Wegener's Granulomatosis Associated with Diffuse Pulmonary Hemorrhage

The authors report a case of Wegner's granulomatosis with the unusual manifestation of diffuse pulmonary hemorrhage. A 58-year-old man complained of bloody sputum and fever. Chest X-ray films showed multiple nodular shadows in both lung fields. He was diagnosed as having Wegener's granulomatosis by transbronchial lung biopsy, which revealed necrotizing granulomatous inflammation with necrotizing vasculitis. Despite treatment with cyclo-phosphamide and prednisolone, his condition rapidly deteriorated. An extensive diffuse alveolar shadow appeared in both lung fields in chest X-ray films, anemia became worse, and he died of respiratory failure. Autopsy revealed diffuse alveolar hemorrhage with necrotizing capillaritis in addition to the typical pathological findings in Wegener's granulomatosis. The capillaritis was characterized by neutrophilic infiltration of alveolar septa, and fibrin thrombi in alveolar capillaries. Diffuse pulmonary hemorrhage is uncommon in Wegener's granulomatosis. However, once diffuse pulmonary hemorrhage occurs, the respiratory condition rapidly deteriorates and is life-threatening. Therefore, accurate diagnosis and appropriate treatment are required. Acta Pathol Jpn 42: 657–661, 1992.     

Primary choriocarcinoma of the lung manifesting as diffuse alveolar hemorrhage

An autopsy case of primary pulmonary choriocarcinoma that manifested as diffuse alveolar hemorrhage is reported. A 44-year-old nurse presented with fever, dry cough, hemoptysis, and progressive dyspnea, and died after a downhill course of 2 weeks. Chest radiographs showed diffuse parenchymal shadows throughout the entire lung and a nodular lesion in the right lower lobe. Findings suggestive of acute renal failure were not seen. The autopsy revealed primary pure choriocarcinoma of the right lower lobe and diffuse alveolar hemorrhage throughout the entire lung. Findings of small vessel vasculitis ("pulmonary alveolar capillaritis") were not observed, and extensive neoplastic involvement of the pulmonary vasculature was considered the cause of the diffuse alveolar hemorrhage. Small metastatic foci were found in the liver, adrenal glands, pancreas, and ovaries. This case shows that primary pulmonary neoplasms, on rare occasions, can produce the clinical and pathologic features of diffuse alveolar hemorrhage, probably through elevated pulmonary venous pressure caused by extensive destruction of the vasculature.     

Surgical pathology of the lung in anti-basement membrane antibody-associated Goodpasture's syndrome

We report the findings of lung biopsies from five patients with anti-basement membrane antibody-associated Goodpasture's syndrome (ABMA-GS). In four patients, pulmonary capillaritis with hemorrhage was found on lung biopsy, confirming that pulmonary capillaritis can be found in ABMA-GS. Although alveolar hemorrhage was the dominant pathologic finding in four of our five patients, all five patients had evidence of injury at the level of the alveolar wall, manifested by hyaline membranes and widening of alveolar walls by edematous connective tissue. In one of our patients, alveolar hemorrhage was only focal, and diffuse alveolar damage was the dominant pathologic finding. This pattern of lung disease has not been previously described in ABMA-GS.     

Severe granulomatous giant cell myocarditis in Wegener's granulomatosis

Summary A 28-year-old male patient suffering from Wegener's granulomatosis died suddenly with signs of cardiac failure after clinical symptoms had basically subsided under chemotherapy. Autopsy revealed pulmonary granulomata, necrotizing vasculitis of the lungs and kidneys, focal and segmental necrotizing glomerulonephritis, and diffuse granulomatous and necrotizing giant cell myocarditis.Histological confirmation of inflammation of the heart in Wegener's disease has rarely been reported. Although cardiac involvement in Wegener's granulomatosis sometimes is suspected, it is usually thought to have no major impact on the course of the disease.By its dramatic clinical and morphologic presentation this case illustrates that the heart, in addition to the lungs and kidneys, may determine the outcome of the idiopathic granulomatous vasculitis of Wegener.     

Microscopic polyangiitis (microscopic polyarteritis)

Microscopic polyangiitis ("microscopic polyarteritis") is a form of necrotizing small vessel vasculitis that most often affects venules, capillaries, arterioles, and small arteries, although it occasionally involves medium-sized arteries. Microscopic polyangiitis is a more appropriate name than microscopic polyarteritis because some patients have no evidence for arterial involvement. The absence or paucity of immunoglobulin localization in vessel walls distinguishes microscopic polyangiitis from immune complex mediated small vessel vasculitis, such as Henoch-Schonlein purpura and cryoglobulinemic vasculitis. Clinical, epidemiological, and pathologic differences warrant the separation of microscopic polyangiitis from polyarteritis nodosa on the basis of involvement of capillaries and venules by the former but not the latter. Pauci-immune necrotizing and crescentic glomerulonephritis, and hemorrhagic pulmonary capillaritis are common in patients with microscopic polyangiitis. Microscopic polyangiitis is the most common cause for pulmonary-renal vasculitic syndrome. The vasculitis in patients with microscopic polyangiitis is pathologically indistinguishable from the vasculitis of Wegener's granulomatosis and Churg-Strauss syndrome. Granulomatous inflammation distinguishes Wegener's granulomatosis from microscopic polyangiitis. Asthma and eosinophilia distinguish Churg-Strauss syndrome from microscopic polyangiitis. Microscopic polyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome are all associated with circulating antineutrophil cytoplasmic autoantibodies.     

Pathology of pulmonary changes in Wegener's granulomatosis, rheumatoid arthritis and polyarteritis nodosa (author's transl)]

Histology of the pulmonary alterations which may occur in Wegener's granulomatosis, rheumatoid arthritis and polyarteritis nodosa is enumerated. 30 own cases with pulmonary lesions are presented. The difficulties of differential diagnosis in lung biopsies are discussed. Both Wegener's granulomatosis and rheumatoid arthritis may terminate in a generalized necrotizing arteritis which cannot be distinguished from polyarteritis nodosa. This as well as various other similarities indicate that these three different disease entities base on an identical hyperergic reaction of the vascular wall. Only the so-called limited type of Wegener's granulomatosis has a relatively favourable prognosis.     

Cardiac involvement in Wegener granulomatosis diagnosed at autopsy

Wegener granulomatosis (WG) is a systemic vasculitis classically involving the lungs, kidneys, and upper respiratory tract. Involvement of other sites does occur but is less frequent. Clinically evident cardiac involvement is uncommon. There are only a few cases in the literature with documentation of the histologic appearance of cardiac involvement in WG. We report a case of a previously healthy 37-year-old man who presented with a one-week history of cough and weakness and a one-day history of shortness of breath. At presentation, he was hypoxic and required intubation. Upon hospitalization, he deteriorated rapidly, became bradycardic and expired the same night. Infection was suspected clinically as the cause of illness and death. At autopsy, the lungs showed diffuse alveolar hemorrhage with capillaritis, diffuse alveolar damage, and parenchymal necrosis with necrotizing granulomas. The heart was enlarged and showed a mixed inflammatory infiltrate composed of neutrophils, eosinophils, and histiocytes, with focal myocyte necrosis. Granulomas, giant cells, and vasculitis were absent. The esophagus showed submucosal vasculitis. A diagnosis of WG was made. Postmortem serology for c-ANCA was positive, and all cultures were negative, confirming the diagnosis. Cardiac involvement is an underrecognized and potentially fatal complication of WG. The histologic findings in the heart may consist of a non-specific inflammatory infiltrate without granulomas or vasculitis, raising a wide differential diagnosis.     

Antineutrophil cytoplasmic autoantibody in the absence of Wegener's granulomatosis or microscopic polyangiitis: implications for the surgical pathologist.

Antineutrophil cytoplasmic antibodies (ANCA) are useful serologic markers for the diagnosis and management of patients with Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). However, problems in diagnosis and classification may occur when patients with other disorders develop ANCA. A 7-year review (1993-1999) disclosed 247 patients whose sera tested positively for ANCA by an indirect immunofluorescence method: 166 patients for cytoplasmic-ANCA (C-ANCA) and 81 patients for perinuclear-ANCA (P-ANCA) Twenty-seven patients had active pulmonary disease and underwent open-lung biopsy or transbronchial biopsy. Eight patients (30%) had a disease other than WG or MPA, and their clinical, pathological, and serological findings were reviewed. The patients, all women, ranged in age from 28 to 77 years (median, 37 y). Dyspnea (n = 6), cough (n = 6), chest pain (n = 2), and/or hemoptysis (n = 2) were present. The duration of symptoms lasted from 3 weeks to 6 years (median, 6 mo). ANCA titers were C-ANCA (n = 4; range, 1:40-1280) or P-ANCA (n = 4; range, 1:40-640). The lung biopsies disclosed nonspecific interstitial pneumonia (n = 4), bronchiolitis obliterans organizing pneumonia (n = 1), diffuse alveolar damage (n = 1), organizing diffuse alveolar hemorrhage without capillaritis (n = 1), and necrotic granuloma (n = 1). No cases showed characteristic histology for WG or MPA. The final diagnoses were various connective tissue disorders (n = 5), chronic hypersensitivity pneumonia (n = 1), postinfectious bronchitis/bronchiectasis (n = 1), and ulcerative colitis-related lung disease (n = 1). Surgical pathologists should be aware that significantly elevated ANCA titers may be associated with diverse forms of pulmonary disease. ANCA positivity alone, in the absence of appropriate clinical or pathologic findings, should not be used to substantiate a diagnosis of WG or MPA.     

Collagen diseases with pulmonary involvement]

Pulmonary involvement is a common feature in patients with various collagen diseases. Some types of the pulmonary involvement are resistant to currently available treatment regimens and thus considered as intractable conditions. These include acute/subacute interstitial pneumonia in dermatomyositis, pulmonary interstitial fibrosis in scleroderma, and diffuse alveolar hemorrhage. Acute/subacute interstitial pneumonia with the histology of diffuse alveolar damage (DAD) is mainly occurred in patients with amyopathic or hypomyopathic dermatomyositis who lack autoantibodies to aminoacyl tRNA synthetases. Intensive immunosuppressive treatment in the early phase of the disease may be effective for this intractable complication. Nearly one-third of patients with scleroderma have slowly progressive pulmonary interstitial fibrosis, leading to end-stage respiratory failure. Non-specific interstitial pneumonia (NSIP) with an excessive fibrotic change is a major histology of these patients. There are accumulating evidences showing the effectiveness of cyclophosphamide in patients with this intractable condition, especially those with active alveolitis. Diffuse alveolar hemorrhage is a fatal complication mainly occurred in patients with systemic lupus erythematosus and those with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, including microscopic polyangitis (MPA) and Wegener's granulomatosus. Immediate diagnosis and introduction of intensive treatment are necessary to save the patients with this complication.     

Pulmonary capillaritis and hemorrhage in patients with systemic vasculitis

Thirteen patients with prominent pulmonary signs and symptoms had pulmonary capillaritis and extensive hemorrhage demonstrated by open-lung biopsy or autopsy. Vasculitis was demonstrated in other organs before or after the lung biopsy or at autopsy. Although there were several suspected causes for the pulmonary capillaritis and different final clinicopathologic diagnoses, the histopathologic features in the lung were similar in all cases and distinctive enough to separate capillaritis from other causes of hemorrhagic lung. All patients were treated with prednisone or cyclophosphamide, or both. Six patients died of their vasculitis, five in respiratory failure and one in renal failure. None of the seven survivors had a clinical recrudescence of pulmonary hemorrhage. By extrapolation from these 13 cases, one may histopathologically recognize pulmonary capillaritis when it causes hemorrhagic lung in a patient without clinically evident extrapulmonary vasculitis. One can then proceed to investigate the patient and possibly determine the nature of the vasculitis.     

Pulmonary angiitis and granulomatosis revisited

Re-examination of the pathologic and clinical features of the entities traditionally classified under the heading "pulmonary angiitis and granulomatosis" indicates that there is little advantage in retaining this artificial category and that these entities should be considered variants of diseases to which they are actually related. Wegener's granulomatosis and allergic angiitis and granulomatosis appear to be examples of true systemic vasculitides in which the lung is a predominant but not the only or even the most important site of involvement. Wegener's granulomatosis may manifest with involvement limited to lung, a form that has been called limited Wegener's; however, many or most such cases progress to classic disease involving kidney and often upper respiratory tract. Similarly, Wegener's granulomatosis may present with disease limited initially to the upper respiratory tract (a form of midline granuloma); this process may also spread to involve lung and kidney. It seems unlikely that limited Wegener's is truly a separate disease category. Evaluation of the pathologic and clinical features of necrotizing sarcoid granulomatosis indicate that it very much resembles ordinary sarcoid in most histologic features, in the nature of extrapulmonary involvement, and in its clinical course and that it probably corresponds to the clinical--radiographic entity of nodular sarcoid. Lymphomatoid granulomatosis appears to have little relationship to the other members of the angiitis and granulomatosis group; its behavior and histologic features are those of a lymphoproliferative disorder that in most cases is or becomes histiocytic lymphoma. Some cases of so-called benign lymphocytic angiitis also fall into this category; the remainder appear to represent a variety of completely unrelated pathologic processes. Last, bronchocentric granulomatosis is most commonly one of the histologic manifestations of allergic bronchopulmonary aspergillosis, although it is likely that other agents or processes produce the same histologic pattern. Although the presence of a common set of pathologic features makes the concept of angiitis and granulomatosis attractive from a morphologic point of view, there is minimal clinical similarity among them, and these diseases appear to be totally separate entities.     

Wegener's granulomatosis: classification and therapy

Wegener's granulomatosis in its classic form is manifested by necrotizing granulomas of the upper and lower respiratory tract, focal necrotizing vasculitis involving both arteries and veins which may be widely disseminated, and focal necrotizing glomerulitis. The disease may present with incomplete expression involving any combination of the major sites, including the upper respiratory tract (E), the lung (L), or the kidney (K). A newly emerging test for the disease called antineutrophil cytoplasmic antibody (ANCA) shows promise in studying the disease in its various expressions. Standard current treatment includes glucocorticoids and cyclophosphamide. Recently, favorable reports of improvement on trimethoprim/sulfamethoxazole combination have appeared, suggesting the possibility that the disease may be incited by a microbial infection.     

Immunopathological studies of an autopsy case with Goodpasture's syndrome and systemic necrotizing angiitis

A rare autopsy case of Goodpasture's syndrome with systemic necrotizing angiitis is reported. The patient, a 56-year-old male, died of respiratory failure with massive pulmonary hemorrhage and renal failure. The autopsy showed widespread hemorrhage in both lungs, diffuse crescentic glomerulonephritis, and systemic necrotizing angiitis in the small arteries. Immunofluorescence studies demonstrated a linear deposition of IgG along the glomerular basement membrane (GBM) as well as the alveolar basement membrane. A granular deposition of C3 was also found along the GBM. Electron microscopy showed that the GBM was irregularly thickened and wrinkled, but electron-dense deposits were indistinct. Anti-GBM antibody activity was detected in the patient's serum and had cross reactivity with normal alveolar basement membrane. The renal eluates contained IgG antibody activity for normal human GBM. These results suggest that glomerulonephritis and pulmonary hemorrhage in the present case were mediated by anti-basement membrane antibodies. We also discussed whether anti-basement membrane antibody is involved in the pathogenesis of systemic necrotizing angiitis.     

A case of drug-induced pneumonitis due to amiodarone]

An 80-year-old man, who had been taking the antiarrhythmic drug amiodarone for chronic atrial fibrillation since October 2004, developed dyspnea and fever in June 2005, and was admitted to our hospital. Chest X-ray and CT scan showed ground-glass opacities in all lung fields. Arterial blood gas analysis revealed hypoxemia. These findings led to a diagnosis of acute respiratory distress syndrome. Oral amiodarone was discontinued, and steroid pulse therapy was started; however, the disease progressed rapidly, and the patient died on the fourth hospital day. Autopsy showed diffuse alveolar damage, accumulation of edema fluid in the alveolar spaces, and the presence of foamy macrophages, leading to a diagnosis of amiodarone-induced pulmonary damage.     

Autopsy case of microscopic polyangiitis with crescentic glomerulonephritis and necrotizing pancreatitis

Herein is reported the case of an 84-year-old woman who initially manifested rapidly progressive glomerulonephritis following a urinary tract infection. Laboratory findings showed a high titer of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA). Treatment with high-dose i.v. steroids resulted in clinical recovery and an undetectable MPO-ANCA titer. Two months later the patient was readmitted in a state of severe shock. Laboratory examination showed the deterioration of renal function, leukocytosis, and coagulation abnormalities consistent with disseminated intravascular coagulation (DIC). The patient died 12 days later. The post-mortem examination revealed necrotizing pancreatitis due to acute-stage vasculitis typified by fibrinoid necrosis of the arterioles and venules, and crescentic glomerulonephritis with healed-stage vasculitis. In the lungs, capillaritis with diffuse alveolar hemorrhage was not evident, but arteriolitis and phlebitis were occasionally seen. This case represents an unusual complication of necrotizing pancreatitis in the setting of microscopic polyangiitis. Thus, it is important to consider reactivation independent of the titer of ANCA in the course of the disease.     

Pulmonary capillaritis and glomerulonephritis in an antineutrophil cytoplasmic antibody-positive patient with prior granulomatous aortitis

A 59-year-old man showed asynchronous development of noninfectious granulomatous aortitis with aneurysm, followed 9 months later by pulmonary capillaritis and glomerulonephritis in association with elevated serum antineutrophil cytoplasmic antibody levels. To our knowledge, the combination of large artery vasculitis and small vessel systemic vasculitis (capillaritis) has not been previously reported. This case may represent a hybrid type of systemic vasculitis combining features of giant cell arteritis and Wegener's granulomatosis.     

Wegener's granulomatosis. Immunomicroscopic and ultrastructural study of four cases

Four cases of Wegener's granulomatosis involving lung are reported in which immunomicroscopy demonstrated that the parenchymal and vascular infiltrates were composed primarily of T cells and monocytes. No IgG, IgA, IgM, or C3 was identified in pulmonary vessels or alveolar septa. Ultrastructural studies failed to demonstrate dense deposits in alveolar septal capillaries or interstitium. These findings indicate that a cellular immune mechanism is active in these forms of pulmonary vasculitis and that immune complex deposition does not play a role.     

IMMUNOPATHOLOGICAL STUDIES OF AN AUTOPSY CASE WITH GOODPASTURE'S SYNDROME AND SYSTEMIC NECROTIZING ANGIITIS

A rare autopsy case of Goodpasture's syndrome with systemic necrotizing angiitis is reported. The patient, a 56-year-old male, died of respiratory failure with massive pulmonary hemorrhage and renal failure. The autopsy showed widespread hemorrhage In both lungs, diffuse crescentic glomerulonephrltis, and systemic necrotizing angiitis in the small arteries. Immunofluorescence studies demonstrated a linear deposition of IgG along the glomerular basement membrane (GBM) as well as the alveolar basement membrane. A granular deposition of C₃ was also found along the GBM. Electron microscopy showed that the GBM was Irregularly thickened and wrinkled, but electron-dense deposits were indistinct. Anti-GBM antibody activity was detected in the patient's serum and had cross reactivity with normal alveolar basement membrane. The renal eluates contained IgG antibody activity for normal human GBM. These results suggest that glomer-ulonephritis and pulmonary hemorrhage in the present case were mediated by anti-basement membrane antibodies. We also discussed whether antibasement membrane antibody is involved in the pathogenesis of systemic necrotizing angiitis.     

Reactivity of antineutrophil cytoplasmic autoantibodies with mononuclear phagocytes.

Antineutrophil cytoplasmic autoantibodies (ANCA) react with proteins found in the granules of neutrophils and the peroxidase-positive lysosomes of monocytes, including myeloperoxidase (MPO), proteinase 3 (PR-3), and elastase. ANCA-associated diseases, such as Wegener's granulomatosis and polyarteritis nodosa, are characterized by necrotizing vascular inflammation. The inflammatory lesions typically contain both neutrophils and mononuclear phagocytes, with the latter sometimes predominating, for example, in the granulomatous lesions of Wegener's granulomatosis. We investigated the presence of the ANCA target antigens PR3, MPO, and elastase in mononuclear phagocyte cytoplasm during the course of differentiation in vitro and in alveolar and peritoneal macrophages. We observed that ANCA antigens were down-regulated during mononuclear phagocyte differentiation, with the loss corresponding to that of peroxidase-positive granules. This suggests that ANCA can directly interact only with monocytes and early exudative macrophages and not with mature macrophages.     

The pulmonary biopsy in the early diagnosis of Wegener's (pathergic) granulomatosis: a study based on 35 open lung biopsies

We reviewed open lung biopsies from 35 patients with Wegener's (pathergic) granulomatosis in order to study the histogenesis of the pulmonary lesions and to identify the early lesions. The process of pathergic necrosis is fundamental in the production of extravascular and vascular lesions and was divided into micronecrotic and macronecrotic types. Micronecrosis, usually with neutrophils (microabscesses), constitutes the early phase in the development of the pathognomonic organized palisading granuloma. The palisading granuloma differs from the compact granuloma of tuberculoid type, which occurs in infections and sarcoidosis but not in Wegener's (pathergic) granulomatosis. There is a progression of disease from micronecrosis to macronecrosis (widespread necrosis) and then to fibrosis. Macronecrosis surrounded by palisading histiocytes or diffuse granulomatous tissue indicates active disease, whereas necrosis surrounded by fibrous tissue indicates previously active disease. Most cases have a combination of micronecrosis, and fibrosis. We established the relative diagnostic value of various histologic features. Arteritis and phlebitis as classically described in Wegener's granulomatosis were present in most but not all cases. We believe that Wegener's granulomatosis primarily affects both vascular and extravascular collagen and reticulum and that vasculitis represents a primary necrosis of walls of blood vessels. We believe that the concept of Wegener's granulomatosis as a vasculitis is too restrictive and does not include many cases with only extravascular histologic changes.