Allergies and Immunologic Diseases

CLINICAL FEATURES: Three patterns of transient lingual papillitis have been documented. The first pattern is localized and involves one to several fungiform papillae that become enlarged and present as elevated papules that are red but may demonstrate a yellow, ulcerated cap (Fig. 9-1). The lesions appear most frequently on the anterior portion of the dorsal surface, are associated with mild to moderate pain, and resolve spontaneously within hours to several days. In a survey of 163 dental school staff members, 56% reported previous episodes of transient lingual papillitis. There was a female predominance, and the vast majority reported a single affected papilla. In one report the occurrence of the lesions appeared to be associated with a food allergy.

In the second pattern the involvement is more generalized and affects a large percentage of the fungiform papillae on the tip and lateral portions of the dorsal surface (Fig. 9-2). Individual papillae are very sensitive, enlarged, erythematous, and occasionally display focal surface erosion. Fever and cervical lymphadenopathy are not rare. In these cases, spread of the process among family members has been reported, suggesting a possible correlation to an unknown virus. Spontaneous resolution occurs in about 7 days, with occasional recurrences reported.

The third pattern of transient lingual papillitis also demonstrates more diffuse involvement. The altered papillae are asymptomatic, appear as elevated white to yellow papules, and have been termed the papulokeratotic variant because of a thickened parakeratotic cap (Fig. 9-3). Although these lesions could be the result of a topical allergy, the histopathology demonstrates features similar to chronic nibbling and suggests the possibility of an unusual pattern of frictional hyperkeratosis.

HISTOPATHOLOGIC FEATURES: On histopathologic examination of the first two variants, affected papillae demonstrate normal surface epithelium that may reveal focal areas of exocytosis or ulceration. The underlying lamina propria exhibits a proliferation of numerous small vascular channels and a mixed inflammatory cellular infiltrate. Investigation for evidence of human papillomavirus (HPV), herpes simplex, and fungal infestation has been negative. The papulokeratotic variant demonstrates marked hyperparakeratosis in which the surface is ragged and reveals bacterial colonization. A chronic lymphocytic infiltrate is noted in the superficial lamina propria with extension into the basilar portion of the adjacent epithelium.

TREATMENT AND PROGNOSIS: Although transient lingual papillitis resolves without therapy, topical corticosteroids, anesthetics, and coating agents have been used to reduce the pain or duration. In an attempt to eliminate the pain, occasional patients have reported removing the affected papillae with devices such as fingernail clippers. The papulokeratotic variant is asymptomatic and requires no therapy. Although frequently unsuccessful, search for a local or systemic triggering event seems prudent.

CLINICAL FEATURES: Aphthous ulcerations are noted more frequently in children and young adults, with approximately 80% of affected individuals reporting their first ulceration before the age of 30. In one large series of 17,235 adults older than 17 years of age, the point prevalence of aphthous ulcerations was 0.89%, with the annual incidence in adults younger than 40 years old being almost twice that of older adults (22.5% versus 13.4%).

DIAGNOSIS: No laboratory procedure provides definitive diagnosis. The diagnosis is made from the clinical presentation and from exclusion of other diseases that produce ulcerations that closely resemble aphthae (see Box 9-1). In patients with complex aphthous ulcerations, a systematic evaluation for an underlying trigger or associated systemic condition is prudent. In a review of 244 patients with complex aphthous ulcerations, an associated triggering condition (e.g., hematologic deficiency, gastrointestinal disease, immunodeficiency, drug reaction) was discovered in almost 60%. Because the histopathologic features are nonspecific, a biopsy is useful only in eliminating differential possibilities and is not beneficial in arriving at the definitive diagnosis.

TREATMENT AND PROGNOSIS: The patient’s medical history should be reviewed for signs and symptoms of any systemic disorder that may be associated with aphthouslike ulcerations. Most patients with mild aphthosis receive either no treatment, therapy with a number of over-the-counter anesthetics or protective bioadhesive products, or periodic topical medicaments that minimize the frequency and severity of the attacks.

In patients with mild disease, the mainstay of therapy is the use of topical corticosteroids, and the list of possible choices is long. Most patients with diffuse minor or herpetiform aphthae respond well to 0.01% dexamethasone elixir used in a rinse-and-expectorate method. Patients with localized ulcerations can be treated successfully with 0.05% augmented betamethasone dipropionate gel or 0.05% fluocinonide gel. Adrenal suppression does not occur with appropriate use of these medications. Major aphthous ulcerations are more resistant to therapy and often warrant more potent corticosteroids (Fig. 9-10). The individual lesions may be injected with triamcinolone acetonide or covered with 0.05% clobetasol propionate gel or 0.05% halobetasol propionate ointment. Triamcinolone tablets also can be dissolved directly over the lesions. In hard-to-reach areas, such as the tonsillar pillars, beclomethasone dipropionate aerosol spray can be used. In resistant cases, systemic corticosteroids may be required to supplement the topical medications and gain control. In such instances, prednisolone or betamethasone syrup in a swish-and-swallow method is preferable to prednisone tablets. In this way the ulcerations will receive both topical and systemic therapy.

Numerous alternatives to corticosteroid agents have been used to treat patients suffering from aphthous ulcerations (the most widely accepted are highlighted in bold). Caution should be exercised, however, because many of these agents have not been examined in a double-blind, placebo-controlled fashion to assess the degree of effectiveness compared with placebo. Furthermore, some of these treatments may have significant side effects or may be quite expensive. Included within the list of therapies are acyclovir, amlexanox, topical 5-aminosalicylic acid, azelastine hydrochloride, benzydamine hydrochloride, carbenoxolone sodium, chemical cauterizing agents, chlorhexidine, colchicine, cyclosporine, dapsone, deglycyrrhizinated liquorice, gamma globulin, hydrogen peroxide, hydroxypropyl cellulose films, interferon-a, irsogladine maleate, levamisole, LongoVital, monoamine oxidase (MAO) inhibitors, pentoxifylline, prostaglandin E-2 gel, sucralfate, sodium cromoglycate (cromolyn), tacrolimus, tetracyclines, thalidomide, transfer factor (extract of immunocytes), triclosan, and vitamin and mineral supplements (especially zinc sulfate). The success of these therapies is highly variable. These treatments do not resolve the underlying problem and are merely an attempt to “beat back brush fires.” Recurrences often continue, although breaking up the cycle may induce longer disease-free intervals between attacks. Surgical removal of aphthous ulcerations has been used but is an inappropriate therapy. Although laser ablation shortens the duration and decreases associated symptoms, its use is of very limited practical benefit because patients cannot return on each recurrence.

Chemical cautery with silver nitrate continues to be suggested as an effective therapy, but it can no longer be recommended because of the numerous safer alternatives and its rare association with massive necrosis (see page 292) and systemic argyria (see page 315). An over-the-counter cautery that uses sulfuric acid and phenolic agents is indicated in certain situations, but patients must be warned of the potential for significant local tissue necrosis related to its misuse.

Patients with complex aphthosis require a more extensive evaluation for occult systemic disease and a search for possible triggers of the immune-mediated mucosal destruction. To go beyond the management of individual recurrences is difficult, expensive, and often frustrating. In spite of this, patients with severe disease should be offered the opportunity to investigate the underlying causes.

As previously mentioned, the immune attacks are usually a result of immunodysregulation, a decreased mucosal barrier, or an elevated antigenic stimulus. The evaluation for systemic disorders usually eliminates the first two causes. Typically, this is followed by patch tests for antigen stimuli or an elimination diet for possible offending foods. Therapeutic trials might be instituted against the viruses and bacteria that have been implicated in subsets of patients with aphthous stomatitis. The investigator should explain to the patient that the underlying causation is diverse; even with the most exhaustive search, the answer may be elusive. In many cases, stress appears involved, and all evaluations in these patients will be within normal limits. In spite of the high likelihood of an expensive and negative evaluation, discovery of an underlying abnormality that can be treated often leads to permanent resolution or dramatic improvement in the course of the recurrences.

CLINICAL FEATURES: As mentioned previously, the highest prevalence occurs in the Middle East and Japan, with a much lower frequency noted in northern Europe, the United States, and the United Kingdom. At the time of discovery, most patients are young adults, with the disease diagnosed uncommonly in blacks, children, and older adults.

Oral involvement is an important component of Behçet’s syndrome, and it is the first manifestation in 25% to 75% of the cases. Oral lesions occur at some point during the disease in 99% of the patients and typically precede other sites of involvement.

The lesions are similar to aphthous ulcerations occurring in otherwise healthy individuals and demonstrate the same duration and frequency. In spite of this, investigators have shown several statistically significant clinical variations that are different from typical aphthous ulcerations and may be used to increase the index of suspicion for Behçet’s syndrome. When compared with patients with aphthae, a larger percentage of those with Behçet’s syndrome demonstrate six or more ulcerations. The lesions commonly involve the soft palate and oropharynx, which are usually infrequent sites for the occurrence of routine aphthae. The individual lesions vary in size, have ragged borders, and are surrounded by a larger zone of diffuse erythema (Fig. 9-11).

All three forms of oral aphthous stomatitis may be seen. Although the majority of affected patients have lesions that resemble minor aphthous ulcerations, some reports have documented a prevalence of major aphthae that approaches 40% in patients affected with Behçet’s syndrome. The herpetiform variant remains uncommon and is noted in approximately 3%. Patients with major aphthae often demonstrate more frequent recurrences and more ulcerations per relapse. In spite of more severe oral disease, the presence of major aphthae in Behçet’s syndrome does not correlate with an increased risk for more severe systemic expression.

The genital lesions are similar in appearance to the oral ulcerations. They occur in 75% of the patients and appear on the vulva, vagina, glans penis, scrotum, and perianal area (Fig. 9-12). These lesions recur less frequently than do the oral ulcerations, are deeper, and tend to heal with scarring. The genital ulcerations cause more symptoms in men than in women andmay be discovered only by a routine examination in women.

Common cutaneous lesions include erythematous papules, vesicles, pustules, pyoderma, folliculitis, acneiform eruptions, and erythema nodosum–like lesions. From a diagnostic standpoint, one of the most important skin manifestations is the presence of positive “pathergy.” One or 2 days after the oblique insertion of a 20-gauge or smaller needle under sterile conditions, a tuberculin-like skin reaction or sterile pustule develops (Fig. 9-13). This skin hyperreactivity (pathergy) appears to be unique to Behçet’s syndrome and is present in 40% to 88% of patients with this disorder.

Ocular involvement is present in 70% to 85% of the cases and is more frequent and severe in males. The most common findings are posterior uveitis, conjunctivitis, corneal ulceration, papilledema, and arteritis. Although Behçet originally described hypopyon (pus in the anterior chamber) as a cause of blindness, this finding currently is rare. The most common secondary ocular complications are cataracts, glaucoma, and neovascularization of the iris and retina.

Arthritis is one of the more common minor manifestations of the disease and is usually self-limiting and nondeforming. The knees, wrists, elbows, and ankles are affected most frequently.

Central nervous system (CNS) involvement is not common but, when present, is associated with a poor prognosis. From 10% to 25% of the patients demonstrate CNS involvement, and the alterations produced result in a number of changes that include paralysis and severe dementia.

Other alterations may be seen that involve the cardiovascular, gastrointestinal, hematologic, pulmonary, muscular, and renal systems. These most likely occur secondary to vasculitis and create a variety of clinical presentations.

DIAGNOSIS: No laboratory finding is diagnostic of Behçet’s syndrome. In an attempt to standardize diagnoses, definitive criteria have been developed. Table 9-1 delineates the requirements proposed by the Behçet’s International Study Group. Although this system is used widely, many authorities exclude acneiform skin lesions in young adults from the criteria because of the high prevalence of this finding in an otherwise normal population.

HISTOPATHOLOGIC FEATURES: The histopathologic features are not specific for Behçet’s syndrome and can be seen in many disorders, including aphthous stomatitis. The pattern most frequently seen is called leukocytoclastic vasculitis. The ulceration is similar in appearance to that seen in aphthous stomatitis, but the small blood vessels classically demonstrate intramural invasion by neutrophils, karyorrhexis of neutrophils, extravasation of red blood cells, and fibrinoid necrosis of the vessel wall.

TREATMENT AND PROGNOSIS: The oral and genital ulcerations typically respond well to potent topical or intralesional corticosteroids or topical tacrolimus. In more severe cases, this therapy can be combined with oral colchicine or dapsone. Patients who fail this initial conservative approach often respond to thalidomide, low-dose methotrexate, systemic corticosteroids, or infliximab (anti–TNF-α antibody). Severe ocular or systemic disease often necessitates combined use of systemic immunosuppressive and immunomodulatory agents (e.g., corticosteroids, cyclosporine, azathioprine, interferon-a2a, cyclophosphamide).

Behçet’s syndrome has a highly variable course. A relapsing and remitting pattern is typical, with attacks becoming more intermittent after 5 to 7 years. The major morbidity and mortality of the disease appear confined to the years immediately after the initial diagnosis; therefore, early aggressive therapy is recommended for patients with severe clinical manifestations. Mortality is typically low; when noted, it most frequently is secondary to pulmonary hemorrhage, CNS hemorrhage, or bowel perforation. In the absence of CNS disease or significant vascular complications, the prognosis is generally good.

CLINICAL FEATURES: Sarcoidosis has a worldwide distribution but is recognized more commonly in the developed world. In North America, blacks are affected 10 to 17 times more frequently than whites. There is a slight female predominance, and the disease exhibits a bimodal age distribution, with the first peak between 25 and 35 years of age and the second peak between 45 and 65 years of age.

Sarcoidosis most commonly appears acutely over a period of days to weeks, and the symptoms are variable. Common clinical symptoms include dyspnea, dry cough, chest pain, fever, malaise, fatigue, arthralgia, and weight loss. Less frequently, sarcoidosis arises insidiously over months to years, without significant symptoms; when clinically evident, pulmonary symptoms are most common. Approximately 20% of patients have no symptoms, and the disease is discovered on routine chest radiographs.

Although any organ may be affected, the lungs, lymph nodes, skin, eyes, and salivary glands are the predominant sites. Lymphoid tissue is involved in almost all cases. The mediastinal and paratracheal lymph nodes are involved commonly, and chest radiographs frequently reveal bilateral hilar lymphadenopathy. Approximately 90% of affected patients will reveal an abnormal chest radiograph sometime during the course of the disease. Cutaneous manifestations occur about 25% of the time. These often appear as chronic, violaceous, indurated lesions that are termed lupus pernio and frequent the nose, ears, lips, and face (Fig. 9-14). Symmetrical, elevated, indurated, purplish plaques also are seen commonly on the limbs, back, and buttocks. Scattered, nonspecific, tender erythematous nodules, known as erythema nodosum, frequently occur on the lower legs.

Ocular involvement is noted in 25% of the cases and most often appears as anterior uveitis. Lesions of the conjunctiva and retina may occur. Involvement of the lacrimal glands often produces keratoconjunctivitis sicca; the salivary glands can be altered similarly, with resultant clinical enlargement and xerostomia. Significant enlargement can occur in any major or minor salivary gland. Removal of intraoral mucoceles that occur in the salivary glands affected by the granulomatous process has led to the initial diagnosis in some cases. The salivary gland enlargement, xerostomia, and keratoconjunctivitis sicca can combine to mimic SjÖgren syndrome (see page 466).

Although lymphoid, pulmonary, cutaneous, and ocular lesions are most common, virtually any organ system may be affected. Other potential sites include the endocrine system, gastrointestinal tract, heart, kidneys, liver, nervous system, and spleen. Intraosseous lesions may occur and most commonly involve the phalanges, metacarpals, and metatarsals. Less frequently, the skull, nasal bones, ribs, and vertebrae are affected.

Two distinctive clinical syndromes are associated with acute sarcoidosis. LÖfgren’s syndrome consists of erythema nodosum, bilateral hilar lymphadenopathy, and arthralgia. Patients with Heerfordt’s syndrome (uveoparotid fever) have parotid enlargement, anterior uveitis of the eye, facial paralysis, and fever.

If salivary gland and lymph node involvement are excluded, clinically evident oral manifestations in sarcoidosis are uncommon. Any oral mucosal site can be affected, most often appearing as a submucosal mass, an isolated papule, an area of granularity, or an ulceration. The mucosal lesions may be normal in color, brown-red, violaceous, or hyperkeratotic (Figs. 9-15 and 9-16). The most frequently affected intraoral soft tissue site is the buccal mucosa, followed by the gingiva, lips, floor of mouth, tongue, and palate. Most cases appearing in the floor of the mouth involve salivary glands and create mucus extravasation. Intraosseous lesions affect either jaw and represent approximately one fourth of all reported intraoral cases. Of these cases, most appeared as ill-defined radiolucencies that occasionally eroded the cortex but never created expansion. In a literature review of 45 reported cases of intraoral sarcoidosis, the oral lesion was the first documented clinical manifestation of the disease in the majority of patients.

HISTOPATHOLOGIC FEATURES: Microscopic examination of sarcoidosis exhibits a classic picture of granulomatous inflammation. Tightly clustered aggregates of epithelioid histiocytes are present, with a surrounding rim of lymphocytes. Intermixed with the histiocytes are scattered Langhans’ or foreign body type giant cells (Fig. 9-17). The granulomas often contain laminated basophilic calcifications, known as Schaumann bodies (degenerated lysosomes), or stellate inclusions, known as asteroid bodies (entrapped fragments of collagen) (Fig. 9-18). In lymph nodes, small yellow-brown structures called Hamazaki-Wesenberg bodies (large lysosomes) may be noted in the subcapsular sinus. None of these structures are specific for sarcoidosis. Special stains for fungal and bacterial organisms are negative. No polarizable, dissolvable, or pigmented foreign material can be detected.

DIAGNOSIS: The diagnosis is established by the clinical and radiographic presentations, the histopathologic appearance, and the presence of negative findings with both special stains and cultures for organisms. Elevated serum angiotensin-converting enzyme (ACE) levels and appropriate documentation of pulmonary involvement strongly support the diagnosis. Other laboratory abnormalities that may be seen include eosinophilia; leukopenia; anemia; thrombocytopenia; and elevation of the serum alkaline phosphatase level, erythrocyte sedimentation rate, serum calcium concentration, and urinary calcium level.

A skin test for sarcoidosis, the Kveim test, can be performed by intradermal injection of a sterilized suspension of human sarcoid tissue. The procedure is no longer widely used because of difficulty in obtaining material for the test, concern related to its accuracy, and the inability to guarantee the absence of contamination (e.g., prions) in this human tissue.

Minor salivary gland biopsy has been promoted as a diagnostic aid in suspected cases of sarcoidosis (see Fig. 9-17). Investigators have documented success rates between 38% and 58%. The misdiagnosis of SjÖgren syndrome from minor salivary gland biopsy specimens has been reported in patients with sarcoidosis. Previously, biopsy of the parotid was avoided because of the fear of salivary fistula formation and damage to the facial nerve. These concerns have been reduced through biopsy of the posterior superficial lobe of the parotid gland, and confirmation of sarcoidosis has been reported in 93% of patients from this procedure.

TREATMENT AND PROGNOSIS: In approximately 60% of patients with sarcoidosis, the symptoms resolve spontaneously within 2 years without treatment. Most initial diagnoses are followed by a 3- to 12-month period of observation to define the general course of the disease. Active intervention is recommended for progressive disease and patients with cardiac or neurologic involvement, hypercalcemia, disfiguring skin disease, or serious ocular lesions that do not respond to local therapy. In patients requiring treatment, corticosteroids remain first-line therapy, but resistance and relapses are common. Medications used in patients with refractory disease include methotrexate, azathioprine, chlorambucil, and cyclophosphamide. Several studies have shown promising results with TNF-α antagonists such as etanercept, infliximab, pentoxyphylline, and thalidomide. Antimalarial medications, such as chloroquine, have demonstrated effectiveness in resolving mucocutaneous sarcoidosis that was resistant to steroids. In 10% to 20% of those affected by sarcoidosis, resolution does not occur even with treatment. CNS and chronic extrathoracic involvement are associated with a poor response to therapy. Approximately 4% to 10% of patients die of pulmonary, cardiac, or CNS complications.

CLINICAL FEATURES: The clinical presentation of orofacial granulomatosis is highly variable. By far, the most frequent site of involvement is the lips. The labial tissues demonstrate a nontender, persistent swelling that may involve one or both lips (Fig. 9-19). On rare occasions, superficial amber vesicles, resembling lymphangiomas, are found. When these signs are combined with facial paralysis and a fissured tongue, the clinical presentation is called Melkersson-Rosenthal syndrome (Figs. 9-20 and 9-21). Involvement of the lips alone is called cheilitis granulomatosa (of Miescher). Some consider cheilitis granulomatosa an oligosymptomatic form of Melkersson-Rosenthal syndrome, but it appears best to include all of these under the term orofacial granulomatosis. In addition to labial edema, swelling of other parts of the face may be seen, and cervical lymphadenopathy rarely has been noted.

Intraoral sites also can be affected, and the predominant lesions are edema, ulcers, and papules. The tongue may develop fissures, edema, paresthesia, erosions, or taste alteration. The gingiva can develop swelling, erythema, pain, or erosions. The buccal mucosa often exhibits a cobblestone appearance of edematous mucosa or focal areas of submucosal enlargement. Linear hyperplastic folds may occur in the mucobuccal fold, with linear ulcerations appear in the base of these folds (Fig. 9-22). The palate may have papules or large areas of hyperplastic tissue. Hyposalivation rarely is reported.

HISTOPATHOLOGIC FEATURES: In classic cases of cheilitis granulomatosa, edema is present in the superficial lamina propria with dilation of lymphatic vessels and scattered lymphocytes seen diffusely and in clusters. Fibrosis may be present in long-term lesions. Scattered aggregates of noncaseating granulomatous inflammation, consisting of lymphocytes and epithelioid histiocytes, are present, with or without multinucleated giant cells. Typically, the granulomas appear to cluster around scattered vessels and are not as well formed or discrete as those seen in sarcoidosis (Fig. 9-23).

Special stains for fungal organisms and acid-fast bacteria are negative. No dissolvable, pigmented, or polarizable foreign material should be present. When the lesions are confined to the gingiva, a thorough search should be made, because many cases of granulomatous gingivitis are due to subtle collections of foreign material (see page 160).

DIAGNOSIS: The initial diagnosis of orofacial granulomatosis is made on histopathologic demonstration of granulomatous inflammation that is associated with negative special stains for organisms and no foreign material. Based on the clinical and historical findings, one or more conditions may have to be considered in the differential diagnosis. It should be stressed that no one cause for the granulomas will be found when large groups of patients with orofacial granulomatosis are studied. (See Tables 9-2 and 9-3 for a list of conditions and suggested procedures that may be appropriate to arrive at a more definitive diagnosis.)

TREATMENT AND PROGNOSIS: The first goal of management should be discovery of the initiating cause, although this may be difficult because the trigger often is elusive. In children and young adults, the search for a dietary allergen or an association with underlying gastrointestinal disease should be considered. Local measures to resolve the clinical manifestations can be attempted but, as would be expected, recurrences are common. The individual lesions have been treated with a variety of interventions, with variable results. Topical or intralesional corticosteroids, radiotherapy, salazosulfapyridine (sulfasalazine), hydroxychloroquine sulfate, azathioprine, cyclosporine A, methotrexate, danazol, dapsone, TNF-α antagonists (infliximab, thalidomide), clofazimine, metronidazole, and numerous other antibiotics have been tried. Currently, most investigators administer intralesional delayed-release high-concentrate triamcinolone to control the progression of this disease (Figs. 9-24 and 9-25). Of the alternatives, clofazimine (antileprosy agent with antigranulomatous properties) is mentioned most frequently as the second choice after corticosteroids. Because of the natural variability of the disease’s progression and the occurrence of spontaneous remissions, therapies are difficult to assess. In the absence of a response to other treatments, surgical recontouring has been used by some but carries a considerable risk of recurrence and rarely appears to be warranted. After excision, some clinicians recommend intralesional steroids to slow recurrences.

The prognosis is highly variable. No therapy has proved to be the “silver bullet” in resolving the individual lesions. In some cases, lesions resolve spontaneously, with or without therapy; in others, they continue to progress in spite of a myriad of therapeutic attempts to stop the progression. The “lucky” subset of patients includes those who have found an initiating causation and have resolved their problems by the exclusion of the offending agent.

CLINICAL FEATURES: Wegener’s granulomatosis demonstrates a wide age range from childhood to old age, with a mean of approximately 40 years and no sex predilection. The disease can involve almost every organ system in the body. With classic Wegener’s granulomatosis, patients initially show involvement of the upper and lower respiratory tract; if the condition remains untreated, then renal involvement often rapidly develops (generalized Wegener’s granulomatosis).

Limited Wegener’s granulomatosis is diagnosed when there is involvement of the respiratory system without rapid development of renal lesions. One subset of patients exhibits lesions primarily of the skin and mucosa, a condition termed superficial Wegener’s granulomatosis. In this form of the disease, systemic involvement develops slowly. These three different clinical patterns highlight the variability of the clinical aggressiveness that can occur in patients with Wegener’s granulomatosis.

Purulent nasal drainage, chronic sinus pain, nasal ulceration, congestion, and fever are frequent findings from upper respiratory tract involvement. Persistent otitis media, sore throat, and epistaxis also are reported. With progression, destruction of the nasal septum can result in a saddle-nose deformity. Patients with lower respiratory tract involvement may be asymptomatic, or they may have dry cough, hemoptysis, dyspnea, or chest pain. Renal involvement usually occurs late in the disease process and is the most frequent cause of death. The glomerulonephritis results in proteinuria and red blood cell casts. Occasionally, the eyes, ears, and skin also are involved.

Oral lesions are seen in the minority of those affected; occasionally, the oral changes may be the only clinically evident finding. The most characteristic oral manifestation is strawberry gingivitis. This distinctive but uncommon pattern of gingival alteration appears to be an early manifestation of Wegener’s granulomatosis and has been documented before renal involvement in most cases. The affected gingiva demonstrates a florid and granular hyperplasia. The surface forms numerous short bulbous projections, which are hemorrhagic and friable; this red, bumpy surface is responsible for the strawberry-like appearance (Fig. 9-26). The buccal surfaces are affected more frequently, and the alterations are classically confined to the attached gingiva. The process appears to begin in the interdental region and demonstrates lateral spread to adjacent areas. At the time of diagnosis, the involvement may be localized or generalized to multiple quadrants. Destruction of underlying bone with the development of tooth mobility has been reported.

Oral ulceration also may be a manifestation of Wegener’s granulomatosis. Unlike the strawberry gingiva, the ulcerations do not form a pattern that is unique. These lesions are clinically nonspecific and may occur on any mucosal surface (Fig. 9-27). In contrast to the gingival changes, the oral ulcerations are diagnosed at a later stage of the disease, with more than 60% of the affected patients demonstrating renal involvement. Other less common orofacial manifestations include facial paralysis, labial mucosal nodules, sinusitis-related toothache, arthralgia of the temporomandibular joint (TMJ), jaw claudication, palatal ulceration from nasal extension, oral-antral fistulae, and poorly healing extraction sites.

Enlargement of one or more major salivary glands from primary involvement of the granulomatous process also has been reported. The glandular involvement also appears early in the course of the disease and may lead to early diagnosis and treatment.

HISTOPATHOLOGIC FEATURES: Wegener’s granulomatosis appears as a pattern of mixed inflammation centered around blood vessels. Involved vessels demonstrate transmural inflammation, often with areas of heavy neutrophilic infiltration, necrosis, and nuclear dust (leukocytoclastic vasculitis). The connective tissue adjacent to the vessel has an inflammatory cellular infiltrate, which contains a variable mixture of histiocytes, lymphocytes, eosinophils, and multinucleated giant cells (Fig. 9-28). Special stains for organisms are negative, and no foreign material can be found. In oral biopsy specimens, the oral epithelium may demonstrate pseudoepitheliomatous hyperplasia and subepithelial abscesses. Because of the paucity of large vessels in many oral mucosal biopsies, vasculitis may be difficult to demonstrate, and the histopathologic presentation may be one of ill-defined collections of epithelioid histiocytes intermixed with eosinophils, lymphocytes, and multinucleated giant cells. In addition, the lesions of strawberry gingivitis typically demonstrate prominent vascularity with extensive red blood cell extravasation (Fig. 9-29).

DIAGNOSIS: The diagnosis of Wegener’s granulomatosis is made from the combination of the clinical presentation and the microscopic finding of necrotizing and granulomatous vasculitis. Radiographic evaluation of the chest and sinuses is recommended to document possible involvement of these areas. The serum creatinine and urinalysis results are used to rule out significant renal alterations.

A laboratory marker for Wegener’s granulomatosis has been identified. Indirect immunofluorescence for serum antibodies directed against cytoplasmic components of neutrophils has been used to support a diagnosis of Wegener’s granulomatosis. There are two reaction patterns of these antineutrophil cytoplasm antibodies (ANCA):

Cytoplasmic localization (c-ANCA) is the most useful in the diagnosis of Wegener’s granulomatosis. Positive immunofluorescence for c-ANCA should be confirmed with a specific enzyme-linked immunosorbent assay (ELISA) test for antibodies against proteinase 3 (PR3), the major antigen for c-ANCA that resides in the azurophilic granules of neutrophils. These combined tests are associated with a sensitivity of 73% and a diagnostic specificity of 99% for Wegener’s granulomatosis. False positives are uncommon and may be associated with a variety of other diseases. In contrast, p-ANCAs are detected in several vasculitides that typically do not present in the oral cavity. With ELISA testing, antibodies directed against myeloperoxidase, a lysosomal enzyme in neutrophils, will be identified.

TREATMENT AND PROGNOSIS: The mean survival of untreated patients with disseminated classic Wegener’s granulomatosis is 5 months; 80% of the patients are dead at 1 year and 90% within 2 years. The prognosis is better for the limited and superficial forms of the disease, although a proportion of patients with localized disease eventually will develop classic Wegener’s granulomatosis.

The first line of therapy is oral prednisone and cyclophosphamide. On remission, the prednisone is gradually discontinued, with continuation of the cyclophosphamide for at least 1 year. Relapse is not uncommon, especially during tapering of the therapy. Although high response rates are noted, serious side effects related to the therapy are not rare. Tri-methoprim-sulfamethoxazole has been used successfully in localized cases and when the immunosuppressive regimen has failed. Low-dose methotrexate and corticosteroids also have been used in patients whose disease is not immediately life threatening or has not responded appropriately to cyclophosphamide. Additional treatment options under study for generalized Wegener’s granulomatosis include cyclosporine, tacrolimus, mycophenolate mofetil, plasmapheresis, antilymphocytic monoclonal antibodies, and intravenous pooled immunoglobulin.

Treatment has a profound effect on the progression of the disease. With appropriate therapy, prolonged remission is noted in up to 75% of affected patients; a cure often is attainable when the disease is diagnosed and appropriately treated while the involvement is localized. Because of a relapse rate up to 30%, maintenance therapy is necessary in many patients. The c-ANCA levels can be used to monitor the disease activity. Patients appear less likely to have relapses if their antineutrophilic antibodies disappear during treatment; in contrast, patients whose levels of antibodies persist are at greater risk for relapse.

CLINICAL FEATURES: The patterns of mucosal alterations associated with the systemic administration of medications are varied, almost as much as the number of drugs that result in these changes. Anaphylactic stomatitis may occur alone or in conjunction with urticarial skin lesions or other signs and symptoms of anaphylaxis (e.g., hoarseness, respiratory distress, vomiting). The affected mucosa may exhibit multiple zones of erythema or numerous aphthouslike ulcerations. Mucosal fixed drug eruptions appear as localized areas of erythema and edema, which can develop into vesiculoerosive lesions and are located most frequently on the labial mucosa. Lichenoid, lupuslike, and pemphigus-like drug reactions resemble their namesakes clinically, histopathologically, and immunologically (Fig. 9-30). These latter chronic drug reactions may involve any mucosal surface, but the most common sites are the posterior buccal mucosa and the lateral borders of the tongue (Figs. 9-31 and 9-32). Bilateral and symmetrical lesions are fairly common.

HISTOPATHOLOGIC FEATURES: Anaphylactic stomatitis typically reveals a nonspecific pattern of subacute mucositis that contains lymphocytes intermixed with eosinophils and neutrophils. Fixed drug eruptions also reveal a mixed inflammatory cellular infiltrate that consists of lymphocytes, eosinophils, and neutrophils, often combined with spongiosis and exocytosis of the epithelium. Vacuolar change of the basal cell layer and individual necrotic epithelial cells are occasionally noted. The drug reactions that simulate lichen planus, lupus erythematosus, and pemphigus resemble their namesakes. The histopathologic and immunologic features of these chronic drug reactions cannot be used reliably to separate them from their associated primary immunologic disease.

Immunofluorescence has been used in an attempt to separate drug reactions from primary vesiculoerosive disease. In most instances, this technique has proven to be unsatisfactory. In spite of these findings, a unique pattern of reaction has been seen when indirect immunofluorescence for IgG has been performed in patients with lichenoid drug reactions. In many of these patients, a distinctive annular fluorescent pattern, termed string of pearls, has been noted along the cell membrane of the basal cell layer of stratified squamous epithelium. The detected circulating antibody has been termed basal cell cytoplasmic antibody. Although further study is desirable, this technique may prove to be a useful adjunct during evaluation of oral lichenoid lesions.

DIAGNOSIS: A detailed medical history must be obtained, and the patient should be questioned closely concerning the use of both prescription and over-the-counter medications. Once a potentially offending medication is discovered, a temporal relationship between the drug’s use and the mucosal alteration must be established. The association may be acute and obvious, or the onset of the oral lesions may be delayed. If more than one medication is suspected, then serial elimination of the medications can be performed in collaboration with the patient’s physician until the offending agent is discovered.

In chronic drug reactions, definitive diagnosis can be made if the mucosal alterations resolve after resolution of the medication and recur on reintroduction of the agent. Presumptive diagnosis is usually sufficient and justified when the mucosal alterations clear after cessation of the offending medication.

In possible lupuslike drug reactions, serum evaluation for generic antinuclear antibodies (ANAs) and antibodies against double-stranded DNA and histones often can be beneficial. Lupuslike drug reactions typically are associated with circulating generic ANAs and antibodies against histones, whereas lupus erythematosus also reveals antibodies to double-stranded DNA (a finding not typically noted in drug reactions). This pattern does not hold true in reactions associated with the TNF-α antagonists, infliximab and etanercept, which simulate systemic lupus erythematosus (SLE) very closely and are associated with antibodies to double-stranded DNA.

TREATMENT AND PROGNOSIS: The responsible medication should be discontinued and, if necessary, replaced with another drug that provides a similar therapeutic result. Localized acute reactions can be resolved with topical corticosteroids. When systemic manifestations are present, anaphylactic stomatitis often warrants systemic administration of adrenaline (epinephrine), corticosteroids, or antihistamines. Chronic oral lesions often resolve on cessation of the offending drug, but topical corticosteroids may sometimes be required for complete resolution.

If discontinuation of the medication is contraindicated, palliative care can be provided; however, corticosteroids often are ineffective as long as the offending medication is continued.

CLINICAL FEATURES: Allergic contact stomatitis can be acute or chronic. Of those cases diagnosed, there is a distinct female predominance in both forms. After eliminating focal trauma, localized signs and symptoms suggest mucositis from an isolated allergen (e.g., dental metal); in contrast, widespread mouth pain suggests an association with a more diffuse trigger such as food, drink, flavorings, or oral hygiene materials.

In patients with acute contact stomatitis, burning is the most frequent symptom. The appearance of the affected mucosa is variable, from a mild and barely visible redness to a brilliantly erythematous lesion with or without edema. Vesicles are rarely seen and, when present, rapidly rupture to form areas of erosion (Fig. 9-33). Superficial ulcerations that resemble aphthae occasionally arise. Itching, stinging, tingling, and edema may be noted.

In chronic cases the affected mucosa is typically in contact with the causative agent and may be erythematous or white and hyperkeratotic. Periodically, erosions may develop within the affected zones. Some allergens, especially toothpastes, can cause widespread erythema, with desquamation of the superficial layers of the epithelium (Fig. 9-34). Allergic contact cheilitis demonstrates clinical features identical to those cases created through chronic irritation, and it most frequently appears as chronic dryness, scaling, fissuring, or cracking of the vermilion border of the lip. Rarely, symptoms identical to orolingual paresthesia can be present without any clinically evident signs. One distinctive pattern, plasma cell gingivitis, is discussed elsewhere (see page 159).

DIAGNOSIS: Usually, the diagnosis of acute contact stomatitis is straightforward because of the temporal relationship between the use of the agent and the resultant eruption. If an acute oral or circumoral reaction is noted within 30 minutes of a dental visit, then allergy to all used dental materials, local anesthetics, and gloves should be investigated.

The diagnosis of chronic contact stomatitis is much more difficult. Most investigators require good oral health, elimination of all other possible causes, and visible oral signs, together with a positive history of allergy and a positive skin test result to the suspected allergen. If allergic contact stomatitis is strongly suspected but skin test results are negative, then direct testing of the oral mucosa can be attempted. The antigen can be placed on the mucosa in a mixture with Orabase or in a rubber cup that is fixed to the mucosa.

TREATMENT AND PROGNOSIS: In mild cases of acute contact stomatitis, removal of the suspected allergen is all that is required. In more severe cases, antihistamine therapy, which is combined with topical anesthetics (e.g., dyclonine HCl), is usually beneficial. Chronic reactions respond to removal of the antigenic source and application of a topical corticosteroid, such as fluocinonide gel or dexamethasone elixir.

When attempting to discover the source of a diffuse allergic mucositis, use of plain baking soda or toothpaste that is free of flavoring or preservatives is recommended. The patient also should be instructed to avoid mouthwash, gum, mints, chocolate, cinnamon-containing products, carbonated drinks, and excessively salty, spicy, or acidic foods. If an association cannot be found, then cutaneous patch testing may provide helpful information.

CLINICAL FEATURES: Perioral dermatitis appears with persistent erythematous papules and papulopustules that involve the skin surrounding the vermilion border of the upper and lower lips (Fig. 9-35). Classically, there is a zone of spared skin immediately adjacent to the vermilion border. Pruritus is variable. In adults, more than 90% of affected patients are women, lending further support to the association with cosmetic use. The prevalence of perioral dermatitis appears to be increasing and may be related to the greater percentage of cosmetic-wearing women in the workforce. In children, the female predominance is dramatically reduced or is nonexistent in some studies. In addition, an identical pattern of periorbital and perinasal dermatitis often is present in younger patients with classic perioral lesions.

Some investigators have reported perioral dermatitis that has arisen solely from use of tartar-control toothpaste (irritant contact dermatitis from pyrophosphate compounds), but close inspection reveals a different clinical presentation. In these reports the dermatitis appears as a zone of erythema without papules or pustules; it involves only the skin immediately adjacent to the vermilion border, without the classic sparing of this area. This pathosis is classified most appropriately as circumoral dermatitis and does not fulfill the classic criteria for perioral dermatitis.

HISTOPATHOLOGIC FEATURES: Biopsy of perioral dermatitis demonstrates a variable pattern. In many cases there is a chronic lymphohistiocytic dermatitis that often exhibits spongiosis of the hair follicles. In other patients a rosacea-like pattern is noted in which there is perifollicular granulomatous inflammation. On occasion, this histopathologic pattern has been misdiagnosed as sarcoidosis.

TREATMENT AND PROGNOSIS: The first step in management is discontinuation of potent topical corticosteroid use, if present. Often, this is followed by a period of exacerbation, which can be minimized by substitution of a less potent corticosteroid before total cessation. Oral tetracycline has been shown to be effective by many investigators, with erythromycin substituted during childhood and pregnancy. Topical metronidazole or erythromycin also has been used successfully in several studies. The pathosis typically demonstrates significant improvement within several weeks and total resolution in a few months. Recurrence is uncommon.

CLINICAL FEATURES: The clinical presentations of contact stomatitis vary somewhat, according to the medium of delivery. Toothpaste results in a more diffuse pattern; the signs associated with chewing gum and candy are more localized. Pain and burning are common symptoms in all cases.

The gingiva is the most frequent site affected by toothpaste, often resembling plasma cell gingivitis (see page 159); enlargement, edema, and erythema are common. Sloughing of the superficial oral epithelium without creation of an erosion is seen commonly. Erythematous mucositis, occasionally combined with erosion, has been reported on the buccal mucosa and tongue. Exfoliative cheilitis and circumoral dermatitis also may occur.

Reactions from chewing gum and candy are more localized and typically do not affect the lip vermilion or perioral skin. Most of the lesions appear on the buccal mucosa and lateral borders of the tongue. Buccal mucosal lesions often are oblong patches that are aligned along the occlusal plane (Fig. 9-36). Individual lesions have an erythematous base but often are predominantly white as a result of hyperkeratosis of the surface epithelium. Ulceration within the lesions may occur. Hyperkeratotic examples often exhibit a ragged surface and occasionally may resemble the pattern seen in morsicatio (see page 286). Lingual involvement may become extensive and spread to the dorsal surface (Fig. 9-37). Significant thickening of the surface epithelium can occur and may raise clinical concern for oral hairy leukoplakia (OHL) (see page 268) or carcinoma (Fig. 9-38).

HISTOPATHOLOGIC FEATURES: Usually, the epithelium in contact stomatitis from artificial cinnamon flavoring is acanthotic, often with elongated rete ridges and thinning of the suprapapillary plates. Hyperkeratosis and extensive neutrophilic exocytosis may be present. The superficial lamina propria demonstrates a heavy inflammatory cell infiltrate that consists predominantly of lymphocytes that may be intermixed with plasma cells, histiocytes, or eosinophils. This infiltrate often obscures the epithelium and connective tissue interface (Fig. 9-39). A characteristic feature in localized cases caused by gum, mints, or candies is the frequent presence of an obvious perivascular inflammatory infiltrate that extends well below the interface zone (Fig. 9-40).

DIAGNOSIS: With a high index of suspicion and knowledge of the variations of the clinical pattern, the diagnosis of localized contact stomatitis often can be made from the clinical appearance and the history of cinnamon use. Often biopsies are performed for atypical or extensive cases because of the differential diagnosis, which includes several significant vesiculoerosive and neoplastic conditions. The histopathologic features are not specific, but they are sufficient to raise a high index of suspicion in an oral and maxillofacial pathologist who is familiar with the pattern. Use of cinnamon-containing toothpaste should be investigated in every patient with an atypical pattern of gingivitis. Diet-related examples often are the most difficult to diagnose and may necessitate cutaneous allergy patch testing or a diet diary to isolate the cause.

TREATMENT AND PROGNOSIS: Typically, the signs and symptoms disappear within 1 week after the discontinuation of the cinnamon product. If the patient resumes intake of the product, then the lesions reappear, usually within 24 hours. On occasion, resolution is more gradual and the patient may benefit from short-term use of a topical corticosteroid.

CLINICAL FEATURES: The most commonly affected sites for lichenoid contact stomatitis are the posterior buccal mucosa and the ventral surface of the lateral borders of the tongue. Gingival cuffs adjacent to subgingival metallic restorations and porcelain-fused-to-metal (PFM) crowns with metal collars also may be affected. The lesions usually are confined to the area of contact but may extend up to 1 cm beyond the point of mucosal association. The affected mucosa may be white or erythematous, with or without peripheral striae (Fig. 9-41). Most patients have no symptoms, but periodic erosion may be noted. In all likelihood, many of the lesions previously reported as the so-called plaque type of lichen planus were, in reality, lichenoid contact stomatitis.

DIAGNOSIS: The diagnosis is made from the clinical appearance of the lesions, the lack of migration, and the correlation to adjacent dental metal (Fig. 9-42). Although the histopathologic features may be indistinguishable from lichen planus, biopsy occasionally is performed to confirm the clinical impression and to rule out other pathoses such as epithelial dysplasia. Although patch testing is not necessary for a strong presumptive diagnosis, the procedure does help identify patients who are predisposed to react to the metal (possibly advantageous in a patient with a single site of lichenoid stomatitis who also has numerous similar, but less corroded, restorations demonstrating mucosal contact). In addition, the patch testing will include a battery of additional dental metals that will assist in the choice of material for future restorations.

HISTOPATHOLOGIC FEATURES: Biopsy of allergic contact stomatitis from dental materials exhibits numerous features of lichen planus. The surface epithelium may be hyperkeratotic, atrophic, or ulcerated. Areas of hydropic degeneration of the basal cell layer often are present. The superficial lamina propria contains a dense bandlike chronic inflammatory cellular infiltrate consisting predominantly of lymphocytes, but there may be scattered plasma cells. On occasion, deeper lymphoid aggregates may be noted, often in a perivascular orientation.

TREATMENT AND PROGNOSIS: Local measures, such as improved oral hygiene, smoothing, polishing, and recontouring, should be attempted before more aggressive measures, because clinically similar lesions have been noted as a result of surface plaque accumulation. If this is unsuccessful, then the amalgam in question should be replaced with a nonmetallic restoration, if possible. Other material choices include yellow gold, white gold, and PFM crowns. As mentioned, cutaneous patch testing not only confirms the diagnosis but also can be used as a guide during the selection of future restorative materials.

CLINICAL FEATURES: Angioedema is characterized by the relatively rapid onset of soft, nontender tissue swelling, which may be solitary or multiple (Fig. 9-43). In the hereditary forms, the initial onset typically is noted in childhood or adolescence. The episodes are unpredictable and intermixed with edema-free intervals. Recurrent skin swelling and abdominal pain are the most frequent presentations. The extremities are the most common cutaneous sites of involvement, although the face, genitals, trunk, and neck also can be affected. Although not individually frequent, edema of the larynx, pharynx, uvula, or soft palate may be noted when patients are monitored for extended periods (and may be associated with respiratory distress). A deeper voice, hoarseness, aphonia, and dyspnea are important warning signs. Recurrent snoring-induced edema of the soft palate has been reported and associated with severe dyspnea. Isolated tongue involvement is uncommon. Involvement of the skin and mucous membranes can cause enlargements that may measure up to several centimeters in diameter (Fig. 9-44). Although pain is unusual, itching is common and erythema may be present. The enlargement typically resolves over 24 to 72 hours. In contrast to the hereditary variants, allergic, acquired, and ACE inhibitor–associated angioedema demonstrate significant involvement of the head and neck, such as the face, lips, tongue, floor of mouth, pharynx, and larynx. The risk of angioedema associated with ACE inhibitors is significantly greater in blacks (three to four times that of other races), and this pattern is the type most frequently encountered by oral health practitioners.

DIAGNOSIS: In cases of allergic causation, the diagnosis of angioedema often is made from the clinical presentation in conjunction with the known antigenic stimulus. When multiple antigenic exposures occur, the diagnosis of the offending agent can be difficult and involves dietary diaries and antigenic testing.

Those patients whose conditions cannot be related to antigenic exposure or medications should be evaluated for the presence of adequate functional C1-INH. In the hereditary types, both forms exhibit normal levels of C1 and decreased levels of functional C1-INH. Type I demonstrates a decreased quantity of C1-INH; type II exhibits normal levels of the inhibitor (but it is not functional). Both acquired forms demonstrate low levels of both C1-INH and C1.

TREATMENT AND PROGNOSIS: The treatment of allergic angioedema usually consists of oral antihistamine therapy. If the attack is not controlled or if laryngeal involvement is present, then intramuscular epinephrine should be administered. If the epinephrine does not stop the attack, then intravenous corticosteroids and antihistamines should be given.

Cases of angioedema related to ACE inhibitors are not IgE-mediated and often do not respond to antihistamines and corticosteroids. Because the airway may have to be opened, affected patients are kept under close observation until the swelling begins to subside. Although the mechanism is unclear, some patients with ACE inhibitor–associated angioedema have responded to C1-INH concentrate. Patients experiencing ACE inhibitor–associated angioedema should avoid all medications in this class of drugs, and their physicians should consider alternative hypertension management strategies. Angiotensin II receptor blockers do not appear to be safe alternatives.

Those cases related to C1-INH deficiency also do not respond to antihistamine, corticosteroid, or adrenergic therapy. Intubation and tracheostomy may be required for laryngeal involvement. Fresh freeze-dried plasma has been used; however, some investigators do not recommend its use because there is a risk of transmitting infection, and it replaces not only C1-INH but also potentially harmful C1 esterase, C1, C2, and C4. C1-INH concentrate and esterase-inhibiting drugs (aprotinin or tranexamic acid) are the treatments of choice for acute attacks. Because acute attacks of hereditary angioedema are not only unpleasant but also potentially life threatening, prevention is paramount. Patients should avoid violent physical activity and trauma. Medical prophylaxis is recommended before any dental or surgical procedure. All patients should carry medical warning cards that state the diagnosis and list elementary precautions. Prophylaxis for C1-INH deficiency is recommended in patients who have more than three attacks per year. Androgens induce hepatic synthesis of C1-INH, and either of the attenuated androgens (danazol or stanozolol) is used for both the hereditary forms and the acquired type that is related to lymphoproliferative disorders. The autoimmune acquired type is best prevented through the use of corticosteroids.