Case 5 -

Microscopic Polyangiitis Presenting as Interstitial Fibrosis Secondary to Chronic Alveolar Hemorrhage Andrew Churg University of British Columbia Vancouver, BC, Canada

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Case History A 56 year old woman presented with shortness of breath which had been steadily increasing for the past 2 years. CT scan on admission showed irregular consolidation superimposed on ground glass opacities. In the past she had been admitted for what was thought to be pneumonia on several occasions and a CT scan 2 years before admission showed Abilateral airspace disease@. The patient had a history of chronic renal failure requiring dialysis, and a diagnosis of pauci-immune cresentic glomerulonephritis made 4 years before admission. A lung biopsy was performed. After the lung biopsy, serum ANCA was obtained; this was positive for p-ANCA (myeloperoxidase). Case 5 - Figure 1 - CT scan from current admission showing areas of consolidation on a background of ground glass infiltrates Case 5 - Figure 2 - Low power view of surgical lung biopsy. Note diffuse interstitial fibrosis and evidence of chronic hemorrhage. Case 5 - Figure 3 - Higher power view of surgical lung biopsy. Hemosiderin deposition is better seen. Case 5 - Figure 4 - Iron and calcium-encrusted elastica in a small pulmonary vessel. This finding is typical of chronic hemorrhage. Case 5 - Figure 5 - Higher power view of another vessel showing the encrusted elastica. Diagnosis Microscopic Polyangiitis Presenting as Interstitial Fibrosis Secondary to Chronic Alveolar Hemorrhage Discussion Microscopic polyangiitis is a form of pauci-immune, generally ANCA-positive, systemic vasculitis which is almost always associated with a necrotizing cresentic glomerulonephritis and frequently associated with pulmonary hemorrhage. Historical and modern vasculitis classification: Microscopic polyangiitis is unfamiliar to many pathologists and clinicians, and is frequently confused with polyarteritis nodosa. This confusion has a historic basis. Polyarteritis nodosa (originally named periarteritis nodosa) was first described in 1866 by Kussmaul and Maier (for a review of the historic development of vasculitis classification see reference 1). Polyarteritis nodosa affected medium sized elastic arteries, for example, renal arteries, and was frequently associated with the formation of visible aneurysms. For the better part of the next 100 years, most physicians labeled every case of vasculitis Apolyarteritis nodosa @, even though it became apparent early in the 20th Century that some forms of vasculitis affected much smaller vessels and were associated with both palpable purpura and glomerulonephritis, features not seen in the original description of polyarteritis nodosa. Davson and colleagues were probably the first to use the term Amicroscopic periarteritis @, intending this to describe a form of vasculitis affecting small vessels and different from classic polyarteritis nodosa. Subsequently Zeek and associates described what they labeled Ahypersensitivity vasculitis@, again an entity that affected small rather than medium sized vessels and was associated with glomerulonephritis and purpura. In 1954, Godman and Churg [2] suggested that Wegener=s granulomatosis, Churg-Strauss syndrome, and what they labeled the Amicroscopic form of periarteritis @ were related conditions, and that, although they might involve small arteries, they characteristically affected arterioles, capillaries, and venules, and had in many respects similar pathologic and clinical features. In 1994 an international consensus conference [3] proposed that the microscopic form of polyarteritis (periarteritis) nodosa be termed Amicroscopic polyangiitis@ to reflect the fact that more than just arterial branches were involved. The modern view is that Wegener=s granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis are forms of Asmall vessel vasculitis @ (ie, they characteristically affect vessels distal to small arteries) and that these three conditions are linked because all are typically pauci-immune; that is, they do not show deposition of immune complexes by immunofluorescence examination of tissue, and all are typically ANCA positive. The type of ANCA varies from disease to disease: Wegeners= granulomatosis is usually associated cANCA (proteinase 3), Churg-Strauss syndrome with pANCA (myeloperoxidase), and microscopic polyangiitis with either [1]. Pathologic Features of Microscopic Polyangiitis: The basic lesion of microscopic polyangiitis is a segmental necrotizing vasculitis that may affect any organ in the body. In the skin involvement of venules leads to leukocytoclastic vasculitis and palpable purpura. Glomerulonephritis, typically necrotizing and cresentic, is seen in 90% of patients, although necrosis of interlobular and arcuate renal arteries may also be present [1]. Renal failure is a common outcome. Other frequent sites of involvement are nerve, skeletal muscle, heart, liver, and gastrointestinal tract. When small arteries are involved, they frequently show fibrinoid necrosis and an infiltrate of neutrophils as the earliest lesions; over time infiltrate becomes chronic and the vessel wall fibrotic; lumenal thromboses are common. The lung is involved in approximately 50% of cases of microscopic polyangiitis and and this involvement is usually in the form of capillaritis with hemorrhage, although necrotizing vasculitis may sometimes be seen in larger intrapulmonary vessels as well. Microscopic polyangiitis is in fact the most common cause of the pulmonary renal syndrome (glomerulonephritis with pulmonary hemorrhage); in the series of 88 patients with pulmonary renal syndrome reported by Niles et al [4], 45% had microscopic polyangiitis and 9% had Wegener =s granulomatosis. Although most cases of microscopic polyangiitis appear as relatively acute disease, in some instances the course is much more indolent [5] and patients may report months to years of arthalgias or small hemoptyses and little else in the way of signs or symptoms [5, 6] . As in the present case, such patients sometimes develop interstitial pulmonary fibrosis secondary to chronic hemorrhage [7, 8, 9, 10, 11] . By CT scan some patients have a picture identical to that seen in UIP. Pathologic descriptions in the literature are few, but some cases have been described as showing vasculitis as well as fibrosis. In the present case, in addition to interstitial fibrosis and hemosiderin, free the interstitium or in macrophages, encrustation of the elastica of small vessels by iron and calcium is seen and is a helpful guide to the presence of chronic hemorrhage. By themselves these morphologic features are not specific and can be seen in chronic hemorrhage of any cause, nor is there evidence of actual vasculitis in this biopsy, but the presence of cresentic glomerulonephritis and positive ANCA indicate that in this instance the underlying disease is microscopic polyangiitis. Differential Diagnosis in the Lung: Microscopic polyangiitis is, by definition, an exclusionary diagnosis. Table 1 shows the morphologic/laboratory separation of different types of pulmonary vasculitis. Microscopic polyangiitis does not show the granulomatous necrosis of Wegener=s granulomatosis, nor does it have the eosinophilic infiltrates and history of asthma seen syndrome. Immune complex mediated vasculitis may be morphologically identical to microscopic polyangiitis in the lung but will have circulating or deposited immune complexes. It should be noted that Wegener=s granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis can appear identical if only capillaritis with hemorrhage is present. Treatment and Prognosis: Patients with microscopic polyangiitis are treated with steroids and, at least initially, cyclophosphamide, although there is a tendency to substitute less toxic immunosuppressive agents such as azathioprine once remission is achieved. Despite treatment, relapses are extremely common. In the series of 85 patients reported by Guillevin et al [5], the overall 5 year survival was 74%. Clinically apparent alveolar hemorrhage in microscopic polyangiitis is a particularly ominous sign and is associated with a significant mortality; Lauque et al [12] reported that 31% of such patients died with a mean followup of 6 months. Treatment is with high dose steroids and immunosuppressive agents, but repeated episodes of hemorrhage are frequent. Table 1: Separation of Pulmonary Vasculitis ** Disease ANCA Immune Complexes anti-GBM Morphology/other features Wegener=s + - - Neutrophils, necrotizing granulomas with basophilic centers Churg-Strauss + - - Asthma, eosinophilic infiltrates, granulomas with eosinophilic centers Microscopic polyangiitis eosinophils + - - No granulomas, no Collagen vascular disease * + - Granular deposits of Ig Henoch-Schoenlein purpura - IgA - Granular deposits of Ig Cryoglobulinemic vasculitis - + - Circulating cryoglobulins Goodpasture=s syndrome - + + Linear deposits of Ig Drug-induced vasculitis + + - Can be ANCA or immunecomplex positive/drug history * Patients with collagen vascular diseases may have positive pANCA fluorescence, but by ELISA these are atypical ANCA; ie, not directed against myeloperoxidase or proteinase 3 ** Adopted from reference 13 References Jennette JC, Thomas DB, Falk RJ. Microscopic polyangiitis (microscopic polyarteritis). Semin Diag Pathol 2001; 18: 3-13. Godman GC, Churg J. Wegener's granulomatosis: pathology and review of the literature. AMA Arch Pathol 1954; 58: 533-553. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, Hagen EC, Hoffman GS, Hunder GG, Kallenberg CG, McClusky RT, Sinico RA, Ress AJ, van Es, LA, Waldherr R, Wiik A: Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37:187-192. Niles JL, Bottinger EP, Saurina GR, Kelly KJ, Pan G, Collins AB, McCluskey RT. The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition. Arch Intern Med 1996;156: 440-445. Guillevin L, Durand-Gasselin B, Cevallos R, Gayraud M, Lhote F, Callard P, Amouroux J, Casassus P, Jarrousse B. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999; 42: 421-430. Savage CO, Winearls CG, Evans DJ, Rees AJ, Lockwood CM. Microscopic polyarteritis: presentation, pathology and prognosis. Q J Med 1985; 56: 467-483. Eschun GM, Mink SN, Sharma S. Pulmonary interstitial fibrosis as a presenting manifestation in perinuclear antineutrophilic cytoplasmic antibody microscopic polyangiitis. Chest 2003; 123: 297-301. Burns A. Pulmonary vasculitis. Thorax. 1998; 53: 220-227. Gaudin PB, Askin FB, Falk RJ, Jennette JC. The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic autoantibodies specific for anti-proteinase 3 and anti-myeloperoxidase. Am J Clin Pathol 1995; 104: 7-16. Homma S, Matsushita H, Nakata K. Pulmonary fibrosis in myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitides. Respirology 2004; 9:190-196. Nada AK, Torres VE, Ryu JH, Lie JT, Holley KE. Pulmonary fibrosis as an unusual clinical manifestation of a pulmonary-renal vasculitis in elderly patients. Mayo Clin Proc 1990; 65: 847-856. Lauque D, Cadranel J, Lazor R, Pourrat J, Ronco P, Guillevin L, Cordier JF. Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature. Medicine (Baltimore) 2000;79 : 222-233. Churg A: Churg-Strauss syndrome, microscopic polyangiitis, and other forms of pulmonary vasculitis. In, Churg A, Myers J, Tazelaar H, Wright JL, editors: Thurlbeck=s Pathology of the Lung, 3rd Edition. New York, Thieme Medical Publishers, 2005, pages 391-412.