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 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 sulfanilamide, 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.

View larger version (111K): [in this window] [in a new window]   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.

View larger version (60K): [in this window] [in a new window]   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.

View larger version (82K): [in this window] [in a new window]   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.

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.

View larger version (74K): [in this window] [in a new window]   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.

	LITERATURE REVIEW

TOP ABSTRACT CASE REPORTS LITERATURE REVIEW DISCUSSION CONCLUSION REFERENCES

 
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 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-) and interferon gamma is a component in the inflammatory process. Neutrophils also play an important role in the WG-related tissue injury. Inflammatory cytokines, such as TNF-, 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 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 drug-induced Wegener-like disease.^39–43 False negative c-ANCA 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 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. 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 Trimethoprim-sulfamethoxazole 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 anti-inflammatory drugs and penicillin, should be used with caution or be avoided.

	DISCUSSION

TOP ABSTRACT CASE REPORTS LITERATURE REVIEW DISCUSSION CONCLUSION REFERENCES

 
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 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 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 (hyper-plastic, 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, non-tender enlargement of the upper lip, but hyper-plastic 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 hyperplasia 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 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 non-tender 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

TOP ABSTRACT CASE REPORTS LITERATURE REVIEW DISCUSSION CONCLUSION REFERENCES

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