Oral manifestations of Wegener's granulomatosis

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Oral manifestations of Wegener’s granulomatosis A report of three cases and a literature review Carol Stewart, DDS, MS; Donald Cohen, DMD, MS, MBA; Indraneel Bhattacharyya, DMD, MSD; Lawrence Scheitler, DDS, MPH; Steven Riley, DMD; Kenneth Calamia, MD; Cesar Migliorati, DDS, MS, PhD; Ronald Baughman, DDS, MSD; Perry Langford, DDS; Joseph Katz, DDS

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Background. Hyperplastic granular gingivitis or “strawberry gingivitis” is a rare manifestation of N Wegener’s granulomatosis (WG), but it is nearly C U U I pathognomonic for this multisystem autoimmune vas- A R N G E D 2 TICLE culitis. The dentist may be the first health care professional to see patients with symptoms and findings of this condition. Early diagnosis and treatment is the most important factor in the management of this potentially fatal disease. Methods. The authors present three case reports that demonstrate the disease spectrum and conducted a literature review focused on current understanding of this disease. Results. The first patient had only the classic gingival manifestations of the disease. The second patient had simultaneous typical gingival lesions, as well as dermatologic findings. The third patient had an atypical oral presentation of aphthous ulcers and erythematous gingiva, as well as respiratory and genital involvement. Reaching a definitive diagnosis sometimes is challenging owing to the subtle onset of the disease and variable clinical and laboratory findings. Conclusion and Clinical Implications. Clinicians should be familiar with the broad variety of oral and systemic components of WG, as well as strategies to facilitate prompt disease recognition and to provide continued oral health care to these medically complex patients. Key Words. Wegener’s granulomatosis; hyperplastic gingivitis. JADA 2007;138(3):338-48. T

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ABSTRACT CON

egener’s granulomatosis (WG) is an uncommon multisystem disorder, initially described by Friedrich Wegener, MD, in 1936.1 At the meeting of the German Pathological Society, he presented autopsy findings of a 38-year-old man with saddle nose deformity; a destroyed nasal septum; inflammation of the nasal mucosa, middle ear, larynx, pharynx and trachea; and large, swollen kidneys. A histological examination revealed a granulomatous necrotizing inflammation of the respiratory tract and kidneys showed evidence of necrotizing glomerulonephritis. Wegener’s colleagues described similar cases at the meeting. In 1939, Wegener2 wrote a definitive report on the subject. However, it was not until 1954, when Godman and Churg3 published an article on WG, that Wegener began to understand the importance of his work. WG is characterized by a patho-

Dr. Stewart is an associate professor, Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, University of Florida, College of Dentistry, Box 100414 JHMHC, Gainesville, Fla. 32610, e-mail “[email protected]”. Address reprint requests to Dr. Stewart. Dr. Cohen is a professor, Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, University of Florida, College of Dentistry, Gainesville. Dr. Bhattacharyya is an assistant professor, Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, University of Florida, College of Dentistry, Gainesville. Dr. Scheitler is the dental chief, Dental Service, Bay Pines VA Healthcare System, St. Petersburg Fla. Dr. Riley is an attending dentist, Malcolm Randall VA Medical Center, Gainesville, Fla. Dr. Calamia is a rheumatologist and internal medicine specialist, Mayo Clinic College of Medicine, Jacksonville, Fla. Dr. Migliorati is a professor, Oral Diagnostic Sciences, Nova Southeastern University College of Dental Medicine, Ft. Lauderdale, Fla. Dr. Baughman is an oral pathologist, AmeriPath, Central Florida, Orlando, Fla. Dr. Langford is a periodontist in private practice, Lakeland, Fla. Dr. Katz is a professor, Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, University of Florida, College of Dentistry, Gainesville.

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logical triad consisting of necrotizing granulomatous lesions in the upper or lower respiratory tracts or both, systemic vasculitis involving both small arteries and veins, and necrotizing glomerulonephritis.3 While WG typically affects the upper and lower airways and frequently the kidneys, it may involve any organ system. The inflammatory granulomatous and vasculitic process can affect the mouth, eyes, ear, nose, throat, lungs, skin and kidneys. According to Cotch and colleagues,4 the disease affects three per 100,000 Americans per year. In Hoffman and colleagues’5 analysis of 158 patients, the mean age was 41 years (range, 9-78 years), and 85 percent were older than 19 years. Ninety-seven percent of the patients were white, 2 percent were African-American, and 1 percent were of other racial backgrounds. Large clinical studies of patients with WG have shown no significant sex difference.5,6 The cause of WG has not been elucidated, but the prevailing thesis supports onset in a genetically susceptible person in conjunction with an environmental trigger. Bacterial antigens, such as Staphylococcus aureus, have been implicated in the initiation and relapse of WG through alteration of immune tolerance leading to enhanced and perpetuated inflammation of vessels.7-9 In addition, environmental exposure to siliconcontaining compounds has been associated with chronic renal failure and vasculitis similar to that found in WG.10 In 1990, the American College of Rheumatology (ACR) proposed specific criteria for the classification of WG. Two of the following four criteria are required to meet the ACR classification for WG: oral ulcers or nasal discharge; the presence of nodules, fixed infiltrates or cavities on a chest radiograph; abnormal urinary sediment (red blood cell casts or more than five red blood cells per high power field); and granulomatous inflammation on biopsy.11 While the criteria included oral ulcers, the mention of oral manifestations of WG sometimes is omitted from reports in the medical literature,12 possibly due to lack of awareness or low prevalence. Dentists receive referrals from physicians, and patients will self-refer for consultation regarding oral lesions and gingivitis. Therefore, it is important that dentists be familiar with the oral manifestations of WG, especially the classic gingival appearance called “strawberry gingivitis,” the clinical spectrum, diagnostic parameters and dental management to facilitate a prompt diagnosis and provide appropriate care.

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CASE REPORTS

Case 1. A 62-year-old man consulted a periodontist (P.L.) after the onset of gingival bleeding and ulceration. The patient believed that the condition was a manifestation of a “tropical disease” because he had been in the Mediterranean area five months before the onset. The patient had been in good health until his involvement in an auto accident resulting in a thoracic injury and pneumonia during his stay abroad. The periodontist performed a biopsy of the affected gingiva. The histopathologic diagnosis was nonspecific gingivitis, with acute and chronic inflammation. The periodontist provided appropriate débridement therapy and prescribed 0.12 percent chlorhexidine gluconate rinses. When conservative therapy failed to resolve the condition, the periodontist promptly referred the patient to the University of Florida College of Dentistry (UFCD) Oral Medicine Clinic in Gainesville. His chief complaint was “sore gums” of four to five months’ duration. Clinical examination (by C.S.) revealed the attached gingival mucosa to be hyperplastic and red-purple, with diffuse petechial hemorrhages in the maxillary and mandibular right quadrant and mandibular anterior regions (Figures 1A, 1B and 1C). He denied sinusitis, difficulty breathing, skin lesions or other systemic concerns. After making a clinically presumptive diagnosis of WG, an oral surgeon performed a second biopsy of the mandibular gingiva. The histopathologic features reported by a pathologist (R.B.) included papillary surface epithelium with a diffuse mononuclear inflammatory cell infiltrate in lobular pattern in focal areas and perivascular mononuclear cell infiltration. Fibrinoid deposits associated with plasma cells and lymphocytes were present; however, features of necrotizing vasculitis were absent. Occasional multinucleated giant cells and

ABBREVIATION KEY. ACR: American College of Rheumatology. ANCA: Antineutrophil cytoplasmic autoantibodies. c-ANCA: Cytoplasmic antineutrophil cytoplasmic autoantibodies. CBC: Complete blood count. CP: Cicatricial pemphigoid. CT: Computerized tomography. ELISA: Enzyme-linked immunosorbent assay. MPA: Microscopic polyangiitis. MPO: Myeloperoxidase. NHL: Non-Hodgkin’s lymphoma. p-ANCA: Perinuclear antineutrophil cytoplasmic autoantibodies. PAS: Periodic acid–Schiff. TNF: Tumor necrosis factor. UFCD: University of Florida College of Dentistry. WG: Wegener’s granulomatosis.

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Figure 1. Case 1. A. Mandibular buccal gingiva showing erythematous hyperplastic gingiva with granular, pebbly or strawberry appearance. B. Mandibular lingual gingiva exhibiting granular, pebbly or strawberry appearance. C. Mandibular anterior facial gingiva exhibiting erythema with petechiae. D. Gingival biopsy exhibiting perivascular inflammation and occasional multinucleated giant cells (arrow). Hematoxylin-eosin stain, magnification × 45.

numerous eosinophils were scattered throughout (Figure 1D). Based primarily on the clinical oral presentation with histopathologic support, the clinician referred the patient to University of Florida College of Medicine’s otorhinolaryngology service for a full work-up to rule out WG. However, when the patient began to experience sinusitis, myalgia and extreme fatigue, he sought treatment in his local area (he lived three hours away from Gainesville). During his hospitalization, clinicians ordered nasal and temporal artery biopsies and placed myringotomy tubes. He was discharged with a diagnosis of polymyalgia rheumatica and a regimen of prednisone 30 milligrams per day and ciprofloxacin 250 mg twice daily. Due to inadequate response to initial treatment, the patient requested an evaluation at the University of Florida College of Medicine. The prednisone had resulted in resolution of the gingival lesions, but the sinusitis remained. A nasal 340

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examination revealed bilateral septal erythema, ulceration and crusting. A sinus computerized tomography (CT) scan was remarkable for “minimal maxillary sinus disease.” Respiratory function tests revealed no significant deficits, and no renal dysfunction was found. On the basis of clinical findings and histopathologic reports, a diagnosis of limited WG was supported. The treatment included cyclophosphamide and prednisone. During the following three months, the patient had frequent exacerbations of his condition. He was lost to further follow-up. Case 2. A 34-year-old woman was referred by her physician to the UFCD Oral Medicine Clinic for evaluation of gingival hyperplasia and bleeding. The patient reported that she had been unable to brush her teeth for one month owing to gingival pain. The remainder of her medical history was negative for systemic illnesses. She had been healthy until this event and was taking no medications. She reported having allergies to sul-

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Figure 2. Case 2. A. Maxillary and mandibular gingiva showing hyperplastic gingivitis at initial presentation. B. Left facial gingiva, showing closer view of gingival lesion. C. Granulomatous lesion on forehead. D. Scalp lesion.

fanilamide, erythromycin and amoxicillin. Her oral examination (conducted by C.S., R.B. and C.M.) was significant for moderately painful gingival lesions (Figures 2A and 2B). The clinician observed a granulomatous lesion on her forehead and an eroded scalp lesion that the patient reported had appeared shortly after the gingival lesions (Figures 2C and 2D). The patient reported having mild sinusitis, but no difficulty breathing. The clinician detected no nasal lesions or crusting. Based on the clinical oral picture, the clinician reached a working diagnosis of WG, with recommendations for a gingival biopsy, dermatology and otolaryngology consultations. The histopathology report of the maxillary anterior gingival biopsy was consistent with WG. The connective tissue was markedly wellvascularized and edematous, with a subacute inflammatory infiltrate containing scattered multinucleated giant cells. The periodic acid–Schiff (PAS) stains used to test for fungal organisms were negative. The diagnosis was limited WG,

involving the skin, mouth and upper respiratory tract. Treatment included prednisone and cyclophosphamide 100 mg per day and prednisone beginning at 60 mg per day that would be reduced rapidly over a set amount of time. The patient’s gingival response was rapid, with improvement noted at one- and two-week follow-up appointments (Figure 3). At the six-month follow-up, the clinician noted resolution of both gingival and forehead lesions (Figure 4, page 343). The patient was followed for an additional six months and remained stable and free of lesions. Case 3. A 53-year-old man was receiving comprehensive oral care from the dental clinic at the Malcolm Randall VA Medical Center. His medical history was significant for hypertension, diabetes, stroke, coronary artery disease and congestive heart failure. He had undergone quadruple coronary artery bypass surgery and mitral valve replacement. He was taking medications to manage these conditions, including 5 mg prednisone. He reported having allergies to propra-

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Figure 3. Case 2. A. Gingival response after one week of therapy consisting of 100 milligrams of cyclophosphamide and 60 mg prednisone. B. Gingival response after two weeks of therapy.

nolol, penicillin, loratadine and iodine. The findings from the initial comprehensive periodontal examination supported a diagnosis of chronic, generalized, moderate Type III periodontitis with localized advanced periodontitis (Type IV). The patient received oral hygiene instruction, frequent periodontal débridements with clindamycin antibiotic premedication, 0.12 percent chlorhexidine gluconate rinses, systemic tetracycline therapy and selected extractions. Some areas of the oral cavity responded favorably to the supportive periodontal therapy. However, there were persistent erythematous, erosive lesions on the lower anterior facial gingiva, cheek and tongue (Figure 5A, page 344). The lesions produced only mild discomfort and were thought to be a response to the medications prescribed by the patient’s cardiologist. Previously, these lesions either were not present or were masked by the inflammation and erythema of the periodontium and keratinized gingiva. Due to persistence of the gingival condition, the clinician (L.S.) referred the patient to the VA’s Infectious Disease/Rheumatology Service for additional evaluation. The patient reported having a two-year history of sinusitis, with chronic nasal congestion, bloody discharge and facial discomfort. He had multiple courses of antibiotics and a CT scan one year before that showed mucosal thickening. Behcet’s syndrome was the clinicians’ initial consideration. They had considered the possibility of WG, but the results from antineutrophil cytoplasmic autoantibodies (ANCA) testing were negative. The patient sought a second opinion from Mayo Clinic in Jacksonville, Fla., and was evaluated by the rheumatologist and internal 342

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medicine specialist (K.C.) Because of severe blanitis, a clinician performed a circumcision and a biopsy from the head of the penis. Pathological findings were consistent with WG, and a concurrent cytoplasmic antineutrophil cytoplasmic autoantibodies (c-ANCA) test was positive (titer 1:64). Since the diagnosis, the patient has been treated with cyclophosphamide and infliximab and then with low-dose prednisone and mycophenolate. He continues to have a focus of chronic, active orbital inflammation. The collapse of the bridge of his nose was due to destruction of the nasal septum or nasal cartilage associated with chronic sinus involvement (Figure 5B). The gingival lesions had resolved in four months (Figure 5C). LITERATURE REVIEW

Clinical presentation. In a large study of 158 patients, 42 percent were diagnosed as having WG within three months.13 In 8 percent, however, the diagnosis was not made until five to 16 years later. Ear, nose and throat features were prevalent in 70 percent of patients at onset and appeared in 90 percent of patients during the course of the disease. Lung involvement initially was present in 45 percent of patients and developed in 85 percent of patients during the course of the disease. Upper respiratory tract involvement may have been followed by progressive renal failure and terminal uremia. The corresponding clinical presentation of the multiorgan disease consists of rhinitis, sinusitis or otitis media in conjunction with cough and hemoptysis. Midface deformities and collapse of the nasal bridge (“saddle nose”) may be seen with nasal and sinus

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Figure 4. Case 2. A. Gingiva after six months of therapy. B. Forehead after six months of therapy. C. Scalp after six months of therapy.

involvement. Hearing loss commonly is reported. Ocular abnormalities include proptosis and are seen as an early manifestation in 15 percent of patients.4 Hu and colleagues14 proposed that skin be added to the classic target-organ system: ear, nose and throat; lung; and kidney. In two cases they reported, skin lesions were the presenting sign. Skin involvement in WG includes palpable purpura, nodules and ulcers. These dermatologic manifestations have been reported in up to 46 percent of affected patients and in 13 percent of affected patients at disease onset. If left untreated, WG often is fatal within the first year of onset.15 However, limited forms of the disease have been reported in which only one or two organ systems have been involved.16,17 The disorder has a more favorable prognosis in the absence of renal involvement. Although initial presentation of WG may manifest in the oral cavity, reports of frequency vary. Oral lesions may be seen in 10 to 62 percent of patients.4,18-20 Oral lesions were the presenting sign in 5 to 6 percent of the patients.18,21 The most characteristic early lesion consists of hyperplastic gingivitis with red-purple edematous interdental papillae diffusely covered with petechiae. The lesion typically displays a pebbly or granular appearance and often is referred to as “strawberry gingivitis.” Initial patches of affected gingiva may coalesce to produce a generalized pattern

involving the attached gingiva and may extend even beyond the mucogingival junction. This highly characteristic strawberry gingivitis has been reported as an initial manifestation of WG.22-32 As the gingival condition may remain localized to the oral cavity for long periods before multiorgan involvement occurs, prompt diagnosis is critical to avoid serious or fatal consequences.27 Other oral manifestations may include tooth mobility, poor healing after extraction, cranial nerve palsies and parotid gland swelling.27 Pathogenesis. While the pathogenesis has not been determined, it appears that both cellular and humoral components are involved. T-cell mediated immunity with production of tumor necrosis factor- alpha (TNF-α) and interferon gamma is a component in the inflammatory process. Neutrophils also play an important role in the WGrelated tissue injury. Inflammatory cytokines, such as TNF-α, stimulate surface expression of antigens on activated neutrophils. Some of these interact with ANCAs, causing degranulation of neutrophils and generation of toxic products, leading to tissue injury.33 Diagnostic recommendations include serologic testing for ANCA. There are two patterns of ANCA seen on immunofluorescent testing: a cytoplasmic pattern and a perinuclear pattern. The cytoplasmic pattern is associated with antibodies to proteinase 3 (c-ANCA or proteinase 3–ANCA) and is highly

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B Figure 5. Case 3. A. Oral presentation with diagnosis of generalized periodontitis, focal severe periodontitis and oral ulcers and erythema. B. Facial appearance with collapsed bridge of nose. C. Oral lesions largely resolved after therapy.

C specific for WG. A perinuclear pattern on perinuclear antineutrophil cytoplasmic autoantibodies (p-ANCA) testing due to anti-myeloperoxidase (MPO) antibodies occasionally is seen in WG. Testing for MPO by enzyme-linked immunosorbent assay (ELISA) is necessary to confirm the specificity of the p-ANCA. c-ANCA is considered to be a sensitive and specific marker for multisystem WG and may be helpful in tracking disease activity and possible relapse.34,35 The presence of c-ANCA in the majority of patients with severe WG suggests an important role for B cells and plasma cells. However, because not all WG patients have ANCA, the role of antibodies to proteinase 3 are not totally defined in WG pathogenesis.36-38 False positive c-ANCA test results have been reported in patients with tuberculosis, Hodgkin’s lymphoma, HIV infection, nasal septal perforation, monoclonal gammopathies and druginduced Wegener-like disease.39-43 False negative cANCA test results also have been reported.44-46 While most patients with WG will have c-ANCA in their serum, it may be less useful in detecting cases of limited or early disease.47 To increase the 344

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sensitivity of diagnostic testing, clinicians can request both testing for ANCA and for antibodies to proteinase 3 by ELISA. Diagnosis. The dentist initially may suspect WG from clinical history and oral presentation. Clinical suspicion should be followed by oral biopsy and laboratory testing, including complete blood count (CBC), erythrocyte sedimentation rate, C-reactive protein, blood urea nitrogen, serum creatinine, urinanalysis, ANCA testing and testing for antibodies to proteinase 3. For respiratory tract symptoms, a chest radiograph is appropriate and a CT scan of the sinuses to further characterize pulmonary abnormalities may be of value. Referral to an otorhinolaryngologist, pulmonologist or nephrologist will be required to obtain necessary biopsies. The histopathologic criteria for a diagnosis of WG include vasculitis, granulomatous inflammation, multinucleated giant cells and necrosis. In most cases, however, the histopathologic findings in the gingival lesions of WG are less specific but may demonstrate acute or chronic inflammation, multinucleated giant cells and pseudoepitheliomatous hyperplasia. While these may be considered nondiagnostic findings, they would be supportive of a WG diagnosis in the presence of strawberry gingivitis or with suggestive systemic or organ system involvement. Management. The mainstay of therapy for generalized multisystemic WG is cyclophosphamide plus corticosteroids. Historically, the combination of cyclophosphamide plus corticosteroids was used for a minimum of 12 months.

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Recent concern about late toxicities associated with cyclophosphamide has led to a shorter induction course, alternative induction regimens for patients with less severe disease and maintenance therapy with less toxic agents such as methotrexate or azathioprine.48 Trimethoprimsulfamethoxazole has been used to minimize the risk of acquiring treatment-related Pneumocystis carinii infection and to prevent relapses.49 During treatment with corticosteroids and immunosuppressive agents, the dentist must alert the treating physician to any signs of oral infection and help the patient maintain an acceptable level of oral hygiene. During the chemotherapy induction phase, elective dental care should be avoided. Antibacterial oral rinses might be helpful for initial management of gingival lesions. After two to four weeks of systemic therapy, the gingival lesions should demonstrate marked improvement. When remission has been achieved, the dentist should continue to deliver routine oral care. Routine periodontal prophylaxis, continued antibiotic rinses and frequent recalls are appropriate. Consultation with the patient’s physician would be appropriate to determine the extent of immunosuppression and possible need for antibiotics owing to low white blood cell counts or other effects of immunosuppressants. Before invasive procedures, medical consultation is important to determine the need for corticosteroid supplementation, owing to possible adrenal suppression from long-term prednisone therapy. Steroid supplementation regimens vary according to the patient’s immune status and the planned procedure. For major oral surgical procedures often performed in a hospital environment, an equivalent of the patient’s usual morning dose followed by pre- and intraoperative supplementation to achieve 100 to 150 mg per day of hydrocortisone equivalent for two to three days has been recommended.50 Adequate analgesia is of critical importance in preventing an adrenal crisis. If renal involvement has occurred, medications eliminated through the kidney, such as aspirin, nonsteroidal antiinflammatory drugs and penicillin, should be used with caution or be avoided. DISCUSSION

In the three case reports, the painful gingival lesions were part of the patient’s initial complaints. In the first case, appropriate dental management resulted in establishing a prompt presumptive diagnosis and medical referral. The

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patient’s reluctance to comply with recommended follow-up and an initial delay in medical confirmation of the diagnosis contributed to some treatment delay. In the second case, prompt verification of the presumptive clinical diagnosis made by the dentist resulted in timely diagnosis and treatment. In the third case, multiple medical problems, initially negative ANCA tests and the oral presentation presented a challenge in establishing the diagnosis. The oral presentation was more suggestive of lichen planus or aphthous ulcerations than of WG. It is possible that the low dose of prednisone the patient was taking at the onset of his disease masked or altered the gingival picture. Alternatively, his presentation may have been an ulcerative process versus the more characteristic hyperplastic gingivitis. The true incidence and exact clinical appearance of the spectrum of oral lesions in WG are difficult to assess. Of 56 cases reviewed by Walton,15 21 had oropharyngeal lesions, seven had tongue involvement and seven implicated the gingiva. Five cases were listed in which oral manifestations were among the initial symptoms. Fauci and colleagues21 reported “oral ulcers” as a presenting sign in five of their patients. They observed parotid gland enlargement and pain in two patients. Oral signs and symptoms of WG as reviewed by Scott and Finch23 included gingival enlargement, inflammation or ulceration independent of nasal lesions, failure of extraction sockets to heal and a neurological disturbance (one case). Vermeulen and Mahowald51 reported jaw claudication after chewing as a presenting symptom associated with this disease. They observed no temporomandibular joint sounds, found range of motion to be within normal limits and found no tenderness on joint palpation. The working diagnosis in their case was temporal arteritis. A lung biopsy, however, confirmed the diagnosis of WG. The differential diagnosis of WG based on oral manifestations and histopathology would include other ANCA-positive vasculitides, orofacial granulomatosis, specific granulomatous diseases (such as sarcoidosis and Crohn’s disease), and granulomatous infectious processes (such as foreign body reactions, deep fungal infections and tuberculosis). In addition, medication-induced gingival changes, blood dyscrasias (such as leukemia and lymphoma) and lesions secondary to an immune-compromised status could be included. These disorders can be excluded from WG by history, physical examination, and appropriate laboratory and

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histopathologic studies. In addition to WG, microscopic polyangiitis (MPA) is another small-vessel vasculitide associated with ANCA. The average age of onset of MPA is about 50 years, and the main clinical features are renal involvement characterized by rapidly progressing glomerulonephritis, as well as lung vasculitis, arthritis and myalgia.52 WG and MPA have overlapping features, as both diseases are associated with renal and pulmonary vasculiltis and may have similar oral manifestations. The classic presentation of WG gingivitis (hyperplastic, granular, friable tissue with scattered petechia) was reported as the first sign of MPA in an otherwise healthy man.53 However, the pulmonary and renal necrotizing vasculitis seen in MPA is nongranulomatous. In contrast, the histopathology of WG shows a granulomatous vasculitis.54 The final diagnosis must be based on correlation of findings with systemic manifestations. Orofacial granulomatosis designates a wide variety of clinical presentations that, on biopsy, reveal a nonspecific granulomatous inflammation. The predominant involvement is a diffuse, nontender enlargement of the upper lip, but hyperplastic gingival mucosa also can be seen. Studies suggest hypersensitive reactions to foods, preservatives and dental restorative materials.55-59 Special stains for microbial organisms and foreign bodies will be negative. Sarcoidosis is a multisystem immune-mediated granulomatous disorder of unknown cause. African-Americans are affected more frequently than are whites, and the highest prevalence is found in people between 30 and 40 years of age. Common clinical symptoms are fatigue and cough with elevated dark plaques on the limbs and back. Ocular and salivary gland involvement may occur. Oral lesions have been reported in the jaws, buccal mucosa, gingiva, lips and floor of the mouth, tongue and palate. Lesions in the gingiva, buccal mucosa and tongue may be the first clinical sign of disease.60 Gingival lesions will appear primarily in the anterior labial gingiva with enlargement, erythema and sometimes with superficial ulcerations.60,61 Tissue biopsies reveal epitheloid histiocytes rimmed by lymphocytes and scattered Langhans’ or foreign body–type giant cells. Crohn’s disease is characterized by a granulomatous chronic, relapsing inflammatory involvement of the gastrointestinal tract, particularly the terminal ileum, that often is diagnosed in children and young adults. Inflammatory gingival hyper346

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plasia may be associated with Crohn’s disease and characterized by granulomatous, erythematous swelling, shallow ulcers and snail-track lesions. The most common areas of oral involvement are the buccal mucosa with cobblestone-appearing lesions, the vestibule showing linear hyperplastic folds and ulcers, the lips that appear diffusely swollen and the palate that may show multiple ulcers. The oral manifestations may precede or follow the intestinal lesions.63-65 Histopathologic evaluation of gingival lesions will show features of chronic granulomatous disease suggestive of sarcoidosis. Other considerations in the differential diagnosis of WG would include specific infections such as tuberculosis and deep fungal infections that also would demonstrate granulomatous inflammation. Lesions may occur on the gingiva, tongue, vestibule and buccal mucosa and appear as diffuse, hyperemic, nodular or papillary proliferations or ulcers. Special stains might include PAS, Gomori methenamine silver, Gram, Giemsa, Warthin-Starry silver and acid-fast bacillus to assess manifestations of blastomycosis, mucormycosis, histoplasmosis, erythematous candidasis or tuberculosis. Specific bacterial infections, particularly in immunocompromised patients, may be erythematous, hyperplastic and necrotizing gingivitis. Biopsy with specific microbial stains usually allows the pathologist to identify the causative organism. Medication-induced gingival enlargement can result from the use of calcium channel blockers used to treat cardiovascular disease and hypertension, phenytoin used for seizure disorders and cyclosporine used as an immunosuppressant for organ transplantation. The gingival enlargement is from excessive collagen production and may be normal in color and firm with a smooth, granular or lobulated surface. Lesions often are painless unless a secondary bacterial or fungal infection has developed.66-68 With inflammation often due to poor oral hygiene, the gingiva may be dark red, edematous and friable, and it may bleed easily, leading a clinician to consider WG. Biopsy of these lesions generally would reveal fibrous connective tissue with a chronic inflammatory cell infiltrate of lymphocytes and plasma cells. Gingival manifestations of WG may have a clinical appearance similar to gingival leukemic infiltrates. Oral lesions may occur in both acute and chronic forms of all types of leukemia, though they occur more commonly in the acute phase of the

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disease. Primary clinical manifestations may include gingivitis, gingival hemorrhage, petechiae, ecchymosis and ulceration of the mucosa.69-71 Lesions usually are generalized and vary in severity. Gingival tissues are enlarged, edematous, easily compressed and tender. The color sometimes is bluish red, and the surface is glossy. In severe cases, the teeth may be nearly covered by the red, boggy gingiva. The gingival enlargement is due to the leukemic infiltrate and will bleed easily on palpation. On biopsy, the gingival tissue will be infiltrated densely by atypical immature leukocytes, the specific type varying with the type of leukemia present. Gingival biopsy combined with a CBC with a white blood cell differential will eliminate WG from consideration. Non-Hodgkin’s lymphoma (NHL) most commonly occurs in adults as a slow-growing nontender mass in a lymph node. However, it might appear as extranodal disease in the oral cavity and could be included in the differential diagnosis for WG. An NHL could manifest as a red-purple nodular lesion of boggy consistency in the tonsillar area, posterior hard palate or buccal vestibule.72,73 Gingival lesions may appear as a gingival swelling with a smooth or ulcerated surface and be the first manifestation of the disease.73 Clinical, histopathologic and hematologic evaluations as well as imaging would confirm a diagnosis of lymphoma. In rare situations, cicatricial pemphigoid (CP) or mucous membrane pemphigoid, might be considered in the differential diagnosis of early WG. CP is a chronic mucocutaneous immune-mediated disease of the basement membrane zone complex with average onset at age 50 or 60 years. The oral manifestation commonly is described as desquamative gingivitis.74,75 A diffusely erythematous gingiva with a positive Nikolsky’s sign or easy sloughing produced by lateral pressure is characteristic of CP. Only in early WG with diffuse erythema and few petechiae would CP be included in a differential diagnosis. Gingival enlargement, granularity and multiple petchiae characteristic of gingival lesions of WG are not observed in oral CP. Direct immunofluorescence studies of perilesional mucosa would confirm the diagnosis of CP. Patients with severe, otherwise unexplained gingivitis or gingival lesions unresponsive to local measures should be evaluated thoroughly. CONCLUSION

The diagnosis of WG can be challenging. We presented three case reports to increase awareness of

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WG and its associated oral manifestations, diagnostic strategies and dental management strategies. Dentists play a critical role in these types of cases, especially when oral manifestations precede pulmonary and renal involvement. Including WG in a differential diagnosis of hyperplastic gingival vasculitis or recalcitrant oral lesions in the presence of sinusitis will hasten a diagnosis and treatment of WG. ■ 1. Wegener F. Über generalisierte, septische efäberkrankungen. Verh Dtsch Pathol Ges 1936;29:202-10. 2. Wegener F. About a peculiar rhinogenic granulomatosis with marked involvement of the arterial system and kidneys. Beitr Pathol Anat 1939;102:30-68. 3. Godman GC, Churg J. Wegener’s granulomatosis: pathology and review of the literature. AMA Arch Pathol 1954;58(6):533-53. 4. Cotch MF, Hoffman GS, Yerg DE, Kaufman GI, Targonski P, Kaslow RA. The epidemiology of Wegener’s granulomatosis: estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources. Arthritis Rheum 1996 39(1):87-92. 5. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116(6):488-98. 6. Hoffman GS, Gross WL. Wegener’s granulomatosis: clinical aspects. In: Hoffman GS, Weyand CM, eds. Inflammatory diseases of blood vessels. New York: Marcel Dekker; 2002:381-97. 7. Stegeman CA, Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, Kallenberg CG. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 1994;120(1):12-7. 8. Popa ER, Stegeman CA, Kallenberg CG, Tervaert JW. Staphylococcus aureus and Wegener’s granulomatosis. Arthritis Res 2002 4(2): 77-9. 9. Capizzi SA, Specks U. Does infection play a role in the pathogenesis of pulmonary vasculitis? Semin Respir Infect 2003;18(1):17-22. 10. Tervaert JW, Stegeman CA, Kallenberg CG. Silicon exposure and vasculitis. Curr Opin Rheumatol 1998;10(1):12-7. 11. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990;33(8):1101-7. 12. Bacon PA. The spectrum of Wegener’s granulomatosis and disease relapse. N Engl J Med 2005;352(4):330-2. 13. Fahey JL, Leonard E, Churg J, Godman G. Wegener’s granulomatosis. Am J Med 1954;17(2):168-79. 14. Hu CH, O’Loughlin S, Winkelmann RK. Cutaneous manifestations of Wegener’s granulomatosis. Arch Dermatol 1977;113(2):175-82. 15. Walton EW. Giant-cell granuloma of the respiratory tract (Wegener’s granulomatosis). Br Med J 1958;2(5091):265-70. 16. Carrington CB, Liebow A. Limited forms of angiitis and granulomatosis of Wegener’s type. Am J Med 1966;41(4):497-527. 17. Hansen LS, Silverman S, Pons VG, et al. Limited Wegener’s granulomatosis: report of a case with oral, renal and skin involvement. Oral Surg Oral Med Oral Pathol 1985;60(5):524-31. 18. Patten SF, Tomecki KJ. Wegener’s granulomatosis: cutaneous and oral mucosal disease. J Am Acad Dermatol 1993;28(5 pt 1):710-8. 19. Daoud MS, Gibson Le, DeRemee RA, Specks U, el-Azhary RA, Su WP. Cutaneous Wegener’s granulomatosis: clinical, histopathologic, and immunopathologic features of thirty patients. J Am Acad Dermatol 1994;31(4):605-12. 20. Frances C, Du LT, Piette JC, et al. Wegener’s granulomatosis: dermatological manifestations in 75 cases with clinicopathologic correlation. Arch Dermatol 1994;130(7):861-7. 21. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983;98(1):76-85. 22. Cohen PS, Meltzer JA. Strawberry gums: a sign of Wegener’s granulomatosis. JAMA 1981;246(22):2610-1. 23. Scott J, Finch LD. Wegener’s granulomatosis presenting as gingivitis: review of the clinical and pathologic features and report of a case. Oral Surg Oral Med Oral Pathol 1972;34(6):920-33. 24. Napier SS, Allen JA, Irwin CR, McCluskey DR. ‘Strawberry gums’: a case of Wegener’s granulomatosis. Br Dent J 1993;175(9):327-9. 25. Eufinger H, Machtens E, Akuamoa-Boateng E. Oral manifesta-

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tions of Wegener’s granulomatosis: review of the literature and report of a case. Int J Oral Maxillofac Surg 1992;21(1):50-3. 26. Israelson H, Binnie WH, Hurt WC. The hyperplastic gingivitis of Wegener’s granulomatosis. J Periodontol 1981;52(2):81-7. 27. Porter SR, Scully C. Immunologically mediated disease. In: Jones JH, Mason DK, eds. Oral manifestations of systemic disease. 2nd ed. London: Balliere Tindall; 1990:183-270. 28. Parsons E, Seymour RA, Macleod RI. Wegener’s granulomatosis: a distinct gingival lesion. J Clin Periodontol 1992;19(1):64-6. 29. Clark WJ, Broumand V, Ruskin JD, Davenport WL. Erythematous, granular, soft tissue lesion of the gingiva. J Oral Maxillofac Surg 1998;56(8):962-7. 30. Lilly J, Juhlin T, Lew D, Vincent S, Lilly G. Wegener’s granulomatosis presenting as oral lesions: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85(2):153-7. 31. Handlers JP, Waterman J, Abrams AM, Melrose RJ. Oral features of Wegener’s granulomatosis. Arch Otolaryngol 1985;111(4):267-70. 32. Velez I, Mufson RA, Stern D, Tamara L. Wegener’s granulomatosis: a case report. N Y State Dent J 2004 Nov;70(8):26-8. 33. Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A 1990;87(11):4115-9. 34. van der Woude FJ, Rasmussen N, Lobatto S, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet 1985;1(8426):425-9. 35. Rao JK, Allen NB, Pincus T. Limitations of the 1990 American College of Rheumatology classification criteria in the diagnosis of vasculitis. Ann Intern Med 1998;129(5):345-52. 36. Cooley P, Taylor KH, Czika W, Seifer C, Taylor JF. Analysis of a biomarker for Wegener’s granulomatosis. Int J Immunogenet 2005;32(4):237-43. 37. Hoffman GS, Specks U. Antineutrophil cytoplasmic antibodies. Arthritis Rheum1998;41(9):1521-37. 38. Davenport A. “False positive” perinuclear and cytoplasmic antineutrophil cytoplasmic antibody results leading to misdiagnosis of Wegener’s granulomatosis and/or microscopic polyarteritis. Clin Nephrol 1992;37(3):124-30. 39. De Clerck LS, Van Offel JF, Smolders WA, et al. Pitfalls with antineutrophil cytoplasmic antibodies (ANCA). Clin Rheumatol 1989;8(4):512-6. 40. Koderisch J, Andrassy K, Rasmussen N, Hartmann M, Tilgen W. “False-positive” anti-neutrophil cytoplasmic antibodies in HIV infection (letter). Lancet 1990;335(8699):1227-8. 41. Mains B. Wegener’s granulomatosis: false positive anti-neutrophil cytoplasmic antibody test. J Laryngol Otol 1989;103(5):524-5. 42. Esnault VL, Jayne DR, Keogan MT, et al. Anti-neutrophil cytoplasm antibodies in patients with monoclonal gammopathies. J Clin Lab Immunol 1990;32(4):153-9. 43. Alon U, Hellerstein S, Warady BA. Anti-neutrophil cytoplasmic antibodies in drug-induced Wegener-like disease (letter). Pediatr Nephrol 1990;4(3):299-300. 44. Mustonen J, Soppi E, Pasternack A, Hallstrom O. Clinical significance of autoantibodies against neutrophil cytoplasmic components in patients with renal disease. Am J Nephrol 1990;10(6):482-8. 45. Andrassy K, Koderisch J, Rufer M, Erb A, Waldherr R, Ritz E. Detection and clinical implication of anti-neutrophil cytoplasm antibodies in Wegener’s granulomatosis and rapidly progressive glomerulonephritis. Clin Nephrol 1989;32(4):159-67. 46. Al Dhanhani A, Macaulay R, Maloney B, Hanly JG. Meningeal involvement in Wegener’s granulomatosis. J Rheumatol 2006;33(2): 364-7. 47. Langford CA. The diagnostic utility of c-ANCA in Wegener’s granulomatosis. Cleve Clin J Med 1998;65(3):135-40. 48. Lynch JP 3rd, White E, Tazelaar H, Langford CA. Wegener’s granulomatosis: evolving concepts in treatment. Semin Respir Crit Care Med 2004;25(5):491-521. 49. Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole (co-trimaxazole) for the prevalence of relapses of Wegener’s granulomatosis. Dutch Co-Trimoxazole Wegener

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Study Group. N Engl J Med 1996;335(1):16-20. 50. Salem M, Tainsh RE Jr, Bromberg J, Loriaux DL, Chernow B. Perioperative glucocorticoid coverage: a reassessment 42 years after emergence of a problem. Ann Surg 1994;219(4):416-25. 51. Vermeulen JP, Mahowald ML. A case of Wegener’s granulomatosis presenting with jaw claudication. J Rheumatol 1984;11(5):707-9. 52. Lhote F, Cohen P, Genereau T, Gayraud M, Guillevin L. Microscopic polyangiitis: clinical aspects and treatment. Ann Med Interne (Paris) 1996;147(3):165-77. 53. Shiboski CH, Regezi JA, Sanchez HC, Silverman S Jr. Oral lesions as the first clinical sign of microscopic polyangiitis: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94(6):707-11. 54. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 1994;37(2):187-92. 55. White A, Nunes C, Escudier M, et al. Improvement in orofacial granulomatosis on a cinnamon- and benzoate-free diet. Inflamm Bowel Dis 2006;12(6):508-14. 56. Taibjee SM, Prais L, Foulds IS. Orofacial granulomatosis worsened by chocolate: results of patch testing to ingredients of Cadbury’s chocolate. Br J Dermatol 2004;150(3):595. 57. Oliver AJ, Rich AM, Reade PC, Varigos GA, Radden BG. Monosodium glutamate-related orofacial granulomatosis: review and case report. Oral Surg Oral Med Oral Pathol 1991;71:560-4. 58. Khamaysi Z, Bergman R, Weltfriend S. Positive patch test reactions to allergens of the dental series and the relation to the clinical presentations. Contact Dermatitis 2006;55(4):216-8. 59. Lazarov A, Kidron D, Tulchinsky Z, Minkow B. Contact orofacial granulomatosis caused by delayed hypersensitivity to gold and mercury. J Am Acad Dermatol 2003;49(6):1117-20. 60. Blinder D, Yahatom R, Taicher S. Oral manifestation of sarcoidosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83(4):458-61. 61. Hogan JJ. Sarcoid gingivitis. Br Dent J 1983;154(4):109-10. 62. Hayter JP, Robertson JM. Sarcoidosis presenting as gingivitis. Br Med J (Clin Res Ed) 1988;296(6635):1504. 63. Harty S, Fleming P, Rowland M, et al. A prospective study of the oral manifestations of Crohn’s disease. Clin Gastroenterol Hepatol 2005;3(9):886-91. 64. Scheper HJ, Brand HS. Oral aspects of Crohn’s disease. Int Dent J 2002;52(3):163-72. 65. Kalmar JR. Crohn’s disease: orofacial considerations and disease pathogenesis. Periodontol 2000 1994;6:101-15. 66. Desai P, Silver JG. Drug-induced gingival enlargements. J Can Dent Assoc 1998;64(4):263-8. 67. Uzel MI, Kantarci A, Hong HH, et al. Connective tissue growth factor in drug-induced gingival overgrowth. J Periodontol 2001;72(7):921-31. 68. Dongari A, McDonnell HT, Langlais RP. Drug-induced gingival overgrowth. Oral Surg Oral Med Oral Pathol 1993;74(4):543-8. 69. Barrett AP. Gingival lesions in leukemia: a classification. J Periodontol 1984;55(10):585-8. 70. Hou GL, Tsai CC. Primary gingival enlargement as a diagnostic indicator in acute myelomonocytic leukemia: a case report. J Periodontol 1988;59(12):852-5. 71. Appel BN, Miggantz RJ. Acute nonlymphocytic leukemia, monocytic variant: report of a case. J Periodontol 1988;59(7):464-8. 72. Kolokotronis A, Konstantinou N, Christakis I, et al. Localized Bcell non-Hodgkin’s lymphoma of oral cavity and maxillofacial region: a clinical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99(3):303-10. 73. Takahashi H, Tezuka F, Fujita S, Okabe H. Primary extranodal non-Hodgkin’s malignant lymphoma of the oral region: analysis of 11 autopsy cases. J Oral Pathol 1987;16(5):241-50. 74. Silverman S, Gorsky M, Lozada-Nur F, Liu A. Oral mucous membrane pemphigoid: a study of sixty-five patients. Oral Surg Oral Med Oral Pathol 1986;61(3):233-7. 75. Dayan, S, Simmons RK, Ahmed AR. Contemporary issues in the diagnosis of oral pemphigoid: a selective review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88(4):424-30.

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