and papules, and erosions or ulcerations, but are associated with a causative factor or underlying disease. These are referred to as oral lichenoid lesions, and are managed by removal of the causative factor or treatment of the underlying disease. Oral lichenoid lesions can be classified into the following categories: Contact reaction to dental materials (discussed elsewhere in this article), Mucosal reaction to systemic medications (see Kentaro Ikeda’s article, “Drug-Induced Oral Complications,” in this issue), Oral lesions of chronic graft versus host disease (see Elizabeth Waring and Alessandro Villa’s article, “Oral Manifestations of Immunodeficiencies and Transplantation Medicine,” in this issue), and Oral lesions of discoid or systemic lupus erythematosus (see Vidya Sankar and Marcel Noujeim’s article, “Oral Manifestations of Autoimmune and Connective Tissue Disorders,” in this issue).
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Lichenoid contact reaction to dental materials, particularly amalgam Description A chronic mucosal lesion with clinical appearance similar to lichen planus, located in direct contact with a dental material, most commonly an amalgam restoration. Most cases represent a type IV, or delayed type hypersensitivity reaction, which is a cell-mediated response. Prevalence Rare. Occurs in a minority of the population but the basis of individual susceptibility is unknown. Clinical presentation White reticular patch or white plaque that may be associated with erythema or ulceration. Develops in an area of mucosa in direct contact with an amalgam restoration (Fig. 13). The amalgam restoration may have been present for months or years. Predilection for buccal mucosa and lateral border of the tongue; other areas of the mucosa such as gingiva or palate are unlikely to have direct surface contact with a restoration. Migration of the lesion does not occur. Pain is uncommon, but may develop when there is erosion or ulceration. Patch testing for allergy to amalgam or mercury Best done in a specialized dermatology clinic or oral medicine center. An array of dental materials, including amalgam and mercuric compounds is placed on the skin of the back or arm and held in place for 48 hours. Test is read at 48 and 72 hours, plus a late reading at 10 to 14 days for increased sensitivity. A positive reaction consists of erythema with or without vesicles. False positives and false negatives occur, so the patch test should be used only where there is a strong clinical indication of a contact reaction to amalgam, and interpreted in the context of clinical and biopsy findings.
Fig. 13 Lichenoid reaction to amalgam. Erythematous patch associated with white striations on the left buccal mucosa opposite a large amalgam restoration on the left maxillary first molar. There were no other oral lesions.
Immunologically Mediated Diseases Histopathology Similar to lichen planus with hyperkeratosis, liquefactive degeneration of the basal cell layer with a bandlike, predominately lymphocytic inflammatory infiltrate in the superficial connective tissue. May be distinguished from lichen planus by the presence of a deeper, perivascular inflammatory infiltrate in addition to the subepithelial infiltrate, and the presence of plasma cells and neutrophils in addition to lymphocytes and histiocytes in the infiltrate. The majority of cases of lichenoid reaction to amalgam cannot be distinguished from lichen planus by histopathologic examination alone (Fig. 14AeD).
183 Diagnosis The strongest diagnostic feature is the clinical demonstration of contact of the mucosal lesion with an amalgam restoration. There are conflicting reports on the usefulness of patch testing. Biopsy should be done to rule out epithelial dysplasia. Differential diagnosis Lichen planus. Lichenoid drug reaction. Chronic graft-versus-host disease. Chronic discoid lupus erythematosus. Oral lesion of systemic lupus erythematosus. Dysplasia or squamous cell carcinoma (Table 4).
Fig. 14 Histologic similarity between lichen planus and lichenoid reaction to amalgam. (A, B) Biopsy of lichen planus of the buccal mucosa showing hyperkeratosis, dense chronic inflammatory infiltrate beneath the epithelium that is predominantly lymphocytic and liquefactive degeneration of basal epithelial cells. (C, D) Biopsy of lichenoid reaction to amalgam (clinical photograph in Fig. 13) showing hyperkeratosis, dense chronic inflammatory infiltrate beneath the epithelium, and liquefactive degeneration of basal epithelial cells. There is also a perivascular inflammatory infiltrate in the deeper connective tissue. The high-power view shows that the inflammatory infiltrate consists of lymphocytes and plasma cells.
184 Table 4
Johnson et al. Differentiation of lichenoid contact reaction to amalgam from lesions with a similar clinical appearance
Diagnosis
Clinical and laboratory findings
Lichenoid contact reaction to amalgam
Location in direct contact with amalgam restoration; typically unilateral, not symmetric; positive patch test to amalgam and/or mercuric compounds; resolution of lesion upon removal of the amalgam restoration
Lichen planus
Multiple lesions that are bilateral and symmetric; lesions may be present on skin and other mucosal surfaces
Lichenoid drug reaction
Associated with use of systemic medications
Chronic graft-versus-host disease
History of bone marrow transplantation
Oral discoid lupus erythematosus
Lesions on sun-exposed skin; histologic findings of edema and extravasation of blood in lamina propria, perivascular inflammatory infiltrate; Periodic acid-Schiff diastase (PASD)-positive eosinophilic material along basement membrane zone and perivascular space; direct immunofluorescence examination shows the eosinophilic deposits to contain IgG
Oral lesion of SLE
Clinical manifestations of SLE in skin, joints, kidneys, lungs, heart, central nervous system; laboratory findings
Epithelial dysplasia
Histologic findings of epithelial dysplasia; not related to contact with amalgam or other dental material; does not resolve with removal of dental restorations in the area of the lesions
Abbreviation: SLE, systemic lupus erythematosus.
Treatment Remove the amalgam restoration; if this is not possible, cover the amalgam with a crown. Diagnosis of lichenoid contact reaction to amalgam is confirmed if resolution occurs within 4 to 5 weeks after elimination of contact with the amalgam. Only the amalgam restorations in contact with a lichenoid lesion require removal; a rubber dam, copious water, and high-speed suction should be used during the procedure.21e23
Contact stomatitisdcinnamon reaction Description Delayed type, cell-mediated hypersensitivity reaction may occur in the oral mucosa in response to a diverse
array of substances including food and food additives, oral hygiene products, and dental materials. Should be distinguished from nonallergic mucosal inflammation that occurs in response to physical and/or chemical irritation of the mucosa Two common types of allergens, cinnamon (cinnamon essential oil or cinnamaldehyde) and dental restorative materials are known for their distinctive reaction patterns seen clinically. (Lichenoid contact reaction to dental materials, particularly amalgam, is discussed elsewhere in this article.) Cinnamon essential oil is widely used as a flavoring agent at concentrations of up to 100 time that of the natural spice. Prolonged and frequent contact with artificially flavored cinnamon products, such as candy and chewing gum, lead to a delayed hypersensitivity T-cellemediated immune response and subsequent inflammatory reaction.
Fig. 15 Contact stomatitis from cinnamon flavoring. (A) Diffuse erythema of the buccal mucosa associated with use of cinnamonflavored gum. The lesion cleared completely when the patient stopped using the cinnamon-containing product. (B) Shaggy hyperkeratosis associated with erythema on the buccal mucosa and retromolar mucosa.
Immunologically Mediated Diseases Prevalence Contact stomatitis is less commonly seen than contact dermatitis; a number of physiologic mechanisms, including the action of saliva, are thought to limit the development of a contact allergic response in the oral mucosa. Factors determining susceptibility are unknown. Clinical presentation Tissue involvement is directly related to the surfaces most in contact with the cinnamon allergen. Toothpaste would create a more diffuse reaction involving the gingiva. Chewing gum and candy results in a more focal presentation, often on the buccal mucosa. Affected mucosa is often erythematous and may show patches and plaques of hyperkeratosis with or without sloughing, associated edema, erosions, and ulcerations (Fig. 15A, B). Painful burning sensation is the most common complaint. Histopathology Hyperkeratosis, atrophic or acanthotic epithelium with neutrophilic exocytosis and a dense inflammatory infiltrate in the superficial lamina propria, consisting predominantly of lymphocytes intermixed with plasma cells, histiocytes, and eosinophils. Perivascular inflammatory infiltrates may be seen within the connective tissue. Histopathologic appearance is not specific for contact stomatitis to cinnamon. Diagnosis Clinical appearance of the lesions and a history of contact of the affected mucosa with cinnamon-flavored products. Diagnosis can be confirmed by withdrawal of the product containing the cinnamon followed by resolution of the lesions (observing a recurrence of the lesions with reintroduction of the offending product would further confirm the diagnosis, although rarely carried out). A biopsy may be required to rule out mucocutaneous diseases such as lichen planus, hairy leukoplakia, hyperplastic candidiasis, and epithelial dysplasia. Cutaneous patch testing may help with the diagnosis, although false positives and false negatives are common. Treatment Lesions usually resolve within 1 to 2 weeks after elimination of the allergenic agent/cinnamon-flavored product. If the lesions are slow to resolve or the patient is experiencing some discomfort then short-term use of topical corticosteroids may be beneficial.24,25
References 1. Al Johani KA, Moles DR, Hodgson TA, et al. Orofacial granulomatosis: clinical features and long-term outcome of therapy. J Am Acad Dermatol 2010;62(4):611e20. 2. Campbell H, Escudier M, Patel P, et al. Distinguishing orofacial granulomatosis from Crohn’s disease: two separate disease entities? Inflamm Bowel Dis 2011;17(10):2109e15.
185 3. Fitzpatrick L, Healy CM, McCartan BE, et al. Patch testing for foodassociated allergies in orofacial granulomatosis. J Oral Pathol Med 2011;40(1):10e3. 4. Lazzerini M, Martelossi S, Cont G, et al. Orofacial granulomatosis in children: think about Crohn’s disease. Dig Liver Dis 2015;47(4): 338e41. 5. McCartan BE, Healy CM, McCreary CE, et al. Characteristics of patients with orofacial granulomatosis. Oral Dis 2011;17(7): 696e704. 6. Miest R, Bruce A, Rogers RS 3rd. Orofacial granulomatosis. Clin Dermatol 2016;34(4):505e13. 7. Mignogna MD, Pollio A, Leuci S, et al. Clinical behaviour and longterm therapeutic response in orofacial granulomatosis patients treated with intralesional triamcinolone acetonide injections alone or in combination with topical pimecrolimus 1%. J Oral Pathol Med 2013;42(1):73e81. 8. Patel P, Brostoff J, Campbell H, et al. Clinical evidence for allergy in orofacial granulomatosis and inflammatory bowel disease. Clin Transl Allergy 2013;3(1):26. 9. Baccaglini L, Lalla RV, Bruce AJ, et al. Urban legends: recurrent aphthous stomatitis. Oral Dis 2011;17(8):755e70. 10. Scully C. Clinical practice. Aphthous ulceration. N Engl J Med 2006; 355(2):165e72. 11. Stoopler ET, Sollecito TP. Recurrent oral ulcers. JAMA 2015; 313(23):2373e4. 12. Davatchi F, Chams-Davatchi C, Shams H, et al. Behcet’s disease: epidemiology, clinical manifestations, and diagnosis. Expert Rev Clin Immunol 2017;13(1):57e65. 13. Rokutanda R, Kishimoto M, Okada M. Update on the diagnosis and management of Behcet’s disease. Open Access Rheumatol 2015;7:1e8. 14. Neville B, Allen C, Damm D, et al. Oral and maxillofacial pathology. 4th edition. St. Louis (MO): Elsevier; 2016. 15. Kumar V, Abbas A, Fausto N, et al. Pathologic basis of disease. 8th edition. Philadelphia: Saunders/Elsevier; 2010. 16. Celentano A, Tovaru S, Yap T, et al. Oral erythema multiforme: trends and clinical findings of a large retrospective European case series. Oral Surg Oral Med Oral Pathol Oral Radiol 2015;120(6):707e16. 17. Staikuniene J, Staneviciute J. Long-term valacyclovir treatment and immune modulation for Herpes-associated erythema multiforme. Cent Eur J Immunol 2015;40(3):387e90. 18. Thongprasom K, Carrozzo M, Furness S, et al. Interventions for treating oral lichen planus. Cochrane Database Syst Rev 2011;(7). CD001168. 19. van der Meij EH, Mast H, van der Waal I. The possible premalignant character of oral lichen planus and oral lichenoid lesions: a prospective five-year follow-up study of 192 patients. Oral Oncol 2007; 43(8):742e8. 20. Lodi G, Scully C, Carrozzo M, et al. Current controversies in oral lichen planus: report of an international consensus meeting. Part 2. Clinical management and malignant transformation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100(2):164e78. 21. McParland H, Warnakulasuriya S. Oral lichenoid contact lesions to mercury and dental amalgamea review. J Biomed Biotechnol 2012; 2012:589569. 22. Thornhill MH, Sankar V, Xu XJ, et al. The role of histopathological characteristics in distinguishing amalgam-associated oral lichenoid reactions and oral lichen planus. J Oral Pathol Med 2006;35(4): 233e40. 23. van der Waal I. Oral lichen planus and oral lichenoid lesions; a critical appraisal with emphasis on the diagnostic aspects. Med Oral Patol Oral Cir Bucal 2009;14(7):E310e4. 24. Tremblay S, Avon SL. Contact allergy to cinnamon: case report. J Can Dent Assoc 2008;74(5):445e61. 25. Vivas AP, Migliari DA. Cinnamon-induced oral mucosal contact reaction. Open Dent J 2015;9:257e9.
Introduction
Swellings
Immune-mediated conditions represent a spectrum of diseases characterized by an individual’s immune system mounting an aberrant attack leading to tissue damage. In this article, we address immune-mediated conditions in which an inappropriate inflammatory reaction results in oral mucosal diseases that range from swelling to ulceration to red/white lesions. The inciting factor for the immune reaction is often difficult or impossible to identify. We highlight the clinical history and appearance of each condition and describe the role of laboratory tests and biopsy in diagnosis. The management of these conditions varies and may include removal of any demonstrable trigger, topical steroid, and other immunosuppressive agents. Conditions that present with self-limited oral lesions only require supportive care. In those conditions where oral lesions are associated with extraoral lesions, timely investigations are important to detect and treat systemic manifestations of disease.
Orofacial granulomatosis
The authors have nothing to disclose. Department of Oral and Maxillofacial Sciences, Faculty of Dentistry, Dalhousie University, 5981 University Avenue, Room 5124, PO Box 15000, Halifax, Nova Scotia B3H 4R2, Canada b Oral Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto, 124 Edward Street Room 308, Toronto, Ontario M5G 1G6, Canada c Oral Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto, 124 Edward Street Room 311, Toronto, Ontario M5G 1G6, Canada d Oral Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto, 124 Edward Street Room 315C, Toronto, Ontario M5G 1G6, Canada * Corresponding author. E-mail address: [email protected] a
Atlas Oral Maxillofacial Surg Clin N Am 25 (2017) 171–185 1061-3315/17/ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cxom.2017.04.009
Description Characterized by persistent swelling of one or both lips and/or intraoral swelling; biopsy shows inflammation with noncaseating granulomas. The etiology and pathogenesis are not fully understood; there may be multiple pathogenetic pathways leading to a common set of clinical manifestations. Patients who are known to have Crohn’s disease or sarcoidosis may rarely develop orofacial swelling with clinical and histologic features nearly identical to orofacial granulomatosis (OFG); it is a matter of debate whether such patients should be classified as having OFG. OFG presenting in childhood is associated with an increased probability of Crohn’s disease, although the signs and symptoms of Crohn’s disease may only appear after an interval of several years. A minority of OFG have been shown to be associated with allergy to food, food preservatives and flavoring agents and oral hygiene products; both type I (immediate, IgEmediated) hypersensitivity and type IV (delayed, cellmediated) hypersensitivity have been shown to be associated with OFG. The remainder of OFG cases are idiopathic with no associated gastrointestinal tract abnormality and no identifiable allergen. Prevalence OFG is an uncommon condition, but the exact prevalence has not been determined. Median age at onset is between 15 and 30 years of age in the majority of case series.
oralmaxsurgeryatlas.theclinics.com
172 Males and females are almost equally affected. Firm swelling of one or both lips is seen in more than 90% of cases; upper and lower lips are equally likely to be affected (Fig. 1A); the swelling varies in severity and may be symmetric or affect one side more than the other (Fig. 2A). Lip swelling may be associated with perioral erythema, angular cheilitis, and vertical fissures of the lip. The swelling is usually painless, although severe swelling with scaling and fissuring of the mucosa may cause discomfort. Lip swelling accompanied by fissured tongue and facial paralysis is known as MelkerssoneRosenthal syndrome. Intraoral lesions include diffuse or segmental swelling of the attached gingiva (see Fig. 1B), cobblestone appearance of the buccal mucosa, linear ulceration and swelling of the buccal vestibule (see Fig. 2B), and swelling of the anterior floor of mouth over Wharton’s ducts. Clinical and laboratory investigations are required to determine if there is an underlying systemic disease (Table 1) or a local cause (Table 2). Patients with Crohn’s disease who have orofacial lesions along with intestinal lesions (“oral Crohn’s disease”) may present clinically similar to OFG patients, but are more likely to have involvement of the mandibular buccal sulcus (Fig. 3A,B); it has also been shown that patients with OFG who have ulcers and swelling of the buccal sulcus are more likely to have concurrent Crohn’s disease upon investigation than OFG patients with predominantly lip swelling. Histopathology Edema in the lamina propria, chronic inflammatory infiltrate with nonnecrotizing granulomas consisting of epithelioid macrophages, and lymphocytes, often with multinucleated giant cells. Nonnecrotizing granulomas may be absent in the biopsy because of sampling problems or fluctuations in the disease process; a repeat biopsy of deeper tissues may be helpful to demonstrate the granulomatous inflammation.
Johnson et al. Special stains are negative for the presence of acid-fast bacilli and fungal organisms. No detectable foreign bodies by conventional or polarized light examination. Diagnosis Based on clinical presentation and biopsy findings. Clinically, the lip swelling of OFG can be distinguished from that of angioedema because the latter condition has a rapid onset and resolves after 24 to 72 hours. Biopsy to demonstrate nonnecrotizing granulomas is useful to support the diagnosis of OFG. Clinical and laboratory investigations are required to determine if there is an underlying systemic disease or an allergy (see Tables 1 and 2). Treatment Investigate for an underlying systemic disease (eg, Crohn’s disease); the orofacial lesions should resolve upon treatment of the systemic disease. Treatment of odontogenic infections may lead to resolution of OFG. Perform cutaneous patch tests and urticarial tests if allergy is suspected; avoid exposure to allergens, for example, by instituting an elimination diet for patients who are found to have an associated allergy. Intralesional injections of triamcinolone acetonide are effective in the majority of patients in reducing lip and oral mucosal swelling; the injections are given every 2 to 4 weeks, typically for 4 to 6 months. Topical corticosteroids or calcineurin inhibitors (tacrolimus, pimecrolimus) may be used as an adjunct to intralesional injections of corticosteroid. Immunosuppressants such as azathioprine, or tumor necrosis factor-a inhibitors such as infliximab may be used in severe cases. Pediatric patients (age < 16 years) with OFG but no gastrointestinal disease should be monitored for signs and symptoms of Crohn’s disease, because a number of
Fig. 1 (A) Diffuse, firm swelling of the lower lip and less extensive swelling of the upper lip in a 22 year-old female. The patient had a surgical reduction of the lower lip 7 years earlier but the swelling has slowly recurred. Biopsy showed nonnecrotizing granulomatous inflammation, consistent with a diagnosis of orofacial granulomatosis. (B) Same patient as A, showing diffuse swelling and erythema of the maxillary labial gingiva. Similar changes were noted in the mandibular anterior gingiva.
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Fig. 2 (A) A 14-year-old healthy female with painless swelling of the right lower lip of several months’ duration. The patient reported no gastrointestinal problems. (B) Same patient as A, showing a painless, deep fissured ulcer surrounded by raised linear folds of tissue in the right mandibular buccal vestibule. Biopsy demonstrated nonnecrotizing granulomatous inflammation, consistent with a diagnosis of orofacial granulomatosis.
studies have suggested that childhood onset of OFG is predictive of the development of Crohn’s disease. Surgical reduction of lip enlargement has been used to improve facial appearance, but there is a risk of recurrence.1e8
Ulcers Recurrent aphthous stomatitis Description Painful, self-limited, recurrent oral ulcers. Unknown cause, but a variety of triggers have been reported, including stress, hormonal effects, food allergy, trauma, and smoking cessation. May also be triggered by use of systemic medications, including nonsteroidal antiinflammatory drugs, betablockers, and nicorandil. Decrease in mucosal barrier, antigenic stimulation, and Tcellemediated immunologic reaction have been implicated in the pathogenesis.
Table 1
Three clinical forms: minor, major, and herpetiform. Predominantly on nonkeratinized mucosa. Prevalence Common, affecting 20% of the population. Usually presents in childhood or adolescence. Eighty percent of affected individuals present with minor aphthous ulcers. Clinical presentation All forms of aphthous ulcers are painful and characterized by a whitish-grey pseudomembrane and an erythematous halo. Minor aphthous ulcers (Fig. 4A, B). Round ulcers, less than 1 cm in diameter. Develop on nonkeratinized tissues; rare on dorsum of tongue, hard palate, and gingiva. Predilection for the buccal and labial mucosa, followed by ventral tongue, soft palate, and floor of mouth. Typically 1 to 5 are present at any given time. Heal in 1 to 2 weeks with no scarring. Major aphthous ulcers (Fig. 5A, B).
: Investigations of patients with orofacial granulomatosis to rule out systemic disease
Clinical presentation
Diagnostic tests
Diagnosis
Gastrointestinal problems, such as bloating, cramps, and diarrhea; perianal symptoms in children Laboratory findings of low hemoglobin, serum iron, vitamin B12, folate Elevated levels of inflammatory markers e erythrocyte sedimentation rate, C-reactive protein
Endoscopy and biopsy
Crohn’s disease
Respiratory problems such as dyspnea Salivary and lacrimal gland dysfunction Elevated levels of inflammatory markers e erythrocyte sedimentation rate, C-reactive protein Serum angiotensin-converting enzyme level
Chest radiography to look for hilar lymphadenopathy Bronchoscopy and biopsy
Sarcoidosis
174 Table 2
Johnson et al. Investigations of patients with orofacial granulomatosis to rule out local causes
Clinical presentation
Diagnostic tests
Diagnosis
Predominantly gingival involvement
Vitality test, periodontal examination, and radiographs of teeth in the vicinity of orofacial swelling
Chronic dental infection
Gingival swelling History of scaling and polishing of teeth
Identification of foreign material in gingival biopsy
Foreign body gingivitis
History of atopy e asthma, eczema, allergic rhinitis Association between exposure to suspected allergen and development/exacerbation of orofacial swelling
Skin patch test against foods, food preservatives, and additives (eg, benzoates, monosodium glutamate, cinnamaldehyde), dental materials Elevated serum IgE levels Response to elimination diet
Allergy
Fig. 3 (A) Elongated ulcer surrounded by thickened mucosa in the left mandibular buccal vestibule in a patient with Crohn’s disease. Note the similarity to Fig. 2B. (B) Diffuse swelling of the maxillary labial gingiva in a patient with Crohn’s disease.
Fig. 4 (A) Minor aphthous ulcers. A 40-year-old female with 2 aphthous ulcers of the labial mucosa. The patient has a history of recurrent oral ulcers since childhood. (B) Aphthous ulcer on the labial mucosa with the characteristic appearance of a round ulcer covered by a whitish-grey pseudomembrane and surrounded by an erythematous halo.
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Fig. 5 (A) Major aphthous ulcer. Adolescent male presented with an ulcer of the right soft palate of 4 weeks’ duration. He has a history of minor aphthous ulcers. (B) Same patient as A, 1 month later. The ulcer has healed, leaving a whitish scar.
Larger, deeper, and more irregular ulcers with a preference for tonsillar pillars, soft palate, and labial mucosa. Diameter of 1 to 3 cm. There may be 1 to 10 ulcers may be present at a time. May extend from nonkeratinized to keratinized tissues. Heal in 2 to 6 weeks, often with scarring. Herpetiform (Fig. 6A, B). Least common form, representing only 5% of recurrent aphthous stomatitis cases. Demonstrates a female predilection and may present in adulthood. Numerous pinhead-sized ulcers, 1 to 3 mm in diameter, that coalesce to form larger ulcers, giving a resemblance to herpetic stomatitis.
Despite the name, infection with herpes virus has not been convincingly demonstrated. Up to 100 ulcers may develop at 1 time, predominantly affecting nonkeratinized mucosa, but may affect keratinized mucosa as well. Heal in 1 to 2 weeks, but frequent recurrences are typical. Histopathology Nonspecific ulceration consisting of loss of surface epithelium with a mixed inflammatory infiltrate composed of neutrophils, lymphocytes, and histiocytes in the underlying connective tissue. The mucosa at the margins of the ulcer shows an inflammatory infiltrate of lymphocytes and histiocytes in the connective tissue and migration of inflammatory cells into the epithelium.
Fig. 6 (A, B) 16 year-old male with herpetiform aphthous ulcers that were reported to be associated with stress. (Courtesy of Dr John Lovas, BSC, DDS, MSc, FRCD(C), Halifax, NS.)
176 Diagnosis Based on history of self-limited, recurrent ulcers, characteristic clinical appearance and exclusion of underlying systemic disease (see below). Biopsy is not required except in rare occasions when a major aphthous ulcer has to be distinguished from malignant disease such as squamous cell carcinoma or lymphoma. Aphthous-like ulcers occur as part of several systemic diseases (Fig. 7AeD, Table 3); control of the systemic disease usually leads to improvement of the oral ulcers. A medical history should be taken to determine if the oral ulcers are associated with gastrointestinal problems including diarrhea, bloating, and signs of malabsorption, fever, lymphadenopathy, weight loss, skin lesions, ulcers
Johnson et al. on other mucosal surfaces, ocular inflammation, and joint pain. Laboratory investigation including complete blood count, red blood cell folate, serum iron, and vitamin B12 should be considered in case of onset of ulcers after adolescence or unusual number, frequency or location of ulcers. Treatment A variety of treatments have been proposed, but none has been consistently effective in preventing recurrence or promoting healing of ulcers. Elimination of suspected triggers, for example, certain fruits, nuts, flavoring agents, and preservatives. Substitution of suspected medications with other medications, if possible.
Fig. 7 (AeD) A 9-year-old male with ulcers of the maxillary and mandibular vestibules and lateral tongue. The patient has a history of ulcers starting at age 5 and experiences 1 to 2 outbreaks per month during which time he takes prednisolone. Diagnosis of periodic fever, aphthae, pharyngitis, adenitis (PFAPA) was made by a pediatric rheumatologist.
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Systemic disorders that are associated with aphthouslike oral ulcers
Systemic disorder
Clinical findings besides oral ulcers
Laboratory tests
Behc‚et syndrome
Genital ulcers, uveitis, skin lesions, joint lesions, central nervous system manifestations (see next section)
Celiac disease (gluten sensitive enteropathy)
Gluten intolerance; bloating, diarrhea, weight loss, dental defects
Small intestine biopsy; antibodies to gliadin and tissue transglutaminase
Cyclic neutropenia
Presents in childhood with cyclical occurrence of fever and infections; usually improves in second decade
Complete blood count and correlation with development of ulcers
Nutritional deficiencies (iron, folate, vitamin B12)
Fatigue, weakness, pallor; atrophic glossitis, angular cheilitis
Serum iron, vitamin B12, red blood cell folate
Immunocompromised conditions, eg, HIV infection
Candidiasis, hairy leukoplakia; Kaposi sarcoma, lymphoma
Complete blood count with immunodeficiency panel; HIV testing
Inflammatory bowel disease (ulcerative colitis and Crohn’s disease)
Diarrhea, abdominal pain, weight loss
Endoscopy, biopsy
Mucosal and genital ulcers with inflamed cartilage
More common in the 4the5th decades of life with oral and genital lesions with relapsing polychronditis
Periodic fever, aphthae, pharyngitis, adenitis
Presents in young children and occurs in 3e5 wk intervals with fever, sore throat and cervical lymphadenopathy in the absence of upper respiratory tract infection
Sweet syndrome (acute febrile neutrophilic dermatoses)
Sudden onset of fever, red papules and plaques on skin, mucosal ulcers, arthralgia/arthritis
Reactive arthritis
Urethritis, arthritis, conjunctivitis; strong male predilection
Abbreviation: HIV, human immunodeficiency virus.
Laser therapy can provide pain relief and reduce healing time. Tetracycline rinse (contents of 250 mg capsule dissolved in 1 tbsp of water); doxycycline and minocycline gel or rinse are also effective. Chlorhexidine rinses 0.12%. Topical glucocorticosteroids, particularly 0.1% triamcinolone acetonide in orabase. Zylactin (over the counter) provides a covering film for symptomatic relief. Systemic glucocorticoids and other immune modulators may be considered in major aphthous stomatitis.9e11
Behc‚et disease Description Behc‚ets disease (BD) is a multisystem inflammatory disease of unknown etiology, currently considered to be a systemic vasculitis. Characterized by recurrent episodes of active disease and remissions, with different durations, most often manifesting as a triad of oral ulcers, genital ulcers, and ocular inflammation. Prevalence BD is rare; the majority of cases are associated with HLAB51 genotype, occurring more commonly in countries along the “silk route”: Turkey, Japan, and the eastern Mediterranean countries. Usual age at onset is between the second and fourth decades. Males are more often diagnosed with BD than females and may have a worse clinical course.
Clinical presentation Oral ulcerations are similar in appearance to aphthous ulcers (both minor and major), with recurrent multifocal presentation, often lasting 1 to 4 weeks and healing without scarring. Oral ulceration is seen in nearly all patients with BD and it is also the most frequent presenting symptom (see Fig. 8AeD). Genital lesions are similar to oral lesions and are present in approximately 75% of cases. Eye lesions are serious and may lead to severe vision loss and blindness. Most commonly include posterior uveitis, conjunctivitis, conjunctival aphthosis, and scleritis. Typical skin lesions consist of erythematous papules, vesicles, or acnelike eruptions, as well as erythema nodosum. Arthritis, thrombophlebitis, gastrointestinal disease, and central nervous system involvement may be seen. Histopathology Nonspecific ulceration of the epithelium. Most frequent pattern seen for skin lesions is leukocytoclastic vasculitis, consisting of infiltration of neutrophils and fibrinoid necrosis of the walls of small blood vessels, and extravasation of red blood cells. Diagnosis Diagnosis of BD is difficult because it is based on clinical manifestations, which may be seen in other diseases as well. No other disease has had so many different classification and diagnostic criteria; there are currently 17 published sets of criteria.
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Fig. 8 (AeD) Behc‚et disease. A 26-year-old male of Turkish descent with multiple large ulcers of the dorsal and lateral tongue, labial and buccal mucosa. The patient has a history of recurrent oral ulcers since childhood associated with pustular lesions of the skin and genital ulcers.
The international criteria for BD were revised in 2014 and state that a patient must get 4 points from a list of symptoms: Oral aphthosis (2 points), Genital aphthosis (2 points), Ocular manifestations (2 points), Skin manifestations (1 point), Vascular manifestations (1 point), Neurologic manifestations (1 point), and Positive pathergy test (1 point). BD must be differentiated from other systemic conditions presenting with oral ulcerations (see Table 3 in Recurrent Aphthous Stomatitis section). Treatment Symptomatic treatment for oral ulcers, such as topical or intralesional corticosteroids. No treatment or medication has been found to be universally effective for BD; different patient groups
have responded to systemic antiinflammatory and immunosuppressive medications such as azathioprine, colchicine, corticosteroids, cyclosporine, dapsone, methotrexate, thalidomide, and tumor necrosis factor-alpha inhibitors.12e14
Erythema multiforme Description Self-limiting condition that presents with an acute onset of erythema, erosions, vesicles, and ulcers affecting the skin and mucous membranes. Clinical and microscopic features suggest that this is an immunologically mediated condition but the pathogenesis is not well-understood. Approximately 50% of cases are associated with a preceding infection, in particular herpes simplex infection;
Immunologically Mediated Diseases
Fig. 9 Hemorrhagic, crusting lesions of the lips in a patient with erythema multiforme.
mycoplasmal infection, histoplasmosis, coccidioidomycosis and EpsteineBarr virus have also been implicated. May also be triggered by use of medications, in particular sulfonamides, penicillin, barbiturates, salicylates and antimalarial drugs (see Kentaro Ikeda’s article, “DrugInduced Oral Complications,” in this issue). Controversial whether erythema multiforme (EM) is a separate condition from StevenseJohnson syndrome and toxic epidermal necrolysis; the latter 2 conditions are characterized by more severe and extensive lesions of the skin and multiple mucosal sites and displays epithelial necrosis upon biopsy; the majority of cases of StevenseJohnson syndrome and toxic epidermal necrolysis are triggered by medications (see Kentaro Ikeda’s article, “Drug-Induced Oral Complications,” in this issue). May also present in association with cancer, in particular carcinomas and lymphomas, and in patients with collagen
179 vascular diseases, such as systemic lupus erythematosus and polyarteritis nodosa. Prevalence Presents in the second to fifth decades of life, with no sex predilection. In comparison, toxic epidermal necrolysis presents in older adults with a female predilection, whereas Stevense Johnson syndrome occurs more commonly in children. Clinical presentation Acute onset with lesions appearing over a few days. Self-limiting course with resolution after 2 to 6 weeks. Flulike symptoms consisting of low-grade fever, malaise, headache, and sore throat may precede the onset of EM by 1 week. EM associated with a precipitating infection (eg, recurrent herpetic labialis) usually presents 10 to 14 days after the infection. Skin lesions typically include symmetric targetoid lesions on the hands and feet. Hemorrhagic crusting of the lips is a characteristic finding (Fig. 9). Erythematous patches and irregular shallow ulcers on any oral mucosal surface, most commonly on the labial and buccal mucosa; often sparing the gingiva and palate (Fig. 10A, B). Exclusive oral involvement is not uncommon; alternatively oral involvement may precede worsening of disease severity. Oral lesions are painful and cause difficulty with eating and drinking. More severe presentation (EM major) involves extensive skin lesions, conjunctival, nasal, and genital lesions. Recurrent episodes may occur in a minority of cases, often after recurrent herpetic labialis. Differential diagnosis includes: Pemphigus vulgaris, Paraneoplastic pemphigus,
Fig. 10 A 55-year-old female with diffuse erythema and ulcers of the lips (A) and buccal mucosa (B) of 2 weeks’ duration. The lesions had a sudden onset, with no history of use of medications or viral infection in the preceding month. There were no associated skin lesions. Topical corticosteroids and prednisone (10 mg/d) were not helpful. The clinical diagnosis of erythema multiforme was confirmed at the 4-week follow-up appointment when the lesions had completely resolved.
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Fig. 11 Oral mucosal and skin lesions of a patient with lichen planus. (A, B) Reticular white lesions associated with mucosal pigmentation in a symmetric presentation on both buccal mucosa. (C) White plaques and a small area of white reticular appearance on the dorsum of the tongue. (D) Pruritic, purplish-red papules on the skin of the forearm.
Erosive lichen planus, Fixed drug reaction, and Infections, including human immunodeficiency virus, primary herpetic gingivostomatitis, and fungal infections. Histopathology Biopsy of perilesional tissue may show subepithelial or intraepithelial vesicle formation with necrosis of the basal cell layer. A mixed inflammatory infiltrate is seen in the connective tissue, composed of lymphocytes, neutrophils, and eosinophils, often with a perivascular distribution. The histologic findings are not diagnostic, but are useful for excluding mucocutaneous diseases with a similar clinical presentation, particularly pemphigus vulgaris and paraneoplastic pemphigus. Direct immunofluorescence is negative for the presence of autoantibodies.
Diagnosis Diagnosis of EM is initially a presumptive diagnosis based on clinical history and the characteristic appearance of skin and mucosal lesions. Diagnosis of EM is confirmed by seeing complete resolution of lesions in 2 to 6 weeks. In cases where the clinical findings are nonspecific, biopsy, and direct and indirect immunofluorescence assays can be used to exclude other skin and mucosal diseases. Determine if there is a precipitating factor such as viral infection or use of systemic medication; this is particularly important for patients with recurrent EM. Treatment Supportive care including soft diet, plenty of fluids, topical anesthetics, and rest. Use of topical or systemic corticosteroids has not been shown to be highly effective.
Immunologically Mediated Diseases Discontinuation of any medication that is suspected to be the trigger. Monitor the patient until all lesions have resolved. Prophylactic antiviral medication is indicated in cases of recurrent EM triggered by herpes simplex infection.14e17
Red and white lesions Lichen planus Description Lichen planus is a chronic inflammatory disorder of skin and/or mucosa characterized by immunologically mediated reactions to basal keratinocytes. The etiology and triggering factors are poorly understood and there is currently no cure. Prevalence Oral lichen planus is common, affecting 0.1% to 2.2% of the population. Usually presents in the fifth and sixth decades. Occurs twice as commonly in women than in men. Clinical presentation Skin lesions are characterized by 4 Ps: purplish, pruritic, polygonal papules, most commonly on the arms and legs (Fig. 11D). Oral lesions are multiple, bilateral, and often symmetric (see Fig. 11AeC). Oral lichen planus often presents with a waxing and waning course. There are 2 major forms of oral lichen planus: reticular and erosive. Reticular lichen planus is more common and usually asymptomatic. Lesions of reticular lichen planus appear as white striae and as an annular and/or lacelike pattern of
181 hyperkeratosis that most commonly affects the bilateral buccal mucosa, but other oral sites may also be affected, including lateral and dorsal tongue, gingivae, palate and vermilion border (see Fig. 11AeC). Erosive lichen planus is usually symptomatic with patients complaining of pain and/or sensitivity, especially with spicy or acidic foods. Erosive lichen planus is characterized by multiple erythematous lesions, erosions and shallow irregularly shaped ulcers that may be bordered by fine radiating white striae (Fig. 12A, B). Gingival involvement may present as desquamative gingivitis. Histopathology The mucosal epithelium shows hyperkeratosis and sawtoothed rete ridges with hydropic degeneration of the basal layer. Colloid (cytoid, hyaline, or Civatte) bodies are degenerating keratinocytes near the epithelialeconnective tissue interface. The connective tissue contains a bandlike infiltrate of lymphocytes that is immediately beneath the epithelium. A fibrinogen band may be seen at the basement membrane zone with direct immunofluorescence studies. The histopathologic features of lichen planus are shared with other conditions, such as lichenoid drug reaction and lichenoid amalgam reaction (please see section on Oral Lichenoid Lesions); clinical correction is required to differentiate among them. Diagnosis Diagnosis of oral lichen planus can be made from the clinical presentation if the oral lesions are sufficiently characteristic. Biopsy may be required to confirm the diagnosis and to exclude dysplasia and malignancy.
Fig. 12 Erosive lichen planus. A 59-year-old male with a 4-year history of ulceration and erythema with peripheral white striations on the buccal mucosa (A, B) and lip mucosa. He was taking hydrochlorothiazide to control hypertension and it was not feasible to alter his medication. The lesions were partly responsive to topical corticosteroids, which provided symptomatic relief.
182 Treatment Reticular lichen planus is not treated because it is usually asymptomatic; however, periodic monitoring is recommended. Erosive lichen planus is usually managed with topical corticosteroids delivered in the form of gels, ointments, mouth rinses, or adhesive pastes. Midpotency topical corticosteroids such as triamcinolone acetonide, potent fluorinated corticosteroids such as fluocinonide, and super-potent corticosteroids such as clobetasol propionate are effective on most patients; the choice of topical steroid type and formulation depends on the distribution and clinical severity of the lesions. Although there are few adrenal suppressive effects associated with use of topical corticosteroids, secondary candidiasis may occur in up to one-third of cases and can be treated with topical antifungal agents. Maintenance of good oral hygiene and removal of local mechanical sources of trauma such as sharp dental cusps, rough dental restorations, and poorly fitting dentures will help to prevent exacerbation of lesions. Intralesional corticosteroid injections, immunomodulatory agents such as topical tacrolimus, and systemic corticosteroids may be considered in cases of erosive lichen planus refractory to treatment with topical corticosteroids, however, use of these less conventional therapies is best restricted to oral medicine specialty practice. Patients with erosive lichen planus should be periodically monitored every 3 to 6 months; a repeat biopsy may be considered for persistent and/or progressive lesions that do not respond to topical steroids.18e20
Oral lichenoid lesions Oral lichen planus is a chronic inflammatory mucosal disease that is associated with a cell-mediated immune reaction to basal keratinocytes. The etiology and pathogenesis are not well-understood (see elsewhere in this article and also Paolo G. Arduino’s article, “Oral Complications of Dermatologic Disorders,” in this issue). Lesions of the oral mucosa may also present with a clinical appearance similar to lichen planus, as white reticular patches, plaques, and papules, and erosions or ulcerations, but are associated with a causative factor or underlying disease. These are referred to as oral lichenoid lesions, and are managed by removal of the causative factor or treatment of the underlying disease. Oral lichenoid lesions can be classified into the following categories: Contact reaction to dental materials (discussed elsewhere in this article), Mucosal reaction to systemic medications (see Kentaro Ikeda’s article, “Drug-Induced Oral Complications,” in this issue), Oral lesions of chronic graft versus host disease (see Elizabeth Waring and Alessandro Villa’s article, “Oral Manifestations of Immunodeficiencies and Transplantation Medicine,” in this issue), and Oral lesions of discoid or systemic lupus erythematosus (see Vidya Sankar and Marcel Noujeim’s article, “Oral Manifestations of Autoimmune and Connective Tissue Disorders,” in this issue).
Johnson et al.
Lichenoid contact reaction to dental materials, particularly amalgam Description A chronic mucosal lesion with clinical appearance similar to lichen planus, located in direct contact with a dental material, most commonly an amalgam restoration. Most cases represent a type IV, or delayed type hypersensitivity reaction, which is a cell-mediated response. Prevalence Rare. Occurs in a minority of the population but the basis of individual susceptibility is unknown. Clinical presentation White reticular patch or white plaque that may be associated with erythema or ulceration. Develops in an area of mucosa in direct contact with an amalgam restoration (Fig. 13). The amalgam restoration may have been present for months or years. Predilection for buccal mucosa and lateral border of the tongue; other areas of the mucosa such as gingiva or palate are unlikely to have direct surface contact with a restoration. Migration of the lesion does not occur. Pain is uncommon, but may develop when there is erosion or ulceration. Patch testing for allergy to amalgam or mercury Best done in a specialized dermatology clinic or oral medicine center. An array of dental materials, including amalgam and mercuric compounds is placed on the skin of the back or arm and held in place for 48 hours. Test is read at 48 and 72 hours, plus a late reading at 10 to 14 days for increased sensitivity. A positive reaction consists of erythema with or without vesicles. False positives and false negatives occur, so the patch test should be used only where there is a strong clinical indication of a contact reaction to amalgam, and interpreted in the context of clinical and biopsy findings.
Fig. 13 Lichenoid reaction to amalgam. Erythematous patch associated with white striations on the left buccal mucosa opposite a large amalgam restoration on the left maxillary first molar. There were no other oral lesions.
Immunologically Mediated Diseases Histopathology Similar to lichen planus with hyperkeratosis, liquefactive degeneration of the basal cell layer with a bandlike, predominately lymphocytic inflammatory infiltrate in the superficial connective tissue. May be distinguished from lichen planus by the presence of a deeper, perivascular inflammatory infiltrate in addition to the subepithelial infiltrate, and the presence of plasma cells and neutrophils in addition to lymphocytes and histiocytes in the infiltrate. The majority of cases of lichenoid reaction to amalgam cannot be distinguished from lichen planus by histopathologic examination alone (Fig. 14AeD).
183 Diagnosis The strongest diagnostic feature is the clinical demonstration of contact of the mucosal lesion with an amalgam restoration. There are conflicting reports on the usefulness of patch testing. Biopsy should be done to rule out epithelial dysplasia. Differential diagnosis Lichen planus. Lichenoid drug reaction. Chronic graft-versus-host disease. Chronic discoid lupus erythematosus. Oral lesion of systemic lupus erythematosus. Dysplasia or squamous cell carcinoma (Table 4).
Fig. 14 Histologic similarity between lichen planus and lichenoid reaction to amalgam. (A, B) Biopsy of lichen planus of the buccal mucosa showing hyperkeratosis, dense chronic inflammatory infiltrate beneath the epithelium that is predominantly lymphocytic and liquefactive degeneration of basal epithelial cells. (C, D) Biopsy of lichenoid reaction to amalgam (clinical photograph in Fig. 13) showing hyperkeratosis, dense chronic inflammatory infiltrate beneath the epithelium, and liquefactive degeneration of basal epithelial cells. There is also a perivascular inflammatory infiltrate in the deeper connective tissue. The high-power view shows that the inflammatory infiltrate consists of lymphocytes and plasma cells.
184 Table 4
Johnson et al. Differentiation of lichenoid contact reaction to amalgam from lesions with a similar clinical appearance
Diagnosis
Clinical and laboratory findings
Lichenoid contact reaction to amalgam
Location in direct contact with amalgam restoration; typically unilateral, not symmetric; positive patch test to amalgam and/or mercuric compounds; resolution of lesion upon removal of the amalgam restoration
Lichen planus
Multiple lesions that are bilateral and symmetric; lesions may be present on skin and other mucosal surfaces
Lichenoid drug reaction
Associated with use of systemic medications
Chronic graft-versus-host disease
History of bone marrow transplantation
Oral discoid lupus erythematosus
Lesions on sun-exposed skin; histologic findings of edema and extravasation of blood in lamina propria, perivascular inflammatory infiltrate; Periodic acid-Schiff diastase (PASD)-positive eosinophilic material along basement membrane zone and perivascular space; direct immunofluorescence examination shows the eosinophilic deposits to contain IgG
Oral lesion of SLE
Clinical manifestations of SLE in skin, joints, kidneys, lungs, heart, central nervous system; laboratory findings
Epithelial dysplasia
Histologic findings of epithelial dysplasia; not related to contact with amalgam or other dental material; does not resolve with removal of dental restorations in the area of the lesions
Abbreviation: SLE, systemic lupus erythematosus.
Treatment Remove the amalgam restoration; if this is not possible, cover the amalgam with a crown. Diagnosis of lichenoid contact reaction to amalgam is confirmed if resolution occurs within 4 to 5 weeks after elimination of contact with the amalgam. Only the amalgam restorations in contact with a lichenoid lesion require removal; a rubber dam, copious water, and high-speed suction should be used during the procedure.21e23
Contact stomatitisdcinnamon reaction Description Delayed type, cell-mediated hypersensitivity reaction may occur in the oral mucosa in response to a diverse
array of substances including food and food additives, oral hygiene products, and dental materials. Should be distinguished from nonallergic mucosal inflammation that occurs in response to physical and/or chemical irritation of the mucosa Two common types of allergens, cinnamon (cinnamon essential oil or cinnamaldehyde) and dental restorative materials are known for their distinctive reaction patterns seen clinically. (Lichenoid contact reaction to dental materials, particularly amalgam, is discussed elsewhere in this article.) Cinnamon essential oil is widely used as a flavoring agent at concentrations of up to 100 time that of the natural spice. Prolonged and frequent contact with artificially flavored cinnamon products, such as candy and chewing gum, lead to a delayed hypersensitivity T-cellemediated immune response and subsequent inflammatory reaction.
Fig. 15 Contact stomatitis from cinnamon flavoring. (A) Diffuse erythema of the buccal mucosa associated with use of cinnamonflavored gum. The lesion cleared completely when the patient stopped using the cinnamon-containing product. (B) Shaggy hyperkeratosis associated with erythema on the buccal mucosa and retromolar mucosa.
Immunologically Mediated Diseases Prevalence Contact stomatitis is less commonly seen than contact dermatitis; a number of physiologic mechanisms, including the action of saliva, are thought to limit the development of a contact allergic response in the oral mucosa. Factors determining susceptibility are unknown. Clinical presentation Tissue involvement is directly related to the surfaces most in contact with the cinnamon allergen. Toothpaste would create a more diffuse reaction involving the gingiva. Chewing gum and candy results in a more focal presentation, often on the buccal mucosa. Affected mucosa is often erythematous and may show patches and plaques of hyperkeratosis with or without sloughing, associated edema, erosions, and ulcerations (Fig. 15A, B). Painful burning sensation is the most common complaint. Histopathology Hyperkeratosis, atrophic or acanthotic epithelium with neutrophilic exocytosis and a dense inflammatory infiltrate in the superficial lamina propria, consisting predominantly of lymphocytes intermixed with plasma cells, histiocytes, and eosinophils. Perivascular inflammatory infiltrates may be seen within the connective tissue. Histopathologic appearance is not specific for contact stomatitis to cinnamon. Diagnosis Clinical appearance of the lesions and a history of contact of the affected mucosa with cinnamon-flavored products. Diagnosis can be confirmed by withdrawal of the product containing the cinnamon followed by resolution of the lesions (observing a recurrence of the lesions with reintroduction of the offending product would further confirm the diagnosis, although rarely carried out). A biopsy may be required to rule out mucocutaneous diseases such as lichen planus, hairy leukoplakia, hyperplastic candidiasis, and epithelial dysplasia. Cutaneous patch testing may help with the diagnosis, although false positives and false negatives are common. Treatment Lesions usually resolve within 1 to 2 weeks after elimination of the allergenic agent/cinnamon-flavored product. If the lesions are slow to resolve or the patient is experiencing some discomfort then short-term use of topical corticosteroids may be beneficial.24,25
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