Lingual infarction in Wegener's Granulomatosis: A case report and review of the literature
© Carter and Brizman; licensee BioMed Central Ltd. 2008
Received: 29 May 2007
Accepted: 21 August 2008
Published: 21 August 2008
Wegener's granulomatosis (WG) is a multi-system disease, characterised by the triad of necrotising granulomata affecting the upper and lower respiratory tracts, disseminated vasculitis and glomerulonephritis. Oral lesions are associated with up to 50% of cases, although are rare as a presenting feature. The most common oral lesions associated with WG are ulceration and strawberry gingivitis. We review the literature regarding oral manifestations of WG and present a case of lingual infarction, an extremely rare oral lesion associated with WG, in a severe, rapidly progressive and ultimately fatal form of the disease.
Wegener's Granulomatosis (WG) is a multi-system disease, characterised by the triad of necrotising granulomata affecting the upper and lower respiratory tracts, disseminated vasculitis and glomerulonephritis. WG is included in the ANCA-associated small-vessel vasculitis group (including also microscopic polyangiitis, Churg-Strauss syndrome and renal-limited vasculitis). Oral lesions are associated with up to 50% of cases, although are rare as a presenting feature. The most common oral lesions associated with WG are ulceration and strawberry gingivitis. We present a case of lingual infarction, an extremely rare oral lesion associated with WG, in a severe, rapidly progressive and ultimately fatal form of the disease.
WG was first described by Freidrich Wegener in 1936 and 1939 [1, 2]. In 1954, Godman and Churg further delineated the clinical and pathological features by describing the classical triad of necrotising granulomata affecting the upper and lower respiratory tracts, disseminated vasculitis and glomerulonephritis . The aetiology of WG remains unknown.
In Europe the prevalence of WG is 5 cases per 100,000 population. The incidence is greater in Northern Europe. WG can occur in all racial groups, but predominantly affects Caucasians. Both sexes are affected equally. WG affects a wide age range (8–99 years) with a mean age at diagnosis of 40 years . Historically WG, if untreated, had a poor prognosis with a mean survival time of 5 months . In recent decades prognosis has improved with the introduction of immunosuppressive therapy using glucocorticosteroids and cyclophosphamide .
WG can be rapidly progressive or mild and indolent. Generalised symptoms such as fever, weight loss, fatigue and malaise may be present. Specifically, pulmonary manifestations such as cough, haemoptysis and pleuritis are the most common presenting symptoms. Renal disease can be the presenting feature in up to 18% of patients . Renal involvement is characterised by abnormal renal function with red cell casts in urinalysis, and glomerulonephritis on renal biopsy. Renal involvement and a late age at onset are associated with an increased risk of mortality . 80–90% of patients will have renal and/or pulmonary involvement at some time in their disease process.
WG can also affect the eyes, skin, joints, nervous system, ear, nose and throat . The most common anatomical site for presenting lesions of WG is the upper airway. Up to 30% of patients may present with nasal problems including nasal obstruction, ulceration, septal perforation, mucus discharge, or epistaxis .
Diagnosis of WG is based on a combination of clinical, histological, biochemical and immunological features. Inconsistency of histopathological findings can make diagnosis based on this method in isolation difficult. In 1985 diagnosis was aided by the description of anti-neutrophil cytoplasmic antibodies (ANCA) associated with WG . Two forms exist: cytoplasmic (cANCA) of which the principal target is protease-3 (PR3) and perinuclear (pANCA) which is directed against myeloperoxidase (MPO). These targets are antigens stored in the azurophilic granules of neutrophils and monocytes.
Lesions of the oral mucosa occur in 6–50% of patients with WG [11, 12]. Duna et al reported oral lesions in 6–13% of patients but as the presenting feature in only 2% . Oral and oropharyngeal ulcers resembling large aphthous ulcers are the most common oral lesion. Indeed at autopsy nearly all patients were reported to have oropharyngeal ulceration [1, 13]. Hyperplastic gingivitis, dark-red to purple in colour with a granular surface, resembling an over-ripe strawberry, either generalised or affecting a single dental papilla, can be considered specific to WG [14–21]. In fact, the combination of 'strawberry gingivitis' exhibiting pseudoepitheliomatous hyperplasia, microabscesses and multi-nucleate giant cells upon biopsy with severe systemic upset can be considered diagnostic for WG . Oro-antral fistulae , palatal osteonecrosis and labial mucosal nodules have also been reported . WG can also affect the salivary glands with reported cases affecting the parotid, submandibular and sublingual salivary glands [24–26].
Lingual necrosis is a rare oral manifestation with only two previously reported cases. Bachmeyer et al reported a case of necrotic lingual ulceration which resolved with immunosuppressive therapy . Rodgers et al reported a case of bilateral infarction of the tongue associated with a severe and rapidly progressive form of WG in 1992 . The patient died 39 days after onset of symptoms (18 days after presentation). At post mortem examination the anterior two thirds of the tongue were infarcted. Our case was also fatal, exhibiting a similar clinical course with a similar anatomical distribution of lingual infarction. WG affects the small arteries of the lung and kidney causing pulmonary and renal infarction [20, 27]. In our case the lingual arteries may have been similarly affected but unfortunately post mortem examination was not performed, therefore we cannot confirm that the lingual infarction was solely a result of lingual end-arteritis.
Lingual infarction can occur secondary to embolism, radiotherapy , tumour infiltration, radical neck dissection , transient ischaemic attack , and cardiac arrest . Lingual infarction has also been reported in cranial arteritis, giant cell arteritis [32–35], and microscopic polyangiitis (MPA) . WG and MPA share many similar clinical and histological features. Oral, upper airway, pulmonary and renal vasculitis are present in both conditions, however the vasculitis associated with WG is granulomatous whereas MPA exhibits non-granulomatous vasculitis .
Most patients with Wegener's granulomatosis exhibit cANCA with PR3 specificity and 25% exhibit pANCA with MPO specificity. In contrast microscopic polyangiitis exhibits cANCA with PR3 specificity in approximately 30% of patients and pANCA with MPO specificity in 60% of patients [36, 37]. A positive ANCA result suggests a systemic vasculitis but in the absence of a tissue biopsy, cANCA/pANCA distribution may suggest either WG or MPA but cannot definitively differentiate between the two diagnoses. In our case a tissue biopsy could not be performed safely due to persistent thrombocytopenia and a post mortem examination was not performed. Therefore the presence of granulomatous vasculitis was not confirmed histologically but the histological differential diagnosis can be complicated in that not all biopsy material associated with WG exhibits the classical pathological triad of granulomatous infiltration, necrosis and vasculitis . The clinical, biochemical and immunological features of our case were suggestive of a WG diagnosis.
Early diagnosis is important, expediting aggressive immunosuppressive therapy with glucocorticosteroids and cyclophosphamide, which can potentially limit a more severe systemic disease progression. Other treatment options include the use of trimethoprim and sulfamethoxazole either as a stand alone treatment or in combination with glucocorticosteroids and cyclophosphamide . More recent treatment options include Cyclosporin, intravenous pooled immunoglobulin, anti-CD20 monoclonal antibodies (Rituximab) and anti-tumour necrosis factor alpha with the latter two options restricted to refractory and relapsed disease [39, 40]. Regular review and maintenance therapy are also important to identify and prevent relapse. A multidisciplinary approach must be undertaken involving oral and maxillofacial surgeons, oral physicians, otorhinolaryngologists, rheumatologists, renal and respiratory physicians, ophthalmologists, and ITU supportive care if required. WG should be considered in the presence of oral lesions associated with a systemic illness. An oral biopsy and blood investigations assessing full blood count, renal and hepatic function, inflammatory markers and autoimmune status, specifically cANCA and pANCA, should be performed.
Oral lesions are associated with the onset of active systemic disease . Therefore isolated oral lesions may herald the onset of further systemic involvement. Mahr et al reported that oral, ear, nose or throat involvement was not associated with survival in their multivariate analysis. Mahr et al did indicate that granulomatous WG probably has a more benign course than vasculitic WG . Our case and the previously reported case of lingual infarction were associated with a severe, rapidly progressive and ultimately fatal form of WG. Thus lingual infarction as a result of vasculitis may indicate more aggressive disease. The severity of oral mucosal lesions, even in the absence of systemic signs, may therefore reflect or predict the severity of the generalised systemic disease and indicate a more aggressive vasculitis.
Written consent for publication of the clinical images could not be obtained because the patient died before written consent could be recorded.
The authors would like to thank Mr John L. Russell, Consultant Maxillofacial Surgeon, Leeds Dental Institute for allowing access to his patient for this case report and for advice in preparation of the manuscript.
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