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0 1992 The Japanese Society of Pathology

Wegener's Granuloma tosis Associated with Diffuse Pulmonary Hemorrhage

Nobuyuki Yoshimum', Osamu Matsubam', Atsuhisa Tamura', Tsutomu Kasuga', and Eugene J. Mark2

The authors report a case of Wegner's granulomatosis with the unusual manifestation of diffuse pulmonary hemor- rhage. 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 dete- riorated. 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 capil- laritis in addition to the typical pathological findings in Wegener's granulomatosis. The capillaritis was character- ized by neutrophilic infiltration of alveolar septa, and fibrin thrombi in alveolar capillaries. Diffuse pulmonary hemor- rhage is uncommon in Wegener's granulomatosis. How- ever, once diffuse pulmonary hemorrhage occurs, the respi- ratory condition rapidly deteriorates and is life-threaten- ing. Therefore, accurate diagnosis and appropriate treat- ment are required. Acta Pathol Jpn 42 : 657-661, 1992.

Key words : Wegener's granulomatosis, Diffuse pulmonary hemorrhage (DP H), Pulmonary ca pilla rit is

The diffuse pulmonary hemorrhage syndrome corn- prises a group of heterogeneous disorders that are char- acterized by clinically hemoptysis, alveolar filling of the chest radiograph and anemia, and pathologically diffuse intra-alveolar hemorrhage (1 -3). This syndrome

Received March 23, 1992. Accepted for publication June 15, 1992. 'Department of Pathology, Faculty of Medicine, Tokyo Medi- cal and Dental University, Tokyo. 2Department of Pathol- ogy, Massachusetts General Hospital, Boston. Mailing address: Osamu Matsubara, M.D., Department of Pathology, Faculty of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan.

includes Goodpasture's syndrome, idiopathic pulmonary hemosiderosis and occasionally systemic lupus ery- thematosus (SLE). Wegener's granulomatosis, which may cause a pulmonary-renal syndrome usually as- sociated with a nodular lung pattern, is not considered to be a common cause of diffuse pulmonary hemorrhage. There have been few detailed pathologic descriptions of the lung in pulmonary diffuse hemorrhage secondary to Wegener's granuloma tosis (4-9), although microscopic evidence of hemorrhage is common in Wegener's granulomatosis(4). We report a case of Wegener's granulomatosis associated with the unusual manifesta- tion of massive alveolar hemorrhage.

CLINICAL SUMMARY

A 58-year-old Japanese man noted aural discharge, followed by difficulty of hearing in 1988, and intermittent productive cough in 1989. He complained pf low grade fever of about 10 days' duration in December 1989, and was admitted to a local hospital on December 22. High fever and dry cough was recorded on day 7 after admis- sion. Difficulty of hearing increased, accompanied by intermittent nasal bleeding. Chest X-ray films showed multiple nodular shadows in both lung fields. Despite treatment with antibiotics and antimycobacterial drugs, his condition rapidly deteriorated, and he started to cough up bloody sputum.

On February 14, 1990, he was transferred to our hospital. On admission, his temperature was 38.2'C, pulse 95/min, respiration P l lm in and blood pressure 90/78mmHg. No crepitations were heard over the lung field. The white blood cell count was 10,600/mm3 (St. 20%, Seg. 59%, Eos. 4%, Lym. 15%, Mon. 3%), CRP 5+, and blood sedimentation rate 54 mm/h. Sero- logical examinations revealed RA 2+, antinuclear anti- body x80, and anti-neutrophili cytoplasmic antibody (ANCA) x64 (moderately positive). The urine

658 Wegener's Granulomatosis with DPH (Yoshimura et a/.)

Figure 1. Transbronchial biopsy reveals granulomatous inflammation in the whole arterial wall. The lumen is occluded by granulomatous inflammatory tissue. a : HE, b : EvG.

contained occult blood. He was diagnosed as having Wegener's gra nulo matosis by t ra nsbronchia I lung bio p sy, which revealed necro t iz ing granuloma t o us inflammation with necrotizing vasculitis and palisading histiocytes (Figs. l a , b). Nasal biopsy also revealed necrotizing granulomatous inflammation. Treatment with 30 m g of prednisolone and 50 m g of cyclophos- phamide daily was started from February 22. He became afebrile and his hardness of hearing improved, but bloody sputum persisted and chest X-ray findings worsened. On February 26, a chest X-ray film showed a widespread interstitial infiltrative shadow over both lower lung fields, immediately followed on a subsequent chest X-ray film by an extensive alveolar shadow. He com- plained of severe dyspnea and arterial blood gas exami- nation showed PO, 2 6 mmHg. Despite pulse therapy with 1,000 mg of methylprednisolon and 75 m g of cyclo-

phosphamide daily, his condition deteriorated and he died due to respiratory failure on March 2.

PATHOLOGICAL FINDINGS

Autopsy was performed 2 h after death. The left lung weighed 1,050 g, and the right lung 900 g with fibrinous pleurisy and about 300 ml of bloody purulent effusion. Both lungs contained multiple yellowish white nodules, many with central necrosis, and showed massive hemor- rhage (Fig. 2). Some nodules were fused with each other irregularly to form miliary to lobular consolidations or wedge-shaped infarct-like masses, and formed central cavities (Fig. 3). Others were well circumscribed nod- ules, with a partly surrounding thin fibrous layer. His- tologically, these lesions were composed of necrotizing granulomatous inflammation characterized by irregularly

Figure 2. Cut sections of the right lung show- ing multiple yellowish white nodules with cav- ities, and diffuse hemorrhage. Most of 5-2 of the right upper lobe is occupied by lobular consolidation of granulomatous tissue. A wedge-shaped granulomatous lesion is seen in the right middle lobe.

Acta Pathologica Japonica 42 (9) : 1992 65 9

Figure 3. A nodular lesion with a central cavity in S-6 of the right lower lobe.

shaped zones of necrosis surrounded by lymphocytes, plasma cells and palisading histiocytes with multinuclear giant cells (Fig. 4). Medium-sized pulmonary muscular arteries and veins adjacent to the areas of necrotic foci showed necrotizing vasculitis characterized by palisad- ing histiocytes (Fig. 5), transmural inflammation, fibrinoid necrosis and destruction of elastic fibers of the media (Fig. 6).

In addition to granulomatous lesions, massive pulmo- nary hemorrhage was observed throughout almost the entire lung, and especially in both lower lobes (Fig. 2). Pulmonary alveolar hemorrhage was also observed in the

Figure 5. Granulomatous vasculitis. A lesion of palisading histiocytes is seen in the pulmonary artery. HE.

Figure 4. Macroscopic nodules and consolidation lesions com- posed of necrotizing granulomatous inflammation with infiltration of lymphocytes, plasma cells, histiocytes and multinuclear giant cells. HE.

peripheral regions of granulomatous lesions. Micro- scopic examination showed extensive intraalveolar h e morrhage and leukocytic infiltration into the alveolar wall. Fibrinoid destruction of the capillary wall within the alveolar septa and extravasation of neutrophils into adjacent air spaces were also seen (Fig. 7). Fibrin thrombi occluded capillaries of the interalveolar septa (Fig. 8). Hemosiderin was present within scattered alve olar and interstitial macrophages as well. Immunohisto- chemical staining for IgG, IgM, IgA and C3 of the ves- sels, including capillaries by the avidin-biotin complex method on paraffin sections of formalin fixed lung tissue,

Figure 6. Granulomatous vasculitis. The arterial wall shows partial necrosis with cellular infiltration and loss of elastic fibers. EvG.

660 Wegener's Granulomatosis with DPH (Yoshimura et a/.)

Figure 7 . Macroscopic diffuse hemorrhagic lesion with exten- sive intraalveolar hemorrhage and leukocytic infiltration to the alveolar wall. HE.

Figure 9. Necrotizing arteritis in the testis. Fibrinoid ne- crosis of the arterial wall with cellular infiltration. HE.

gave negative results. The upper and lower respiratory tract (paranasal

sinuses, nasopharynx and trachea) displayed marked ulceration and granulomatous inflammation. Systemic vasculitis involved the spleen, extracapsular fatty tissue of the kidney, gallbladder, urinary bladder, left temporal lobe of the cerebrum, testis (Fig. 9), stomach and small intestine. In the kidney, only a few glomeruli showed focal sclerosing or fibrinoid necrosis of capillary tufts. In organs other than the respiratory tract and lungs, granulomatous vasculitis involved relatively small ves- sels with or without fibrinoid necrosis.

Figure 8. High power view of a hemorrhagic lesion showing fibrinoid destruction of the capillary wall within the alveolar septa and extravasation of neutrophils into the adjacent air spaces. Fibrinous thrombi occlude capillaries of the inter- alveolar septa. HE.

DISCUSSION

A variety of diseases are involved in the differential diagnosis of diffuse pulmonary hemorrhage, many of which commonly including Goodpasture's syndrome, idiopathic pulmonary hemosiderosis, W egener's granulomatosis and SLE(1-3). As in most cases the diffuse pulmonary hemorrhage is life-threatening, careful examination of the lung biopsy material is necessary for accurate diagnosis. The presence of capillaritis is a useful histological criterion for distinguishing patients with Goodpasture's syndrome or idiopathic pulmonary hemosiderosis from those with underlying vasculitis (1). The coexistence with vasculitis and inflammatory granulomatous inflammation is usually a feature of Wegener's granulomatosis (4, 6, 7, 10). Immunohisto- chemical studies can also be helpful, since antiglomerular basement membrane antibody deposition is usually found in Goodpasture's syndrome and immune complex- es in some cases of SLE.

In Wegenet's granulomatosis, clinical and histological findings of diffuse pulmonary hemorrhage are rare, although microscopic evidence of intraalveolar hemor- rhage is common. Myers and Katzenstein(4) found evidence of capillaritis and intraalveolar bleeding in seven of 20 cases of Wegener's granulomatosis. How- ever in these cases, the changes were always focal and localized to the periphery of the necrotizing granulomas. Several cases of Wegener's granulomatosis related to diffuse pulmonary hemorrhage have been reported (7-9). Two of 13 cases (15%) of Wegener's granulomatosis reported by Brandwein et a/ . (9) showed diffuse pulmo-

Acta Pathologica Japonica 42 (9) : 1992 661

nary hemorrhage. Colby (7) speculated that the actual percentage of patients with Wegener's granulomatosis and diffuse pulmonary hemorrhage is probably about 5%.

Macroscopically, our case showed diffuse pulmonary hemorrhage throughout almost all the lung, especially both lower lobes. Microscopic examination showed extensive intraalveolar hemorrhage, leukocytes infiltra- tion to the alveolar septa and fibrinoid destruction of the capillary wall. In 1985, Mark and Ramirez (1) perform- ed detailed histopathological examinations of 13 cases of systemic vasculitis with pulmonary hemorrhage and capillaritis. The histopathological feature which they found in capillaritis were as follows; 1) fibrin thrombi occluding capillaries in interalveolar septa ; 2) fibrin clots attached to interalveolar septa in a sessile manner; 3) fibrinoid necrosis of capillary walls ; 4) neutrophils and nuclear dust in the fibrin, in the interstitinum, and in the immediately adjacent alveolar blood; and 5) inter- stitial red blood cells and interstitial hemosiderin. How- ever, all of the above mentioned feature were not obser- ved in all cases. In 1987, Myers and Katzeustein (4) studied a case of Wegener's granulomatosis with diffuse pulmonary hemorrhaga They emphasized that there was infiltration of necrotic neutrophils, e.g. pyknosis and karyorrhexis, in the alveolar septum in the specimen of open lung biopsy. However, this same finding could not be seen in autopsy. We could not find any necrotic neutrophils in the lesions of diffuse pulmonary hemor- rhage and thought that this finding may be related to the effect of treatment given prior to death.

Beside diffuse pulmonary hemorrhage, we observed localized alveolar hemorrhage around granulomatous lesions. This finding seems noteworthy in relation to the histogenesis of Wegener's granulomatosis. There are reports that vasculitis was begin as alveolar capillaritis, followed by involvement of both arteries and veins and parenchymal necrosis (2,6, 7). Moreover it is very interesting that organs that are rich in capillaries, such as the lung, kidney and nasal mucosa are the most common sites of Wegener's granulomatosis.

Diffuse pulmonary hemorrhage is not a common manifestation of Wegener's granulomatosis. However, once diffuse pulmonary hemorrhage occurs rapid, life- threatening deterioration of the respiratory condition occurs. There is difficulty in histopathologically identify-

ing pulmonary capillaritis because the anatomical struc- ture of lung is different from other organ(1). For this reason, the number of pulmonary capillaritis seems to be underestimated. Therefore, clinicians and pathologists should be aware that accurate diagnosis and appropriate treatment a re required.

Acknowledgements : We thank Ms. M. Onsen for skillful tech- nical assistance, and Ms. H. Mizuno for preparing this manu- script.

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