Practical Pulmonary Pathology 3rd ed. Kevin O. Leslie, MD

Chapter 11. Pulmonary Vasculitis and Pulmonary Hemorrhage

William David Travis, MD, Kevin O. Leslie, MD, and Mary Beth Beasley, MD

Pulmonary vasculitis

Overview of Pulmonary Vasculitis

Inflammation of arteries and veins can occur in many inflammatory lung diseases, including infections. By convention, the diagnostic term pulmonary vasculitis is restricted to a relatively limited number of diseases in which vascular inflammation is thought to be a major component of the pathologic process. Most pulmonary vasculitides are believed to be immune-mediated diseases, although their etiology and pathogenesis remain unknown. By best estimates, the overall annual incidence of the major forms of vasculitis is 39 per 1 million.¹

When pulmonary vasculitis occurs, there is inflammation of the vessel wall, often accompanied by fibrin and sometimes, necrosis. Cuffing of blood vessels by inflammatory cells, a nonspecific finding, must be distinguished from infiltration of inflammatory cells into the media and intima of arteries and veins (Fig. 11.1).

A diagnosis of pulmonary vasculitis carries a strong implication for immediate therapeutic intervention (typically immunosuppression) and There fore should never be made lightly. Furthermore, serologic and clinical correlation with the pathologic findings is essential for a correct diagnosis. Typical histologic examples of pulmonary vasculitis-capillaritis are shown in Fig. 11.2.

The general category of pulmonary vasculitis includes a number of different diseases that can be more easily understood by dividing them into three main groups: (1) idiopathic vasculitic syndromes that commonly involve the lung (e.g., granulomatosis with polyangiitis [GPA]/ Wegener granulomatosis), (2) vasculitic disorders that rarely involve the lung (a much larger number), and (3) miscellaneous conditions that produce pulmonary vascular inflammation (Box 11.1).²’³

GPA, eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome (CSS), and microscopic polyangiitis are the idiopathic vasculitis syndromes that commonly affect the lung. The conditions of bronchocentric granulomatosis and lymphomatoid granulomatosis traditionally have been grouped in the category of pulmonary angiitis and granulomatosis; however, neither of these entities is currently thought to be a vasculitic condition. Bronchocentric granulomatosis is a morphologic pattern of airway inflammation that occurs in a variety of conditions, especially infection, and lymphomatoid granulomatosis (also known as angiocentric immunoproliferative disorder) is now known to represent a lymphoproliferative disease in which prominent vascular involvement occurs.^4-6

Figure 11.1 Vascular inflammation versus vasculitis. (A) Vessel-associated inflammation. (B) True vasculitis. Note the disruption of the media by inflammatory cells in true vasculitis.

Figure 11.2 Common histopathologic manifestations of pulmonary vasculitis. Histopathologic appearance in three of the most common manifestations of pulmonary vasculitis: Granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA).

Idiopathic vasculitis syndromes that rarely affect the lung include such diseases as necrotizing sarcoid granulomatosis, Takayasu arteritis, giant cell arteritis, and Behçet syndrome, among others. Necrotizing sarcoid granulomatosis was formerly regarded as one of the major vasculitic syndromes, but it is very rare and does not typically cause a systemic vasculitis, so it is now grouped with the syndromes that uncommonly affect the lung. Pulmonary vascular inflammation also occurs in a number of miscellaneous systemic disorders, in diffuse pulmonary hemorrhage syndromes (discussed later), and in a variety of secondary or localized forms.

Vasculitic syndromes pose major challenges to the surgical pathologist. First, as with many nonneoplastic lung diseases, the diagnosis does not rest on pathology alone. Correlation among clinical, radiologic, and pathologic features is required for most of these entities. Second, because these are rare disorders, few pathologists have much experience with their diagnostic subtleties. Third, the pathologic features of these infrequently encountered conditions overlap with those of common inflammatory lesions, including necrotizing infectious granulomas produced by mycobacteria or fungi. Because most vasculitis syndromes are treated with immunosuppressive agents, separation from infectious conditions is essential. With the use of antineutrophilic cytoplasmic antibody (ANCA) testing, the diagnosis often is suspected early in the course of disease, so biopsies may be obtained before the tissues show all of the classic histologic manifestations. In addition, partial treatment before the biopsy can alter the expected histologic findings. Finally, in many cases, the histopathologic findings may not be classic, requiring the recognition of subtle clues to suspect the diagnosis.

Idiopathic Vasculitic Syndromes That Commonly Affect the Lung

The major vasculitides that commonly affect the lung primarily include those classified under the heading of ANCA-associated vasculitis as proposed in the 2012 International Chapel Hill Consensus Conference on the nomenclature of vasculitides.⁷ This classification adopted the nomenclature changes proposed by the American College of Rheumatology, the American Society of Nephrology, and the European League Against Rheumatism, in particular with regard to Wegener granulomatosis, which is now known as GPA. This same classification system recommends the terminology eosinophilic granulomatosis with polyangiitis for CSS.⁷

Granulomatosis With Polyangiitis (Wegener Granulomatosis)

GPA is a rare systemic inflammatory disease of unknown etiology that has vasculitis as a major histologic manifestation. GPA predominantly affects the upper and lower respiratory tract and the kidneys.⁷ Although this pattern of involvement is often referred to as the classic triad of GPA, more frequently only one or two sites may be involved. In one series reported by DeRemee and associates, involvement of all three sites was seen in only 14 of 50 patients.⁸ Limited GPA historically has been defined as disease involving the lungs without associated glomerular disease,⁹ although the term is also used to describe active disease without involvement that threatens the function of a vital organ or the patient’s life.¹⁰

Despite the designation granulomatosis, well-defined granulomas without necrosis (sarcoid-like) are not a feature of this disease. The necrotizing lesions of GPA have a peripheral zone of palisaded histiocytes, contrasting with the more epithelioid histiocytes seen at the periphery of necrosis produced by mycobacteria or fungi (Fig. 11.3). In fact, when well-formed (sarcoid-like) granulomas without necrosis are present in a potential case of GPA, another diagnosis should be considered (usually infection).

Figure 11.3 the granulomas of granulomatosis with polyangiitis (GPA). GPA granulomas (A) tend to be more palisaded than those seen in granulomatous infection (B). Also note the blue (basophilic) necrosis of GPA, compared with the pink (eosinophilic) necrosis of infection.

Clinical Features

GPA affects about 1 in every 3 million people in the United States¹¹ and 1 in 8.5 million people in the United Kingdom.¹² ttere is debate as to whether GPA occurs more frequently during cold seasons, with some studies suggesting an increased occurrence in winter months.¹² Other studies have disputed these results.¹¹ Although the etiology of GPA remains essentially unknown, several theories have been proposed. One theory is that an inciting inflammatory event invokes a specific immune response leading to the production of ANCAs (also discussed in the Laboratory Studies section), with ANCA playing a direct role in inciting tissue damage.^13,14 A potential link between infections and the development of GPA is being explored. It has been noted that a subtype of ANCA directed against lysosomal membrane-associated protein 2 (LAMP-2) is found in more than 90% of patients with pauci-immune necrotizing glomerulonephritis and frequently coexists with antiproteinase-3 and antimyeloperoxidase. LAMP-2 has been observed to activate neutrophils and cause injury to vascular endothelial cells in the absence of neutrophils. LAMP-2 cross-reacts with the bacterial adhesin FimH, and one study found that infection with bacteria expressing FimH occurred in 69% of patients in whom ANCA-positive glomerulonephritis subsequently developed.^15,16 Although such findings suggest a potential link between infection and the production of ANCA, further study is needed in regard to a link between infection and GPA. Similarly, other studies have demonstrated a link between T cells and the development of ANCA and have shown a particular role for T-helper 1 (Th1) lymphocytes, although the role of the Th1 lymphocytic pathway in the development of GPA is still being elucidated.¹⁷ Genetic factors, toxic exposures, and deficient proteinase-3 clearance are also being explored as potential causes and contributing factors.^11,18

GPA occurs at any age but typically is a disease of adults, with a mean age of 50 years.^18-20 A list of the clinical manifestations of GPA is presented in Table 11.1. Body sites most commonly affected are the head and neck region, followed by the lung, kidney, and eye.^19,21 Patients may experience a number of other complaints such as hoarseness, stridor, earache, hearing loss, otorrhea, cough, dyspnea, hemoptysis, or pleuritic pain. Pulmonary symptoms in the absence of upper respiratory tract manifestations are unusual. Destructive inflammation of the nose may result in a saddlenose deformity. In addition, patients may exhibit more generalized systemic signs and symptoms including arthralgias, fever, cutaneous lesions, weight loss, and peripheral neuropathy.²² Rarely GPA may involve the salivary glands, pancreas, breast, mediastinum, gastrointestinal tract, prostate and urethra, vagina and cervix, heart, spleen, or peripheral or central nervous system.^2,23-25

The most frequent abnormality on pulmonary function testing is airflow obstruction, often associated with a reduced diffusing capacity of the lung for carbon monoxide, but restrictive or mixed patterns can occur. When significant airflow obstruction is identified, patients may be at risk for tracheal obstruction or lobar collapse secondary to bronchial wall damage resulting from the disease.

Laboratory Studies

Nonspecific abnormalities on general laboratory tests are often present in patients with GPA. The most common of these include leukocytosis, thrombocytosis (>400,000 cells/ |L), marked elevation of the erythrocyte sedimentation rate, and normochromic normocytic anemia. The diagnosis of GPA has been dramatically aided by the discovery and use of serum _ANCA.^26-30

Two major immunofluorescence patterns occur as expressions of ANCA (Fig. 11.4): the cytoplasmic or classic type (c-ANCA) and the perinuclear type (p-ANCA).³¹ the c-ANCA pattern is associated with GPA and is present in the vast majority of patients with active generalized disease. Partial or complete remission of disease is reflected in a lower frequency of a positive test result, but 30% to 40% of patients in complete remission still have identifiable antibodies.³² the p-ANCA pattern can be seen in a small percentage of patients with GPA, but it is more characteristic of idiopathic necrotizing and crescentic glomerulonephritis, microscopic polyangiitis, polyarteritis nodosa, and EGPA.³³

The ANCA immunofluorescence patterns have been shown to correspond to specific antigen immunoreactivities; c-ANCA typically has specificity for proteinase-3 (PR3-ANCA), whereas most p-ANCAs have a specificity for myeloperoxidase (MPO-ANCA). Studies have shown no significant difference in the lung biopsy findings from GPA patients with c-ANCAs versus those with p-ANCAs.^34,35 Levels of c-ANCA in the bronchoalveolar lavage fluid have not been shown to be a more specific predictor of GPA or of the level of disease.³⁶ Importantly, the presence or absence of a positive serum test for c-ANCA alone is not sufficiently specific to make or exclude the diagnosis of GPA, and c-ANCA may occasionally be encountered in patients with other vasculitic syndromes or infection.³⁷

Table 11.1 Granulomatosis With Polyangiitis/Wegener Granulomatosis: Clinical Manifestations

Manifestation	Frequency (%)
	At Presentation	During Course of Disease
Head and neck manifestations	73	92
Sinusitis	51	85
Nasal disease	36	68
Otitis media	25	44
Hearing loss	14	42
Subglottic stenosis	8	16
Ear pain	1	14
Oral lesions	3	10
Pulmonary manifestations	45	85
Infiltrates	23	66
Nodule	22	59
Cough	19	46
Hemoptysis	12	30
Pleuritis	10	28
Renal manifestations	18	77
Eye manifestations	15	52
Conjunctivitis	5	18
Dacryocystitis	1	18
Scleritis	6	16
Proptosis	2	15
Eye pain	3	11
Visual loss	0	8
Retinal lesions	0	4
Corneal ulcers	0	1
Iritis	0	2
Systemic manifestations
Joints	32	67
Fever	23	50
Skin changes	13	46
Weight loss	15	35
Peripheral nervous system abnormalities	1	15
Central nervous system abnormalities	1	8
Pericarditis	2	6

Data from Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener's granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488-498.

Figure 11.4 Antineutrophilic cytoplasmic antibody (ANCA) immunofluorescence. Left, Cytoplasmic staining of neutrophils characterizes the c-ANCA pattern. Right, Perinuclear accentuation of staining is seen with the p-ANCA pattern. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.1.)

Figure 11.5 Granulomatosis with polyangiitis (GPA): radiographic features. Posteroanterior chest radiograph from a patient with GPA. Note the multifocal nodules, some of which appear cavitated. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.2.)

Figure 11.6 Granulomatosis with polyangiitis: computed tomography (CT) features. Chest CT scan (lung window) demonstrates multifocal, ill-defined small nodular opacities in close relationship to pulmonary arteries. Note the thick walls of these well-marginated lesions. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.3.)

Radiologic Features

Most patients with pulmonary disease have multiple opacities (Figs. 11.5 and 11.6) in the form of well-marginated nodules or masses of variable size (0.5 to 10 cm). Lesions may wax and wane over time. Most occur in the lower lobes.^38-40 Poorly defined or even spiculated nodules may also be seen.⁴¹ Cavitation of nodules occurs in 25% to 50% of cases, with cavity walls typically being thick and irregular. Such lesions may evolve into thin-walled cysts or disappear completely with therapy.^40,42 GPA is often included in the differential diagnosis for interstitial lung disease because multifocal, ill-defined parenchymal consolidations can occur (with or without cavitation) and diffuse reticular and nodular interstitial opacities have also been reported.^40,43

Patients with GPA may present initially with pulmonary hemorrhage. In this setting, diffuse infiltrates on chest radiographs and diffuse air space opacities on computed tomograms are observed (Fig. 11.6). In children, pulmonary hemorrhage is a common presentation of GPA, whereas pulmonary nodules occur less frequently in pediatric patients.²⁰

Pleural eflusion accompanies GPA in 20% to 50% of cases, sometimes with focal pleural thickening. Hilar or mediastinal lymphadenopathy is an unusual finding in GPA and, when significant, should raise concern for an alternate diagnosis. On rare occasions, GPA occurs as a solitary pulmonary nodule (with or without cavitation), or as an isolated area of consolidation.⁴⁴

Computed tomography (CT) provides optimal visualization of the number, location, and morphologic characteristics of the pulmonary abnormalities in GPA. Well-marginated nodules and masses, sometimes with spiculated borders, are typical findings. A feeding vessel is seen in 88% of nodules (Fig. 11.6), consistent with the angiocentric nature of this disorder.⁴⁵ Cavitation is identified in 50% of cases. Another very common finding in GPA is wedge-shaped peripheral opacities mimicking the CT appearance of infarct. Other, less common radiologic presentations include air bronchograms and the CT halo sign (ground-glass opacity surrounding a pulmonary nodule or mass).^45,46 Stenosis of the trachea or large airways may occur in short or long segments and may be complicated by partial or complete lobar collapse.^43,47,48

Pathologic Features

GPA is characterized by the presence of multiple bilateral pulmonary nodules, often with cavitation⁴⁹ (Fig. 11.7; see also Fig. 11.6). Solid nodular zones of consolidation with areas of punctate or geographic necrosis are typical findings (Figs. 11.8 and 11.9). GPA can rarely present with a solitary lung lesion, but solitary granulomatous disease is more likely to be of infectious origin.⁵⁰ When dealing with a solitary granulomatous lung nodule, a combination of both the classical histology and typical clinical or serologic findings of GPA should be present before making a diagnosis.⁴⁴ Even when special stains for organisms and cultures are negative, most of these solitary lesions represent old fungal or mycobacterial infection. Rarely the lesions of GPA may predominantly involve bronchi. When acute lung hemorrhage is prominent, the cut surface of the lung is bloody and dark red.

At scanning magnification, the pulmonary lesions of GPA simulate their radiologic appearance (Fig. 11.8). The classic findings consist of nodular areas of consolidation with variable zones of necrosis. Major diagnostic criteria, presented in Box 11.2, include parenchymal necrosis (Fig. 11.9), vasculitis (Fig. 11.10), and granulomatous inflammation (Fig. 11.11). Another important feature is a mixed inflammatory infiltrate composed of neutrophils, lymphocytes, plasma cells, macrophages, giant cells, and eosinophils (Fig. 11.12). Parenchymal necrosis can take the form of neutrophilic microabscesses (Fig. 11.13) or large zones of geographic necrosis (Fig. 11.9). The neutrophilic micro abscesses are nearly pathognomonic of the disease and can be found within the mixed inflammatory infiltrate or within fibrous connective tissue including the adventitial collagen of larger arteries and veins and the pleura. Early microabscesses may consist of a small collection of neutrophils surrounding a focus of degenerated, often hypereosinophilic, collagen.⁴⁹

Figure 11.7 Granulomatosis with polyangiitis: gross specimen. (A) This necrotizing granuloma is cavitated with a necrotic center and an inflammatory border. (B) Multiple scattered nodular foci of consolidation are present. Yellow-white areas represent necrosis. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.5.)

Figure 11.8 Granulomatosis with polyangiitis: nodular lesions. A characteristic nodular lesion seen at scanning magnification shows the thick inflammatory wall surrounding irregular zones of basophilic necrosis. Note the airways and arteries visible within the lesion.

Figure 11.9 Granulomatosis with polyangiitis: geographic necrosis. The basophilic necrosis can be appreciated at scanning magnification.

Figure 11.10 Granulomatosis with polyangiitis (GPA): vasculitis. The vasculitis of GPA is characterized by necrotizing granulomas involving adventitia and media. This narrowed vessel shows palisaded granulomas with basophilic necrosis accompanied by inflammation and fibrosis of the adventitia.

Figure 11.11 Granulomatosis with polyangiitis (GPA): granulomatous inflammation. (A) the granulomatous inflammation of GPA generally has a palisaded configuration. (B) A closer view of palisaded histiocytes can be seen bordering basophilic necrosis with nuclear debris.

Figure 11.12 Granulomatosis with polyangiitis (GPA): associated inflammation. Inflammatory infiltrate of GPA is generally mixed with plasma cells, lymphocytes (A), and a variable number of eosinophils (B).

Figure 11.13 Granulomatosis with polyangiitis (GPA): collagen necrosis. Collagen necrosis is thought to be the primary pathologic event in GPA. Zones of collagen necrosis can be vague (A) or discrete and associated with giant cells and granulomatosis inflammation (B).

Figure 11.14 Granulomatosis with polyangiitis (GPA): basophilic necrosis. (A) the necrosis of GPA is basophilic owing to an abundance of nuclear debris. (B) In necrotizing granulomatous infection, the necrosis typically has an eosinophilic appearance with some preservation of structure in areas of necrosis (this background structure visible within necrosis often is absent in GPA).

As illustrated in Fig. 11.9, the classic geographic necrosis of GPA is typically basophilic, owing to the presence of numerous necrotic neutrophils. The necrotic centers of GPA lesions often lack the ghosted image of lung structure, a diagnostic clue useful in the case with atypical features (Fig. 11.14). This likely occurs because the necrotic zones of GPA generally are not the result of infarct-like zonal parenchymal necrosis but rather occur by progressive expansion of collagen necrosis.

The granulomatous inflammation of GPA typically includes giant cells scattered randomly or in loose aggregates. Also commonly observed are palisaded histiocytes (Fig. 11.15), giant cells lining the border of geographic necrosis or microabscesses, and microgranulomas consisting of small foci of palisaded histiocytes arranged in a cartwheel pattern around a central nidus of necrosis (Fig. 11.16).⁴⁹ the presence of tightly cohesive, sarcoid-like granulomas is very rare in GPA and suggests infection or necrotizing sarcoid. Also, the presence of granulomas without associated necrosis favors an infectious etiology over GPA.^2,23,49

The vasculitis of GPA typically affects small arteries and veins up to 5 mm in diameter. When vasculitis is seen in the surgical biopsy, it most often occurs within the dense inflammatory infiltrate surrounding nodular or geographic areas of necrosis (Fig. 11.17). Vasculitis in GPA may comprise a variety of inflammatory cells including acute or chronic mural inflammation, necrotizing stellate granulomas, nonnecrotizing stellate granulomas, and giant cells.⁴⁹ Cicatricial changes consisting of mural fibrosis or luminal obliteration may be seen in specimens following therapy. Destruction of the vascular elastic laminae is commonly observed (Fig. 11.18). Sometimes the inflammation is limited to the endothelium (endothelialitis) and subendothelial aspect of the vessel wall. Despite these potential vascular changes, if necrotizing vasculitis is held as a requirement for the diagnosis, many cases of GPA will be missed.

Figure 11.15 Granulomatosis with polyangiitis: giant cells. (A) the characteristic giant cells (arrows) have smudged basophilic nuclei, often marginated at the periphery of the cell. (B) A typical multinucleate giant cell is evident at the periphery of necrosis (upper left).

As mentioned, all types of inflammatory cells may occur in GPA, including neutrophils, lymphocytes, plasma cells, eosinophils, histiocytes, and giant cells. Occasionally the inflammatory infiltrate consists mostly of lymphoid cells, but this is unusual. In such cases, distinction of GPA from lymphomatoid granulomatosis may be difficult.

Another distinctive vascular manifestation of GPA is capillaritis (Fig. 11.19). In many cases, capillaritis is only focally evident in the biopsy.⁴⁹ When capillaritis is prominent, it is distinctive and easily recognized. In the rare case of GPA dominated by capillaritis, a careful search throughout the rest of the biopsy should be made for more typical findings of GPA such as granulomas, foci of necrosis (such as neutrophilic microabscesses), multinucleate giant cells, and vasculitis affecting arterioles or veins.

In addition to these major histologic features, a variety of minor histologic features may be encountered (Box 11.3), including alveolar hemorrhage, interstitial fibrosis, lipoid pneumonia, organizing pneumonia, lymphoid hyperplasia, extravascular tissue eosinophils, and xanthomatous lesions. GPA can also involve the airways, causing chronic bronchiolitis, acute bronchiolitis or bronchopneumonia, the histologic pattern of organizing pneumonia (see later on), bronchocentric granulomatosis, follicular bronchiolitis, and bronchial stenosis.^49,51 Occasionally one of these minor lesions may be the dominant lung biopsy finding.⁴⁹ Diffuse pulmonary hemorrhage is a severe life-threatening manifestation of GPA. The pattern of bronchocentric granulomatosis is another rare manifestation of GPA encountered in 1% of cases.^49,51 Organizing pneumonia (Fig. 11.20) can be seen in 70% of lung biopsies from patients with GPA⁴⁹; rarely, it may be sufficiently dominant that some have referred to this manifestation as the bronchiolitis obliterans organizing pneumonia (BOOP) variant of GPA.^49,52 This should not be confused with the idiopathic entity of BOOP (cryptogenic organizing pneumonia) but should be recognized as nonspecific secondary organization following alveolar injury related to the underlying lesions of GPA.

Figure 11.16 Granulomatosis with polyangiitis: types of granulomatous inflammation. Three examples of granulomatous inflammation at the periphery of necrosis: palisaded histiocytes (A); epithelioid histiocytes with little organization (B); plump eosinophilic histiocytes (C).

Figure 11.17 Granulomatosis with polyangiitis: vasculitis. Vasculitis at the edge of basophilic necrosis. Note the adventitial fibrosis and expansion of the vascular media by inflammatory cells. Multinucleate giant cells can be seen at the interface of muscularis and adventitia in a focal distribution (lower right).

Figure 11.18 Granulomatosis with polyangiitis: elastic tissue stains. (A) Elastic tissue stains demonstrate disruption of the elastic lamina in involved arteries. (B) Granuloma can be seen displacing elastic lamina and protruding into the vessel lumen.

Figure 11.19 Granulomatosis with polyangiitis (GPA): capillaritis. (A) Capillaritis can be seen in GPA and at times may be the dominant feature. (B) At higher magnification, an alveolar wall with increased neutrophils and disruption of capillaries is visible. Note the hemosiderin aggregates at upper right.

The lung biopsy findings from patients with GPA may not show classic histologic findings, especially if patients are biopsied very early in the course of disease or following therapy.^49,53 Interstitial fibrosis (sometimes with scattered giant cells, but without necrosis) (Fig. 11.21), bronchial or bronchiolar scarring, and cicatricial vascular changes (Fig. 11.22) are common in lung biopsies from patients who have received therapy.^49,53 Wedge biopsies provide the best results for an accurate diagnosis of GPA. Transbronchial biopsies rarely yield diagnostic information, although in the appropriate clinical context the presence of a few neutrophil microabscesses, giant cells, or capillaritis may be helpful in supporting the diagnosis. Transthoracic needle core biopsies may occasionally show features suggesting a diagnosis of GPA.

Figure 11.20 Granulomatosis with polyangiitis (GPA): organizing pneumonia. Organization may be prominent in GPA and at times may be the dominant feature. Often capillaritis is evident, as are the “footprints” of previous hemorrhage (hemosiderin at center). Scattered multinucleate giant cells may be seen.

Figure 11.21 Granulomatosis with polyangiitis: treatment effect. Areas of lung fibrosis may occur after treatment for this disorder, frequently associated with parenchymal collapse (right). Here, a bronchiole and accompanying pulmonary artery show inflammatory sequelae of the disease.

Differential Diagnosis

The differential diagnosis for GPA based on lung biopsy tissue depends somewhat on the constellation of changes present and includes granulomatous infection,⁵⁰ lymphomatoid granulomatosis,^4,54 EGPA,^55-58 sarcoidosis, necrotizing sarcoid granulomatosis,^59-61 rheumatoid nodules,⁶² bronchocentric granulomatosis,^53,62,63 and diffuse pulmonary hemorrhage syndromes.^62,64

Occasionally, a form of diffuse large B cell malignant lymphoma commonly referred to as lymphomatoid granulomatosis (Chapter 16) can bear a striking resemblance to GPA (Fig. 11.23).⁶ Like classic GPA, this neoplastic process is characterized pathologically by the presence of multiple necrotic pulmonary nodules. In addition to major clinical differences between these diseases, important histopathologic differences become evident at closer inspection. First, the necrotic areas in lymphomatoid granulomatosis typically demonstrate pale shadows of large necrotic cells (dead lymphoma cells). Second, within the necrotic zones, and at the periphery of necrosis, medium-sized blood vessels can be seen whose outline is expanded by an angiocentric infiltration of lymphoid cells. As noted, this is a diffuse large B cell lymphoma in which the atypical B lymphoid cells are infected with Epstein-Barr virus (EBV) and associated with a T lymphocyte-rich inflammatory reaction and vasculitis. In high-grade disease, the vasocentric infiltrate is composed mainly of large atypical B cells. In lower-grade forms, the infiltrate may be polymorphous with more prominent T cells and a mixture of plasma cells, and eosinophils. Immunohistochemistry for CD20 and CD3 highlights the large malignant B cells and background of inflammatory T cells. Immunohistochemistry for EBV latent membrane protein 1 (LMP-1) and in situ hybridization studies for EBV are valuable diagnostic tools in this setting. Third, lymphomatoid granulomatosis is a vasodestructive lymphoid neoplasm, so necrosis and obliteration of vessels are common. GPA may show necrosis in vascular adventitia, but wholesale medial necrosis in arteries and veins is unusual. Fourth, the atypical cells of lymphomatoid granulomatosis often contain EBV,^4,63 a finding not expected in GPA. Finally, granulomatous inflammation is comparatively rare in lymphomatoid granulomatosis, so the presence of granulomas in nodular lung lesions should suggest a diagnosis other than lymphomatoid granulomatosis (e.g., infection or GPA).

Prominent tissue eosinophilia occurs in approximately 5% of cases of GPA (Fig. 11.24). With this finding, the differential diagnosis should include EGPA (see later), along with fungal or parasitic infection.^55,58,65,66 Peripheral blood eosinophilia is characteristic of EGPA and is uncommon in GPA.⁶⁷ Also, asthma is not a characteristic feature of GPA, although rarely, asthmatic individuals may develop GPA, presumably at a rate similar to that seen in the general population. The distinction between GPA and EGPA is usually straightforward, but some cases may require careful assessment of all of the clinical, pathologic, and laboratory data (Table 11.2).

Figure 11.22 Granulomatosis with polyangiitis: treatment effect. (A) Significant vascular scarring consequent to treatment. (B) Remnants of the inflammatory infiltrate may persist within the vascular media. Note the giant cell within the media (upper center).

Figure 11.23 Granulomatosis with polyangiitis (GPA): prominent lymphoid infiltrates. (A) GPA may be dominated by lymphocytes. When this occurs, differentiation from lymphoma (specifically, angiocentric lymphoma) may be difficult. (B and C) Note the expansile appearance of the inflammatory infiltrate with vessel wall destruction. Closer inspection will often reveal a degree of atypia in the lymphoid cells not seen in GPA.

Figure 11.24 Granulomatosis with polyangiitis: prominent eosinophils. When eosinophils are a prominent histopathologic feature, the differential diagnosis will include Churg-Strauss syndrome/eosinophilic granulomatosis with polyangiitis. Here a vessel is obliterated by inflammation and fibroblastic proliferation, and eosinophils are abundant. Note the multinucleate giant cell in the upper left.

Table 11.2 Granulomatosis With Polyangiitis/Wegener Granulomatosis Versus Eosinophilic Granulomatosis With Polyangiitis/Churg-Strauss Syndrome: Distinguishing Features

Clinical/Pathologic Feature	Granulomatosis With Polyangiitis	Eosinophilic Granulomatosis With Polyangiitis
Asthma	Rare	Characteristic (diagnostic criterion)
Eosinophilia Peripheral Tissue	Up to 12% Up to 6%	Characteristic* Characteristic*
Sinus disease	Destructive, often causing saddlenose deformity	Less severe, usually allergic rhinitis
Renal disease	More severe	Usually mild
Cardiac disease	Rare	Common
ANCA	Usually c-ANCA	Usually p-ANCA

*Eosinophilia may be fleeting and may be difficult to demonstrate during steroid therapy. ANCA (c-ANCA, p-ANCA), Antineutrophil cytoplasmic antibodies (cytoplasmic, perinuclear).

Perhaps the most important, and often problematic, consideration in the diagnosis of GPA is the exclusion of infection. Mycobacteria and fungi can cause necrotizing granulomatous inflammation and vasculitis resembling that seen in GPA. Solitary necrotizing granulomas can be associated with vasculitis in 87% of mycobacterial lung infections and 57% of fungal lung infections.⁵² Also, neutrophilic microabscesses are a feature of certain infections, such as blastomycosis and nocardiosis.

A number of important clues can be helpful in the approach to this differential diagnosis, even before special stains for organisms or culture data (which should be routinely ordered in such cases) are available. First, if the lesion is solitary, a high index of suspicion for infection is appropriate.⁴⁴ Second, GPA does not tend to make granulomas without central necrosis,⁵¹ except in the rare occurrence of infection superimposed on the necrotic center of a GPA lesion. Third, the necrosis of infection may show the ghosted outlines of underlying lung parenchyma, a finding uncharacteristic of GPA. Fourth, the patient with infection, in whom a bilateral multiple-nodular appearance on radiologic studies may simulate that in GPA, is typically quite ill, with generalized systemic symptoms. By contrast, the patient with GPA may be relatively asymptomatic, despite numerous necrotic nodules in the lung. Finally, when strictly morphologic assessment fails to clarify the diagnosis, inquiry regarding the presence of sinonasal disease or renal disease and serologic data (c-ANCA and p-ANCA) will usually resolve the quandary.

When GPA presents with a predominantly bronchocentric pattern of lung involvement, bronchocentric granulomatosis must be considered in the differential diagnosis.^49,51 Patients with bronchocentric GPA should demonstrate other distinguishing features of GPA, including renal or sinus involvement and a positive ANCA serology.

Diagnosis

The histologic features of GPA can be very suggestive of the diagnosis, but as a general rule, it is extremely important to correlate the histopathology with clinical and serologic findings before making a definitive diagnosis on a lung biopsy specimen. The diagnosis can be impossible to make in cases in which only partial clinical or pathologic criteria are present. In these situations a purely descriptive diagnosis with a differential diagnosis may be necessary. As mentioned earlier, ANCA serology can be helpful, as long as one keeps in mind that ANCAs are not specific for GPA.⁶⁸ Moreover, when all other clinical and histopathologic findings are compelling for GPA, the diagnosis is still possible despite negative ANCA studies.³⁷

Treatment and Prognosis

GPA is commonly a fatal disease if left untreated, with up to 90% of patients dying within 2 years of diagnosis, most often from respiratory or renal failure. Fortunately, therapy with cyclophosphamide and prednisone is very effective in achieving remissions, with 85% to 90% of patients responding to therapy and approximately 75% experiencing complete remission.⁶⁹ the median time to remission is 12 months, although occasional patients require treatment for more than 2 years before all symptoms resolve. Even in those patients who initially respond to therapy, relapses are common, with up to 50% of initial responders experiencing at least one relapse requiring another course of therapy. Trimethoprim-sulfamethoxazole, pulse cyclophosphamide, and methotrexate are also used to treat GPA.^19,70-72 Trimethoprim-sulfamethoxazole may reduce relapses for those patients who are in remission.⁷³ the mechanism of this protective action is unknown. Rituximab has more recently shown promise in treatment of GPA, particularly limited disease refractory to standard therapy.⁷⁴ Initial trials of antagonists of tumor necrosis factor-alpha (TNF-a) showed some benefit, but formal trials did not support the initial findings; thus further study is needed to determine the efficacy of this potential therapy.⁷⁵ the outcome with GPA seems to be significantly worse for patients older than 60 years of age than for younger patients, despite similar clinical manifestations and treatment regimen. Lung function frequently improves after treatment, but in some patients the diffusing capacity may never return to normal.

Table 11.3 Eosinophilic Granulomatosis With Polyangiitis/Churg-Strauss Syndrome: Clinical Manifestations

Manifestation	Frequency (% of Patients Affected)
Pulmonary infiltrates	72
Mononeuritis multiplex	66
Abdominal pain	59
Arthritis/arthralgias	51
Mild/moderate renal disease	49
Purpura	48
Cardiac failure	47
Myalgia	41
Loffler syndrome	40
Erythema/urticaria	35
Diarrhea	33
Pericarditis	32
Skin nodules	30
Pleural effusion	29
Hypertension	29
Central nervous system abnormalities	27
Gastrointestinal bleeding	18
Renal failure	9

Modified from Lanham J, Churg J. Churg-Strauss syndrome. In: Churg A, Churg J, eds. Systemic Vasculitides. New York: Igaku-Shoin; 1991:101-120.

Eosinophilic Granulomatosis With Polyangiitis/Churg-Strauss Syndrome

EGPA, also known as CSS or allergic angiitis and granulomatosis, is a multisystem disorder characterized by the triad of asthma, peripheral blood eosinophilia, and vasculitis.^{55,56,58,66,67,76-78} Although EGPA was initially described by Churg and Strauss based on a series of autopsy cases,⁵⁵ it is now recognized primarily as a clinical entity. Accordingly, most cases today are diagnosed on the basis of clinical findings rather than lung biopsy.^65,79

In 1990 the American College of Rheumatology (ACR) proposed two approaches to the diagnosis of EGPA (Table 11.3): a traditional format classification and a classification tree.^80,81 According to the traditional format classification, six criteria are identified: (1) asthma, (2) eosinophils greater than 10% of the white blood cell differential count, (3) mononeuropathy (including multiplex) or polyneuropathy, (4) nonfixed radiographic pulmonary infiltrates, (5) paranasal sinus abnormalities, and (6) a biopsy containing a blood vessel with extravascular eosinophils.⁸⁰ If four of six of these criteria are met, the diagnosis can be established with a sensitivity of 85% and a specificity of 99.7%.^{80 the} ACR criteria for EGPA have been retained in the subsequent 1994 Chapel Hill consensus conference criteria.⁷

The major criteria used in the classification tree are asthma, eosino- philia with greater than 10% eosinophils, and a history of allergy.⁸⁰ According to this method, patients with well-documented systemic vasculitis, but lacking a history of asthma, can be diagnosed with EGPA if they have peripheral blood eosinophilia (>10% eosinophils) and a history of allergy other than drug sensitivity.⁸⁰ This seems appropriate because patients without asthma but with a history of allergic disease can develop EGPA.^82-84

Both classification methods appear to be useful in the diagnosis, with greater sensitivity provided by the classification tree and greater specificity by the traditional approach.⁸⁰

Clinical Features

EGPA occurs in a wide age range (7-74 years; mean 38-54) and has an estimated incidence of 0.11 to 2.66 per million per year. No gender or ethnic predisposition has been demonstrated.

The exact etiology of EGPA is unknown, but understanding of pathogenesis has expanded in recent years. Although an ANCA-associated vasculitis, the prevalence of ANCA positivity is only around 40% and is typically perinuclear MPO-ANCA. Based on this, there is a hypothesis that two disease subtypes exist, which is under further study. The disease is also considered to be mediated by Th2 cells via upregulation of cytokines; however, this upregulation does not explain all aspects of the disease. Activated tissue eosinophils and a component of B-cell and humeral response may also be contributing factors. HLA-BRB1*04 and *07 alleles as well as HLADRB4 are associated with increased risk of disease development. Increased IgG4 has been observed, suggesting EGPA may be related to the ever-expanding list of IgG4-related disorders.^79,85

EGPA mainly involves the upper respiratory tract, lungs, skin, and peripheral nerves.^56,58,65 Involvement of the heart and kidney also occurs and may be associated with a worse outcome.

EGPA often progresses through three distinct phases. In the early or prodromal phase, the disease manifests as allergic rhinitis, asthma, peripheral eosinophilia, and/or eosinophilic infiltrative disease.^56,58,65,67 Recurrent episodes of asthma may develop over a period of years before the onset of vasculitis, and some data suggest that the interval between the onset of asthma and the subsequent vasculitis phase of the disease has a direct association with prognosis.^55,56,65 In the prodromal phase, tissue infiltration by eosinophils can affect the lungs or the gastrointestinal tract. Pulmonary manifestations may take the form of Loffler syndrome, with fleeting pulmonary infiltrates or even chronic eosinophilic pneumonia.

The prodromal phase is followed by the vasculitis phase. During this phase, patients develop systemic signs and symptoms of vasculitis, such as mononeuritis multiplex and cutaneous leukocytoclastic vasculitis. Results of the p-ANCA assay are usually positive. The ACR criteria necessary for diagnosis are present only during this phase.⁵⁸ Unfortunately, most of the permanent damage is done by the disease during this phase. For this reason, when eosinophilic pneumonia occurs in an asthmatic patient, EGPA should always be raised as a possibility in the differential diagnosis, especially when prominent eosinophilic vasculitis is present in the lung biopsy.

The vasculitis phase is followed by a postvasculitis phase. Here, patients may experience neuropathy and hypertension, typically with persistent asthma and allergic rhinitis.⁵⁸ Proteinuria and gastrointestinal involvement are poor prognostic indicators.⁸⁶

A major difference between EGPA and GPA is the frequency of cardiac and renal involvement. Although the heart may be involved in both disorders, up to 47% of EGPA patients develop cardiac disease. EGPA can cause cardiac failure, pericarditis, hypertension, and acute myocardial infarction.^55,56,65 Also, although renal disease is characteristic in GPA, it is less frequent and less severe in patients with EGPA.^55,58,87

Peripheral neuropathy, often in the form of mononeuritis multiplex, is seen in approximately two-thirds of patients with EGPA. The most common cutaneous manifestation is leukocytoclastic vasculitis.⁸⁸ Sinonasal manifestations include nasal obstruction, nasal polyps, rhinor- rhea, and thick intranasal crusts.⁸⁹ Central nervous system involvement can occur in 25% of cases.^58,65,78 Gastrointestinal hemorrhage and perforation are potential complications.⁹⁰ Serologic studies usually show the p-ANCA pattern, although c-ANCA can also be seen ( The inverse of ANCA types in GPA).⁹¹ Elevated serum IgE is also a characteristic finding in EGPA.⁵⁶,⁵⁸,⁶⁵

An EGPA-like syndrome develops as a rare complication in steroid- dependent asthmatics successfully treated with leukotriene receptor antagonists (e.g., pranlukast).^92-96 This complication is probably related to steroid withdrawal facilitated by the drugs, which unmasks underlying EGPA, rather than a manifestation of the drugs. To this point, a similar unmasking of EGPA has occurred in asthmatic patients whose withdrawal from oral steroids was facilitated by inhaled steroids.⁷⁹ Also, an unusual association between an EGPA-like vasculitis and the illicit use of free base cocaine has been reported.⁹⁷

There are no laboratory tests specific for EGPA. Peripheral blood eosinophilia (eosinophil counts usually 5000 to 9000/pL) is the most characteristic finding. Other nonspecific laboratory abnormalities include normochromic normocytic anemia, markedly elevated erythrocyte sedimentation rate, leukocytosis, elevated IgE level, and hypergammaglobulinemia. Bronchoalveolar lavage fluid shows a high percentage of eosinophils (usually >33%). Pulmonary function abnormalities most often reflect the patient’s underlying asthma.⁷⁹

Radiologic Features

EGPA most commonly manifests radiologically as multifocal lung parenchymal infiltrates that change in location and size over time (Fig. 11.25).^40,55,98 the infiltrates may also exhibit a peripheral distribution, there by mimicking those of chronic eosinophilic pneumonia. Lung involvement by pulmonary consolidation may be widespread. Diffuse miliary nodules have also been reported.^38,98 Cavitation of nodules is rare and when present should suggest superimposed infection.⁹⁹ Eosinophilic pleural eflusions may be seen in 29% of cases.^40,99 Hilar lymphadenopathy is infrequent. The chest radiograph can be normal in appearance in as many as 25% of patients.⁴⁰

High-resolution CT (HRCT) features of EGPA most commonly consist of parenchymal opacifications (consolidation or ground-glass attenuation), followed in frequency by pulmonary nodules, bronchial wall thickening or dilatation, interlobular septal thickening, and normal anatomy.¹⁰⁰ One case report described “stellate-shaped” peripheral pulmonary arteries and peribronchial and septal interstitial thickening. Small patchy opacities were also noted. These HRCT abnormalities correlated with eosinophilic infiltration and foci of eosinophilic pneumonia, respectively.¹⁰¹

Figure 11.25 Eosinophilic granulomatosis with polyangiitis (EGPA)/Churg-Strauss syndrome: computed tomography (CT) features. Chest CT scan (lung window) in a patient with a 10-year history of asthma and peripheral eosinophilia demonstrates multifocal peripheral subpleural consolidations. The diagnosis of EGPA was confirmed at open lung biopsy. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.18.)

Figure 11.26 Eosinophilic granulomatosis with polyangiitis (EGPA): eosinophilic pneumonia. Eosinophilic pneumonia is the most consistent manifestation of EGPA. Here, the triad of air space eosinophils, eosinophilic macrophages with fibrin, and atypical alveolar lining cells can be readily appreciated.

Figure 11.27 Eosinophilic granulomatosis with polyangiitis: allergic granulomas. Characteristic allergic granuloma is readily apparent. Note the vaguely palisaded histiocytes at the periphery of eosinophilic necrosis (center). Multinucleate giant cells may be present and typically have a brightly eosinophilic cytoplasm.

Figure 11.28 Eosinophilic granulomatosis with polyangiitis (EGPA): vasculitis. Vasculitis is characteristic in EGPA. (A) A medium-sized artery infiltrated by eosinophils and scattered lymphocytes. (B) A venule infiltrated by eosinophils. Note fibrin and eosinophils in surrounding air spaces.

Pathologic Features

The findings on lung biopsy depend on the stage of the disease during which the biopsy is obtained and whether the patient has received therapy, particularly steroids. Lung biopsies from EGPA patients in the full-blown vasculitic phase may show asthmatic bronchitis, eosinophilic pneumonia (Fig. 11.26), extravascular stellate granulomas (Fig. 11.27), and vasculitis (Fig. 11.28).^55,58 In some cases, the inflammatory lesions extend along the pleura and interlobular septa. The extravascular granulomas have a border of palisaded histiocytes and multinucleate giant cells, surrounding a central necrotic zone replete with eosinophils and eosinophil cellular debris. Such lesions have been called allergic granulomas. Vasculitis can affect arteries, veins, or capillaries. The vascular inflammatory infiltrates can be composed of chronic inflammatory cells, eosinophils, epithelioid cells, multinucleate giant cells, and neutrophils.

Diffuse pulmonary hemorrhage and capillaritis (Fig. 11.29) can be seen.^87,102 In patients who are partially treated, the pathologic (and clinical) features may be incomplete.⁹⁸ Lung biopsy is not required for diagnosis, if pulmonary infiltrates are present in association with other systemic findings that fulfill the required diagnostic criteria.

Differential Diagnosis

The differential diagnosis of EGPA includes eosinophilic pneumonia from any cause, GPA,⁴⁹ allergic bronchopulmonary fungal disease (ABPFD),¹⁰³ infection (especially parasitic and fungal),¹⁰⁴ Hodgkin disease, and drug-induced vasculitis.¹⁰⁵

Eosinophilic pneumonia and ABPFD lack systemic vasculitis, although some cases of eosinophilic pneumonia can show a mild nonnecrotizing vasculitis, and allergic granulomas may be present. Features helpful in distinguishing EGPA from GPA are summarized in Table 11.2. Pathologic features similar to those of EGPA can also be mimicked by certain parasitic infections, such as those caused by Strongyloides stercoralis¹⁰⁶ and Toxocara canis.¹⁰⁷ There fore parasitic infection should be carefully excluded when EGPA is in the differential diagnosis on histopathologic grounds. Some fungal infections, especially those due to Aspergillus species and Coccidioides immitis, may be associated with granulomatous inflammation, prominent eosinophilia, and vasculitis. Rarely, Hodgkin disease with prominent eosinophils and vascular inflammation may be confused with EGPA. Drugs such as carbamazepine also can cause an EGPA-like syndrome, so attention should be paid to the patient’s drug history.¹⁰⁵

Figure 11.29 Eosinophilic granulomatosis with polyangiitis (EGPA): pulmonary hemorrhage. Diffuse pulmonary hemorrhage with capillaritis can occur in EGPA. Capillaritis is demonstrated here, associated with aggregated air space fibrin and eosinophils.

Treatment and Prognosis

Most patients with EGPA respond to systemic corticosteroids. To avoid irreversible organ injury, some authorities have favored treatment with cytotoxic immunosuppressive agents, such as cyclophosphamide, from the outset.⁵⁸ Azathioprine, interferon-a, and high-dose intravenous immune globulin have been used with apparent benefit in patients with severe, fulminant disease or in patients unresponsive to systemic corticosteroids. Plasma exchange has occasionally been used but appears to have no added benefit to that observed with treatment with systemic corticosteroids, with or without the addition of cyclophosphamide.¹⁰⁷ More recently, rituximab and mepolizumab, a monoclonal antibody targeting interleukin 5, an eosinophil survival factor, have shown promise.⁷⁹

Patients who die from EGPA typically have cardiac complications such as congestive heart failure or myocardial infarction. Other, less common causes of death include renal failure, cerebral hemorrhage, gastrointestinal perforation or hemorrhage, status asthmaticus, and respiratory failure.^58,108

Microscopic Polyangiitis

Microscopic polyangiitis encompasses the spectrum of vasculitic disorders that previously have been called systemic necrotizing vasculitis, leukocytoclastic vasculitis, and hypersensitivity vasculitis.¹⁰⁹¹¹²

An International Consensus Conference on the Nomenclature of Systemic Vasculitides defined microscopic polyangiitis as a vasculitis restricted to arterioles, venules, and capillaries. The designation polyangiitis was favored over polyarteritis because venules are affected as well as arterioles. Microscopic polyangiitis differs from polyarteritis nodosa in that it involves arterioles, venules, and capillaries, as opposed to medium-sized arteries.^7,113115

Table 11.4 Microscopic Polyangiitis: Clinical Features at Presentation

Manifestation	Number of Patients Affected (n = 29)	Frequency (%)
Pulmonary	29	100
Dyspnea	26	90
Cough	26	90
Hemoptysis	23	79
Chest pain	5	17
Crackles	13	45
Renal	28	97
Fever (temperature > 37.5°C)	18	62
Weight loss	13	45
Musculoskeletal	15	52
Arthralgias	13	4
Arthritis	4	14
Myalgia	6	21
Ear, nose, and throat	9	31
Epistaxis	5	17
Sore throat	1	3
Mouth ulcers	2	7
Hearing loss	1	3
Skin	5	17
Purpura	4	14
Nodules	1	3
Erythema elevatum diutinum	1	3
Bullae	1	3
Hypertension	7	25
Ocular	7	25
Episcleritis	5	17
Xerophthalmia	2	7
Peripheral neuropathy	2	7
Gastrointestinal bleeding	1	3

From Lauque D, Cadranel J, Lazor R, et al. Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature. Groupe d'Etudes et de Recherche sur les Maladies "Orphelines” Pulmonaires (GERM"O”P). Medicine (Baltimore). 2000;79:222-233.

Clinical Features

Systemic manifestations of microscopic polyangiitis are more common than pulmonary manifestations and include glomerulonephritis (in 97% of the cases), fever (in 62%), myalgia and arthralgia (in 52%), weight loss (in 45%), ear, nose, and throat symptoms (in 31%), and skin involvement (in 17%) (Table 11.4).^113,116 Approximately 50% of the patients develop pulmonary involvement,¹¹⁶ and these persons are typically middle-aged or older (average age, 56 ± 17 years) when this occurs. Women are affected slightly more often than men (1.5: 1 female- to-male ratio).¹¹⁶ Onset of symptoms is rapid in most patients, but up to 28% may have symptoms for more than 1 year before diagnosis.

Bronchoalveolar lavage fluid typically shows acute hemorrhage or hemosiderin-laden macrophages when the lungs are involved. Kidney biopsies may show a necrotizing glomerulonephritis.¹¹⁶ More than 80% of patients have a positive ANCA, most often demonstrating the perinuclear type (p-ANCA).¹¹³ Microscopic polyangiitis is the most common cause of so-called pulmonary hemorrhage renal syndrome.^113,117

Figure 11.30 Microscopic polyangiitis: pulmonary hemorrhage. Alveolar hemorrhage with capillaritis is a common manifestation of this disorder.

Radiographic Features

The typical findings in microscopic polyangiitis are manifestations of pulmonary hemorrhage. Bilateral alveolar infiltrates are seen on plain chest films, and ground-glass attenuation is seen on CT scans. The lower lung zones may be most frequently affected.¹¹⁶

Pathologic Features

Surgical lung biopsies in microscopic polyangiitis typically show pulmonary hemorrhage, hemosiderin-laden macrophages in alveolar spaces, and neutrophilic capillaritis (Fig. 11.30).^35,113 At scanning magnification, neutrophilic capillaritis often appears as scattered foci of increased alveolar wall cellularity, in a background of alveolar hemorrhage (Fig. 11.31). Closer inspection reveals the presence of neutrophils within the alveolar walls, sometimes spilling over into the surrounding alveolar spaces. In severe cases, the neutrophils may fill the alveoli and focally resemble an acute infectious pneumonia (Fig. 11.32). Identification of distinctive fibrinoid necrosis of capillary walls is often not possible. Alveolar fibrin may accompany the lesions of capillaritis, sometimes in a polypoid fashion (Fig. 11.33). As the lesions of capillaritis heal, polypoid plugs of organizing fibrosis may be seen, sometimes resulting in an organizing pneumonia pattern (Fig. 11.34) (previously referred to as a BOOP pattern). The presence of hemosiderin (typically within alveolar macrophages) is essential for an accurate diagnosis because blood alone may be present in lung biopsies as an artifactual finding.

Hyaline membranes (Fig. 11.35) identical to those of diffuse alveolar damage (DAD) may also be seen.^35,117 In some cases it may be difficult to distinguish hemorrhagic DAD from a diffuse pulmonary hemorrhage syndrome with capillaritis. Pulmonary fibrosis^34,35 and progressive obstructive airway disease with emphysematous features^118,119 have also been reported in patients with microscopic polyangiitis.

Differential Diagnosis

The differential diagnosis for microscopic polyangiitis includes hemorrhagic lung infections, GPA with prominent capillaritis, Goodpasture syndrome, certain systemic collagen vascular diseases (e.g., systemic lupus erythematosus [SLE]) and other small-vessel vasculitides, such as Henoch-Schonlein purpura (IgA vasculitis) and cryoglobulinemia, and even certain rare drug reactions (e.g., diphenylhydantoin).¹²⁰

Figure 11.31 Microscopic polyangiitis: capillaritis. (A) the capillaritis of microscopic polyangiitis can be quite diffuse. (B) At higher magnification, fibrin and capillary disruption associated with neutrophils can be seen. Note the hemosiderin-laden macrophages in adjacent air spaces (bottom left).

GPA typically has granulomatous inflammation often consisting of palisaded histiocytes surrounding necrosis. Pure capillaritis forms of GPA cannot be reliably distinguished from microscopic polyangiitis on histologic grounds. In most of these instances, some areas of collagen necrosis will be present in GPA. Unfortunately, granulomatous inflammation may not be included in the tissue sampled if a conservative approach is taken to obtaining tissue biopsies in patients with GPA. Moreover, on occasion granulomas can be absent altogether in GPA, or the biopsy may be obtained during a phase of disease in which granulomas are not prominent. In these scenarios, clinical and serologic data are often helpful in separating these two diseases, even when biopsies cannot.

As mentioned earlier, microscopic polyangiitis is distinguished from polyarteritis nodosa by the involvement of vessels smaller than mediumsized arteries in microscopic polyangiitis, such as arterioles, venules, and capillaries (Table 11.5).¹¹³

Figure 11.32 Microscopic polyangiitis: pseudobronchopneumonia. Capillaritis may result in shedding of neutrophils into air spaces. When this occurs, neutrophilic acute bronchopneumonia may be simulated.

Figure 11.34 Microscopic polyangiitis: fibrin polyps. Polypoid fibrin plugs may resolve with air space organization. Air space fibroblasts fill alveoli in this biopsy section. Note the cellular interstitium replete with neutrophils.

Figure 11.33 Microscopic polyangiitis: classic features. Note the characteristic capillaritis with aggregated air space fibrin and hemosiderin-laden macrophages.

Figure 11.35 Microscopic polyangiitis: hyaline membranes. Hyaline membranes may be a feature of microscopic polyangiitis as well as other diffuse alveolar hemorrhage syndromes. Note the diffuse capillaritis evident here.

Finally, microscopic polyangiitis must be distinguished from a heterogeneous group of vasculitic disorders affecting venules, capillaries, and arterioles, some of which are associated with drugs or other agents (Box 11.4).^{110-112,120,123} Microscopic polyangiitis is not associated with immune deposits in lung as are some other types of small-vessel vasculitis, such as Henoch-Schonlein purpura, cryoglobulinemic vasculitis, serum sickness, and lupus vasculitis.^113,114 Other conditions known to produce small-vessel vasculitis (listed in Box 11.4) can typically be excluded on clinical and serologic grounds.

Treatment and Prognosis

Microscopic polyangiitis is treated with immunosuppressive agents.¹¹³ Lauque and colleagues treated a group of 29 patients using corticosteroids (in 100%) with cyclophosphamide (in 79%), plasmapheresis (in 24%), dialysis (in 28%), and mechanical ventilation (in 10%).¹¹⁶ the 5-year survival rate was 68%, with causes of death divided equally between vasculitis and side effects of treatment. Complete recovery occurred in most patients (69%). Pulmonary function abnormalities persisted in 24%, and 11 patients relapsed, 2 of whom died of alveolar hemorrhage.¹¹⁶

Table 11.5 Microscopic Polyangiitis: Differential Diagnosis

Feature	Microscopic Polyangiitis	Granulomatosis with Polyangiitis	Polyarteritis Nodosa
Size of Affected Vessels
Medium-sized arteries	Sometimes	Sometimes	Yes (bronchial arteries)
Arterioles, venules,	Yes	Yes	No
capillaries
Granulomatous	No	Yes	No
inflammation
Lung involvement	Common	Common	Uncommon
ANCA	Mostly p-ANCA	Mostly c-ANCA	Mostly p-ANCA

ANCA (c-ANCA, p-ANCA), Antineutrophil cytoplasmic antibodies (cytoplasmic, perinuclear).

Vasculitic Syndromes That Uncommonly Affect the Lung

Necrotizing Sarcoid Granulomatosis

Necrotizing sarcoid granulomatosis is a rare granulomatous disease that primarily affects the lungs. Nodular masses of confluent sarcoidlike or epithelioid granulomas are seen in the lung parenchyma, often with extensive areas of necrosis and vasculitis. Debate continues over whether necrotizing sarcoid granulomatosis is a vasculitic syndrome, a variant of sarcoidosis, or simply a manifestation of unusual infection. The principal argument against the disorder being a vasculitic syndrome is that it is not a systemic vasculitic disorder and the lung pathology is primarily that of necrotizing granulomatous inflammation rather than vasculitis. A case of necrotizing sarcoid was recently reported in a patient who had family members with typical sarcoid, potentially lending further support to the theory of a primary granulomatous disorder.¹³⁴

Clinical Features

Necrotizing sarcoid granulomatosis is typically a disease of adults. A summary of clinical and radiologic features reported in case studies is presented in Table 11.6. The average age of patients who develop the disease is 50, but it can occur from adolescence to late adulthood.^2,76,135 Women are affected twice as often as men.^136,137 the usual presentation includes cough, fever, chest pain, dyspnea, malaise, and weight loss.^60,136-138 Up to one-fourth of patients may be asymptomatic at the time of diagnosis. Extrapulmonary manifestations are uncommon, with rare reports of uveitis and hypothalamic insufficiency.^60,139-141 Upper airway disease, glomerulonephritis, and systemic vasculitis are not expected findings. To date, positive ANCAs have not been reported in this disease.

Table 11.6 Necrotizing Sarcoid Granulomatosis: Summary of Reported Clinical-Radiologic Features

Feature	Reported	Findings
	Liebow	Saldana	Churg et al.	Koss et al.	Others
Number of cases	11	30	32	13	8
Male-to-female ratio	~1 : 1	12 : 18	1 : 4	3 : 10	3 : 5
Bilateral (%)	82	12	72	62	50
Solitary (%)	18*	88	22	15	25
Hilar adenopathy (%)	9	7	65	8	25
Cavitation (%)	NA	3	0	23	13
Recurrence (%)	25	11	12	15	13
Died (%)	0	0	4*	0	13*

'Described as “localized, unilateral disease.”

’One patient died of pneumonia several months after resection of a solitary nodule. ’Patient died of oat cell carcinoma.

NA, Not available.

Data from Liebow A. The J. Burns Amberson lecture—pulmonary angiitis and granulomatosis. Am Rev Respir Dis. 1973;108:1-18; Saldana M. Necrotizing sarcoid granulomatosis: clinicopathologic observations in 24 patients [Abstract]. Lab Invest 1978;38:364; Churg A, Carrington C, Gupta R. Necrotizing sarcoid granulomatosis. Chest. 1979;76:406-413; and Koss MN, Hochholzer L, Feigin DS, et al. Necrotizing sarcoid-like granulomatosis: clinical, pathologic, and immunopathologic findings. Human Pathol. 1980;11(suppl):510-519. Other case reports include Beach RC, Corrin B, Scopes JW, Graham E. Necrotizing sarcoid granulomatosis with neurologic lesions in a child. J Pediatr. 1980;97:950-953; Singh N, Cole S, Krause PJ, et al. Necrotizing sarcoid granulomatosis with extrapulmonary involvement. Clinical, pathologic, ultrastructural, and immunologic features. Am Rev Respir Dis. 1981;124:189-192; Stephen JG, Braimbridge MV, Corrin B, et al. Necrotizing “sarcoidal” angiitis and granulomatosis of the lung. Thorax. 1976;31:356-360; Rolfes D, Weiss M, Sanders M. Necrotizing sarcoid granulomatosis with suppurative features. Am J Clin Pathol. 1984;82:602-607; Spiteri MA, Gledhill A, Campbell D, Clarke SW. Necrotizing sarcoid granulomatosis. Br J Dis Chest. 1987;81:70-75; Chabalko J. Solitary lung lesion with cavitation due to necrotizing sarcoid granulomatosis. Del Med J. 1986;58:15-16; and Fisher M, Christ M, Bernstein J. Necrotizing sarcoid-like granulomatosis: radiologic-pathologic correlation. J Can Assoc Radiol. 1984;35:313-315.

Radiologic Features

Necrotizing sarcoid granulomatosis usually manifests as bilateral, multifocal parenchymal nodular opacities. Nodules may be well marginated or have ill-defined borders (Fig. 11.36). Like the granulomas of sarcoidosis, lesions typically have a bronchovascular and subpleural distribution, but unlike in sarcoidosis, they may be more numerous in the lower lung zones.^{40,60,76,77,142} Solitary lesions and parenchymal consolidations may occur but are unusual manifestations.

On CT scans, cavitation and heterogeneous contrast enhancement of the lesions may be seen (Fig. 11.37), correlating with intralesional necrosis.¹³⁹ Pleural involvement with thickening or effusion may also be observed.¹⁴² Hilar lymphadenopathy is variable and not seen as frequently as in sarcoidosis.⁵⁹

Figure 11.36 Necrotizing sarcoid granulomatosis. Posteroanterior chest radiographs from a 40-year-old man with fatigue, fever, and dyspnea. (A) At clinical presentation, note diffuse bilateral air space consolidation with a predilection for the bases and the midlung zones. (B) After biopsy and steroid therapy, marked improvement is evident, with residual parenchymal consolidation in the lung periphery and lower lobes. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.24.)

Figure 11.37 Necrotizing sarcoid granulomatosis: computed tomography (CT) features. Chest CT scan (lung window) in a 41-year-old man with cough demonstrates multifocal small nodules. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.25.)

Pathologic Features

Confluent nonnecrotizing granulomas form large nodules in the lung parenchyma (Fig. 11.38). Large zones of necrosis are present in the nodules (Fig. 11.39), and vasculitis (Fig. 11.40) is typically present. The granulomas in necrotizing sarcoid granulomatosis resemble those of sarcoidosis, except for the presence of necrosis, with tight clusters of giant cells and epithelioid cells (Fig. 11.41). One can also see a sarcoidal pattern of lung involvement with a lymphangitic distribution to the granulomas.^59,60,137 In addition to the large zones of necrosis, smaller foci of necrosis are often present.⁵⁹

The vasculitis of necrotizing sarcoid granulomatosis can affect both arteries and veins. Three patterns of vasculitis can be seen: necrotizing granulomas (Fig. 11.42), giant cell vasculitis (Fig. 11.43), and infiltration by chronic inflammatory cells.¹⁴³ Necrotizing granulomas may be present circumferentially along the vascular walls (Fig. 11.44).

Differential Diagnosis

The differential diagnosis for necrotizing sarcoid granulomatosis includes granulomatous infection, nodular sarcoidosis, and GPA. The most important of these entities, and the most difficult to exclude, is granulomatous infection,^59,65 especially because granulomatous infections caused by mycobacteria and fungi can produce both vasculitis and sarcoid-like granulomas.^49,50 Some investigators regard necrotizing sarcoid granulomatosis as representing the subset of sarcoidosis referred to as nodular sarcoidosis, but true necrosis, as seen in this disorder, is not typically present in the nodular form of sarcoidosis. The key features distinguishing necrotizing sarcoid granulomatosis from GPA are summarized in Table 11.7.

Treatment and Prognosis

The prognosis for patients with necrotizing sarcoid granulomatosis is excellent.^137,144 Localized disease can be cured by surgical resection alone. Patients with bilateral opacities or nodules may respond to systemic corticosteroids. A small percentage of patients will have persistent opacities^60,61 or will experience a relapse.^59,145 the only deaths reported in patients with necrotizing sarcoid granulomatosis have been due to opportunistic infections, so cytotoxic immunosuppression generally is not recommended.⁶⁰

Giant Cell (Temporal) Arteritis

Giant cell arteritis is a vasculitis that most commonly involves the temporal arteries in older individuals. Vascular lesions include giant cells, typically centered on the vascular elastic lamina (Fig. 11.45). Lower respiratory tract involvement is extremely rare, although the disease can be associated with upper respiratory tract symptoms in approximately 10% of patients.¹⁴⁶ When the lungs are involved, patients may have nodules,^147,148 interstitial opacities,¹⁴⁹ and unilateral pleural effusions on chest radiographs.¹⁴⁶ Pulmonary arterial involvement is rarer still,¹⁵⁰ but giant cell arteritis can affect the pulmonary trunk and main pulmonary arteries, as well as large and medium-sized intrapulmonary elastic arteries.¹⁵⁰ Histologically the vasculitis shows medial and adventitial chronic inflammation with included giant cells. This causes destruction of the elastic laminae sometimes with focal fibrinoid medial necrosis.¹⁵⁰ Bronchoscopic biopsies may show granulomatous inflammation of pulmonary arteries and fragmented elastic fibers.^147,150 Giant cell arteritis can be distinguished from GPA, necrotizing sarcoid granulomatosis, EGPA, and granulomatous infections by the absence of parenchymal inflammation. The temporal artery involvement and older age of patients with giant cell arteritis distinguishes them from those with Takayasu arteritis.¹⁵⁰

Figure 11.38 Necrotizing sarcoid granulomatosis: large nodules with variable necrosis. Large parenchymal inflammatory nodules with necrosis are typically seen. (A) Confluent nonnecrotizing granulomas are a dominant feature. (B) Elastic tissue stains help demonstrate vascular involvement within and around nodules (upper right, off center).

Figure 11.39 Necrotizing sarcoid granulomatosis: large zones of necrosis. Large zones of necrosis are seen at right.

Figure 11.40 Necrotizing sarcoid granulomatosis: vasculitis. Vasculitis is a typical feature of this disorder. Here, lymphocytes and plasma cells infiltrate the media and subintimal region of a pulmonary artery. Note the adventitial fibrosis.

A very rare disorder known as idiopathic isolated pulmonary giant cell arteritis has also been described.¹⁵¹¹⁵³ the disease is limited to the lungs. Dyspnea on exertion may be a presenting manifestation, but patients usually lack hemoptysis, fever, or elevation of the erythrocyte sedimentation rate. The vasculitis is usually an unsuspected finding seen first in a surgical or an autopsy specimen.^151,152 Histologically, organized arterial thrombi with recanalization are identified, and narrowing of large pulmonary arteries is seen. The vasculitis is characterized by a destructive inflammatory infiltrate of giant cells, histiocytes, and lymphocytes causing fragmentation ofelastic laminae.^151-153 Peripheral lung infarcts can occur.

Figure 11.41 Necrotizing sarcoid granulomatosis: sarcoid-like granulomas. (A) the granulomas in this disorder resemble those of sarcoidosis. (B) Admixed multinucleate giant cells are typically seen.

Figure 11.42 Necrotizing sarcoid granulomatosis: granulomatous vasculitis. (A) Granulomatous vasculitis (arrows) is a common pattern in this disorder. (B) An elastic tissue stain is often helpful in defining distorted arteries (arrows) within the inflammatory process.

Figure 11.43 Necrotizing sarcoid granulomatosis: giant cells in arteries. Giant cells may be a prominent component of the vasculitis.

Table 11.7 Granulomatosis With Polyangiitis/Wegener Granulomatosis Versus Necrotizing Sarcoidosis: Distinguishing Features

Clinical/Pathologic Feature	Granulomatosis With Polyangiitis	Necrotizing Sarcoidosis
Lung involvement	66%—85%	100%
Extrapulmonary involvement	90%-100% ENT, kidney, skin, neurologic	<10% Ocular, neurologic
ANCA	Yes	No
Histopathologic pattern
Sarcoidal granulomas	Rare	Characteristic
Vasculitis	Characteristic	Characteristic

ANCA, Antineutrophil cytoplasmic antibodies; ENT, ear, nose, and throat.

Figure 11.44 Necrotizing sarcoid granulomatosis: circumferential vascular envelopment. (A) In this disorder, granulomas may envelop arteries in a circumferential fashion. (B) An elastic tissue stain shows both subintimal granulomas, as well as granulomas involving the adventitia in a circumferential fashion.

Figure 11.45 Giant cell arteritis: involvement of a large pulmonary artery. (A) A central pulmonary artery shows extensive medial damage. (B) the area designated by an arrow in part A at higher magnification. Note the multinucleate giant cell and inflammation along the elastic lamina of the vessel.

Disseminated visceral giant cell angiitis is another rare form of giant cell arteritis that affects extracranial small arteries and arterioles, including those in the lung. This is a very rare condition, with only five reported cases, in males, three of whom had lung involvement.^154,155 In all of these cases, the disorder was recognized as an incidental autopsy finding.¹⁵⁴ Extracranial small arteries and arterioles were affected, and each patient demonstrated involvement of at least three of the following organs: heart, lung, kidneys, liver, pancreas, and stomach. The vasculitis showed prominent multinucleate giant cells of both foreign body and Langerhans types, but most of the inflammatory cells consisted of histiocytes, lymphocytes, and plasma cells. A relationship has been proposed between sarcoidosis and disseminated visceral giant cell arteritis, but the occurrence of these two manifestations together is so rare that it is difficult to confirm.^156-158

Polyarteritis Nodosa

Classic polyarteritis nodosa is a vasculitis that involves arteries of medium and small size (Fig. 11.46). It can involve virtually any organ but rarely affects the lungs. Most cases previously reported as polyarteritis nodosa with lung involvement were probably examples of EGPA^111,159-161 or possibly small-vessel vasculitis (i.e., microscopic polyangiitis). Polyarteritis nodosa differs from EGPA and microscopic polyangiitis in that only arteries are affected. The tissue eosinophilia and extravascular granulomas characteristic of EGPA are not seen. Polyarteritis nodosa differs from microscopic polyangiitis in that medium-sized arteries are affected (primarily bronchial arteries),^12,161 whereas in microscopic polyangiitis, smaller arteries, venules, and capillaries typically manifest the disease.^113,114

Takayasu Arteritis

Takayasu arteritis is a vasculitis that primarily affects the aorta and its branches. The arteritis is comprised of lymphocytes, macrophages, and giant cells that infiltrate the adventitia, media, and intima of these vessels.

Clinical Features

Takayasu arteritis most commonly affects women less than 40 years of age.¹⁶² Pulmonary arteries are involved in 12% to 86% of patients with the disease,^162-165 and rarely, pulmonary artery involvement may be the presenting manifestation.¹⁶⁶ Takayasu arteritis may affect the kidneys, heart, skin, and gastrointestinal tract.¹⁶⁷ Because it is difficult to obtain tissue biopsy specimens from large vessels such as the aorta or pulmonary artery, the diagnosis is usually established by angiography. Pulmonary artery stenosis, irregular narrowing, and occlusion may be seen.^163,164,168 Fistulas between pulmonary arteries and systemic arteries may occur.¹⁶⁹

Figure 11.46 Polyarteritis nodosa: arteritis. (A) Arteries of medium and small size are typically involved. (B) the vasculitic process at higher magnification.

Figure 11.47 Takayasu arteritis. The wall of this pulmonary artery is infiltrated by lymphocytes and giant cells. (From Travis WD, Colby TV Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.29.)

Radiographic Features

CT scan findings in Takayasu arteritis frequently include areas of low attenuation in the lung, presumably on the basis of regional hypoperfusion related to upstream arteritis.¹⁷⁰ Subpleural linear reticular changes and pleural thickening also occur.¹⁷⁰

Pathologic Features

Takayasu arteritis involves the adventitia, media, and intima of large elastic pulmonary arteries (Fig. 11.47). Infiltration by lymphocytes, macrophages, and giant cells is characteristic. Thrombi may also be seen. There is progression to diffuse or nodular fibrosis of the artery wall with disintegration or loss of elastic fibers.^171,172 the fibrosis can result in stenosis or obliteration of the vascular lumen and cause aneurysm formation or dilatation of the artery. Matsubara and associates described a stenosis-recanalization phenomenon they called “blood vessels in blood vessels,” occurring within the pulmonary elastic and muscular arteries.¹⁷²

Treatment

Corticosteroid therapy is often effective, but some patients with Takayasu arteritis require the addition of a cytotoxic agent (e.g., cyclophosphamide) for management. Stenotic arterial lesions have been successfully corrected by surgical techniques.¹⁷³

Behçet Syndrome

Behçet syndrome is a multisystem inflammatory disorder characterized by skin lesions, oral and genital ulcers, and iridocyclitis. Debate continues over the nature of the disease. The etiology is unknown, but environmental, genetic, viral, bacterial, and immunologic factors have been implicated in its pathogenesis. The lung manifestations are clearly vasculitic, but an immune complex-mediated hypersensitivity reaction has been proposed for the mucocutaneous lesions, and an association with human leukocyte antigen (HLA)-B51 has been identified.¹⁷⁴

Clinical Features

Behçet syndrome has a worldwide distribution but is most commonly a disease of the Mediterranean basin, the Middle East, and Japan.^{175,176 the} disease typically affects individuals between adolescence and middle age. The diagnosis is based primarily on clinical criteria (Box 11.5). The clinical feature that is common to all patients with Behçet syndrome is recurrent painful aphthous oral or genital ulcers. Oral ulceration occurring more than three times in 1 year is required to meet the diagnostic criteria for the disease. These lesions must be distinguished from ulcers related to viral infection such as herpes simplex, and other diseases such as inflammatory bowel disease or SLE.

Symptoms of pulmonary involvement include dyspnea, cough, chest pain, and hemoptysis.¹⁷⁶ Males are more likely to develop lung manifestations, particularly hemoptysis.^176,177 the presence of circulating immune complexes in patients with active pulmonary disease suggests that immune complexes may be important in the pathogenesis of the lung involvement.¹⁷⁷

Figure 11.48 Behçet syndrome: vasculitis. The wall of this small artery is infiltrated by lymphocytes. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.30.)

Radiographic Features

Air space consolidation consistent with pulmonary hemorrhage, lung infarction, and pulmonary artery aneurysms may be seen when the lungs are involved.^178,179 'Thoracic involvement in the patient with Behçet syndrome can sometimes be suggested on CT images by the presence of thrombosis in the pulmonary arteries or in the superior vena cava. Characteristic aneurysms of the pulmonary arteries can also occur.^178,179 Pulmonary aneurysms and thromboses can be detected with angiography as well.¹⁷⁶

Pathologic Features

Pulmonary involvement is characterized by a lymphocytic and necrotizing vasculitis that involves pulmonary arteries of all sizes, veins, and alveolar septal capillaries (Fig. 11.48). Additional findings include aneurysms of elastic pulmonary arteries, arterial and venous thrombosis (Fig. 11.49), pulmonary infarcts (Fig. 11.50), bronchial erosion by pulmonary artery aneurysms, and arteriobronchial fistulas.^176,180,181 Perivascular adventitial fibrosis may be prominent. Collateral vessels lacking elastic lamellae may develop in the periadventitial fibrous tissues around thrombosed arteries and aneurysms (Fig. 11.51). Hemorrhage¹⁸² and acute interstitial pneumonia¹⁸³ may occur as life-threatening pulmonary complications.

Treatment

A variety of treatments have been used to address the mucocutaneous manifestations of the disease, including oral colchicine, topical anesthetics, and corticosteroids (topical, intralesional, or systemic). Thalidomide and dapsone have also been shown to be effective. Aggressive immunosuppression with combined systemic corticosteroids and another agent (azathioprine, cyclophosphamide, cyclosporine, chlorambucil) may be necessary when significant ocular, neurologic, gastrointestinal, and vascular manifestations occur. Patients who develop thromboses require anticoagulation.¹⁷⁷ Severe hemoptysis may require surgical intervention.¹⁸² the clinical course of Behçet syndrome is characterized by exacerbations and remissions. Over time, the disease may decrease in severity.

Figure 11.49 Behçet syndrome: organizing thrombus. The web of fibrosis traversing the lumen of this elastic artery is a recanalized thrombus. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.31.)

Figure 11.50 Behçet syndrome: pulmonary infarct. A pulmonary infarct can be seen here on elastic tissue stain. The arrows designate disrupted elastica of a pulmonary artery at the edge of a lung infarct (red).

Secondary Vasculitis

Pulmonary Infection and Septic Emboli

When pulmonary vessels are involved by inflammation and necrosis in the setting of infection, secondary vasculitis should always be a strong consideration. Certain bacterial pneumonias, especially those caused by Pseudomonas aeruginosa™⁴ and Legionella pneumophila,¹⁵⁵ are well known for their tendency to invade and produce necrosis of blood vessel walls. The necrotizing granulomas produced in response to fungal and mycobacterial infections commonly involve blood vessel walls, causing potential confusion with vascular involvement by GPA.⁵⁰ Necrotizing vasculitis may also be a consequence of angioinvasive fungal infections in the immunocompromised patient, especially infections due to Aspergillus and Mucor species. Such vasculitis may be granulomatous and frequently causes pulmonary infarction. Pulmonary vasculitis can also accompany certain parasitic pulmonary infections such as Dirofilaria immitis, Schistosoma, and Wuchereria infections. In HIV- infected patients, vasculitis can even be a rare complication of Pneumocystis pneumonia.¹⁸⁶

Figure 11.51 Behçet syndrome: collateral vessels. The collateral vessels in the periad- ventitial tissues surrounding this large elastic artery lack elastic lamellae. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.33.)

Classic Sarcoidosis

Classic sarcoidosis can produce so-called granulomatous vasculitis (involvement of blood vessel walls by typical sarcoid granulomas) as an incidental histologic finding in surgical lung biopsies (see Chapter 8).¹⁸⁷

In rare instances, a systemic vasculitis can occur in patients with sarcoidosis. Fernandes and colleagues reported 6 cases in which patients exhibited features of both sarcoidosis and systemic vasculitis and reviewed 22 similar cases that had been previously reported.¹⁸⁸ the group included 13 children and 15 adults who developed fever, peripheral adenopathy, hilar adenopathy, rash, pulmonary parenchymal disease, musculoskeletal symptoms, and scleritis or iridocyclitis.¹⁸⁸

Radiologic Features

Arteriography demonstrated involvement of medium-sized or large arteries in approximately one-half of the patients and features of small- vessel disease in the remaining patients.¹⁸⁸

Pathologic Features

Pathologic findings consisted of sarcoid-like granulomas, sometimes with foci of necrosis, involving vessels in the skin, lymph node, lung, synovium, bone, bone marrow, liver, trachea, or sclera.

Therapy and Prognosis

Patients may respond to prednisone alone; as reported by Fernandes and colleagues, however, relapses tended to occur when the medication was tapered or withdrawn.¹⁸⁸

Pulmonary Hemorrhage

Hemorrhage in the lung may occur as a localized phenomenon or as a diffuse disease. Clinically significant hemorrhage is nearly always accompanied by hemoptysis. When blood is identified in the lung biopsy specimen, the question frequently arises as to whether it is a real finding or simply an artifact related to the procedure. Real pulmonary hemorrhage can be caused by a number of unrelated mechanisms. Pulmonary vasculitis and vasculitic syndromes, such as Goodpasture syndrome, are important clinical causes of lung hemorrhage and typically require urgent therapy. Because the differential diagnosis is broad in scope, and the consequences of accurate diagnosis are significant, a diagnostic approach to pulmonary hemorrhage is presented here. A useful algorithm for this exercise is presented in Fig. 11.52.

Clinical View of Pulmonary Hemorrhage

The occurrence of hemoptysis is alarming to patient and clinician alike. The potential causes of hemoptysis are presented in Box 11.6. The distinction of localized from diffuse hemorrhage is important for management purposes but is not always feasible. With the classic presentation of sudden unilateral chest pain followed by expectoration of bright red blood, pulmonary embolus is usually high on the list of diagnostic possibilities. In most instances, however, the clinician must rely heavily on the radiologic findings in the approach to the patient with hemoptysis because the physical examination is typically limited in defining the origin or extent of any hemorrhagic event. Bronchoscopy plays an important role as well in defining a potential localized source of bleeding and documenting the presence of hemosiderin-laden macrophages (siderophages) in lavage specimens examined under the microscope. Localized causes of pulmonary hemorrhage are often straightforward and include thromboembolism, tumor, abscess, bronchiectasis, and broncholithiasis. Dieulafoy disease is a rare entity characterized by an abnormal submucosal location of arterial branches. This abnormality is more frequently described in the gastrointestinal tract, but rare bronchial cases have been reported.¹⁸⁹ At times, localized hemorrhage may be life-threatening, requiring lobectomy for control. In this situation, blood may be abundant in the lung parenchyma, but no exact origin for bleeding can be identified (analogous to colectomy for massive hemorrhage associated with diverticulosis). Diffuse pulmonary hemorrhage is more complicated in terms of etiology and will be the main focus here.

Morphologic Approach to Pulmonary Hemorrhage

Not all patients with hemoptysis have histologic evidence of hemorrhage, and conversely, not all hemorrhage, or hemosiderin, seen in lung tissue is associated with hemoptysis or other evidence of lung hemorrhage. For the pathologist, the first step in the evaluation of extravascular blood seen in a biopsy specimen is to ascertain the context in which it occurs. Clinically significant hemorrhage is rarely seen in biopsy specimens as blood alone. When intact red cells abound, the most common cause is trauma related to the biopsy procedure, especially in the case of thoracoscopic biopsies because of intraoperative manipulation.¹⁹⁰ In artifactual hemorrhage (Fig. 11.53), fibrin, hemosiderin-laden macrophages, and cellular reactive changes in adjacent alveolar walls are typically lacking. Also, focal areas of organization may be seen within the air spaces in true hemorrhage and may be a useful marker for associated lung injury.

Figure 11.52 Diffuse alveolar hemorrhage. Algorithm. BAL, Bronchoalveolar lavage; CT, computed tomography; GPA, granulomatosis with polyangiitis; OLBx, open lung biopsy; SLE, systemic lupus erythematosus; TBBx, transbronchial biopsy. (From Colby TV, Fukuoka J, Ewaskow SP, et al. Pathologic approach to pulmonary hemorrhage. Ann Diagn Pathol. 2001;5: 309-319.)

Unfortunately, the presence of siderophages alone is not sufficiently specific for active hemorrhage in the absence of other, more acute findings. Siderophages can occur as early as 2 days after an episode of alveolar hemorrhage, but can persist for weeks or even months after the event. Furthermore, the distinction of siderophages caused by hemorrhage from the pigmented macrophages seen in the lungs of cigare The smokers can be difficult on occasion.

The Prussian blue histochemical stain for iron is sometimes cited as a means of distinguishing siderophages from hemorrhage from macrophages seen in smokers (Fig. 11.54), but caution must be exerted because so-called smoker’s macrophages may contain considerable amounts of stainable iron (Fig. 11.55). The pigment in smoker’s macrophages tends to be finely granular and light brown, typically admixed with punctate black pigment. True siderophages, on the other hand, are characterized by the presence of coarse, golden-brown pigment that is minimally refractile (Fig. 11.56). Also, it is important to keep in mind that the Prussian blue stain reacts with other iron-associated substances in the lung, in addition to hemosiderin. Occupational dusts may contain iron and simulate siderophages in the patient with pneumoconiosis.

Box 11.6 Causes of Hemoptysis

Infectious Diseases	Ruptured bronchus
Bacterial	Tracheocarotid fistula
Lung abscess*	Bronchoscopy
Bronchitis*	Swan-Ganz catheterization
Tuberculosis*	Lung biopsy
Bronchiectasis (including cystic fibrosis)	Transtracheal aspirate
Chronic pneumonia	Lymphangiography
Viral	Hickman catheter-induced cavabronchial fistula
Fungal Mycetoma	Immunologic Conditions
Parasitic	Vasculitides
Paragonimiasis (in endemic areas)*	Granulomatosis with polyangiitis/Wegener granulomatosis Systemic lupus erythematosus
Cardiovascular Diseases	Microscopic polyangiitis
Left ventricular failure*	Goodpasture syndrome/antiglomerular basement membrane antibody syndrome
Pulmonary thromboembolism with infarction*	Idiopathic pulmonary hemosiderosis
Mitral stenosis	Other lung-renal syndromes
Tricuspid endocarditis Pulmonary hypertension	Drugs and Toxins
Aneurysms	Anticoagulants
Aortic aneurysm	Cocaine
Subclavian artery aneurysm	Penicillamine
Left ventricular pseudoaneurysm	Trimellitic anhydride
Vascular prostheses	Solvents
Arteriovenous malformation	Amiodarone
Portal hypertension Absence of the inferior vena cava	Miscellaneous Entities
Pulmonary artery agenesis with lung systemic vascularization	Increased bleeding tendency
	Coagulopathy
Neoplasms	Thrombocytopenia
Pulmonary carcinoma*	Amyloidosis
Squamous cell carcinoma	Broncholithiasis
Small cell carcinoma*	Endometriosis
Carcinoid tumor	Thoracic splenosis
Tracheobronchial gland tumors	Aspirated foreign body
Metastatic carcinoma/sarcoma	Intralobar sequestration Radiation
Trauma	Lymphangiomyomatosis
Aortic tear	Factitious
Lung contusion	Bronchiolitis obliterans organizing pneumonia (BOOP)
Lithotripsy	Lipoid pneumonia

*Most common causes.

From Colby TV, Fukuoka J, Ewaskow SP, et al. Pathologic approach to pulmonary hemorrhage. Ann Diagn Pathol. 2001;5:309-319; data from Fraser R, Müller N, Colman N, Paré P. Fraser and Fare's Diagnosis of Diseases of the Chest. 4th ed. Philadelphia: Saunders; 1999.

Figure 11.53 Diffuse alveolar hemorrhage: artifactual hemorrhage. The distinction of artifactual hemorrhage into alveolar spaces from true hemorrhage can be difficult at times. (A) Artifactual hemorrhage in alveolar spaces. (B) Note the absence of fibrin and hemosiderin-laden macrophages. Also, the interstitium exhibits no evidence of cellular reaction.

Figure 11.54 Diffuse alveolar hemorrhage: iron in smoker's macrophages. (A) the pigmented macrophages in the lungs of smokers can contain iron in their cytoplasm, evident as granular brown material. (B) An iron stain will show this phenomenon.

Figure 11.55 Diffuse alveolar hemorrhage: iron in smoker's macrophages. (A) Caution is advised in interpreting the significance of pigment in macrophages. (B) Here, pigmented macrophages in the lung of a cigare The smoker contain abundant hemosiderin. Other histopathologic features of immunologically mediated hemorrhage are not seen.

When all of the elements in the biopsy add up to real hemorrhage, and the patient has radiologic evidence of diffuse alveolar infiltrates, the differential diagnosis becomes one of diffuse alveolar hemorrhage (DAH). The potential causes of DAH are presented in Box 11.7. It is useful to divide DAH into two forms characterized by the presence or absence of capillaritis, respectively. Rapidly evolving acute DAH is often accompanied by capillaritis and evokes a differential diagnosis of narrow scope.

Diffuse Alveolar Hemorrhage

The histopathology of DAH is stereotypical, regardless of etiology. This fact is important for the surgical pathologist because a specific diagnosis requires clinical and serologic data.^62,191 A generic designation such as “[acute] and/or [organizing] pulmonary hemorrhage [with] or [without] capillaritis” followed by a differential diagnosis is often all that is required.

Most causes of DAH are immunologically mediated. Some of these diseases have specific patterns of immunoglobulin deposition that can be visualized in tissue sections using immunofluorescence staining of a specially prepared portion of the surgical lung biopsy. When such staining is performed correctly, the results can be diagnostically useful and visually striking. Fortunately, in practice today, immunofluorescence staining is rarely necessary for diagnosis because serologic studies are widely available and reasonably specific for the subtypes of DAH. For those forms of DAH mediated by immune complexes, deposits in the lung tissue can also be visualized ultrastructurally. Again, although historically interesting, electron microscopy really plays no role in the diagnosis of DAH today. A comparison of the major defined pulmonary vasculitis syndromes is presented in Table 11.8.

Figure 11.56 Diffuse alveolar hemorrhage: true hemosiderin-laden macrophages of hemorrhage. (A) In contrast with smoker’s macrophages with iron, true siderophages have granular refractile hemosiderin, which aggregates into large and small globular particles. (B) An iron stain accentuates this distinction.

Specific Forms of Diffuse Alveolar Hemorrhage

Goodpasture Syndrome

Goodpasture syndrome (antiglomerular basement membrane antibody disease) affects persons of all ages and both sexes, but the typical patient is a young male smoker.¹⁹² Circulating antibodies directed against the noncollagenous domain of the alpha 3 chain of collagen type IV are identified in patients with Goodpasture syndrome. Using immunolocalization techniques, these antibodies can also be detected in the lung and kidney, where they are deposited in association with basement membranes. The histopathology of Goodpasture syndrome in the lung is not specific and resembles that in other DAH syndromes (Fig. 11.57). Capillaritis may be present but generally is not prominent.¹⁹³ Hyaline membranes may accompany the pulmonary hemorrhage of Goodpasture syndrome (Fig. 11.58).

Granulomatosis With Polyangiitis (Wegener Granulomatosis)

A minority of patients with GPA present with pulmonary hemorrhage, although hemorrhage may occur in the course of the disease.¹⁹³ the typical systemic and serologic features of GPA, as outlined earlier, often accompany DAH, making a clinical diagnosis possible even when the lung biopsy lacks diagnostic features. DAH in GPA is often attended by dramatic capillaritis (Fig. 11.59). A careful search may reveal small foci of collagen necrosis, typically involving the adventitia of pulmonary arteries and the collagen surrounding bronchi and bronchioles. The presence of scattered giant cells may also be helpful in suggesting GPA as a possible underlying disorder in DAH.

Microscopic Polyangiitis

Microscopic polyangiitis was discussed in detail earlier in this chapter. When alveolar hemorrhage dominates the presentation, distinction from GPA may be impossible on biopsy findings alone (Fig. 11.60). The frequency of extrathoracic site involvement in the two diseases and the common presence of p-ANCA in microscopic polyangiitis usually suffice to differentiate them.

Systemic Lupus Erythematosus

DAH occurs more commonly in SLE than in any other connective tissue disease. Nevertheless, DAH is the presenting manifestation of the disease in only 11% of patients with SLE.¹⁹⁴ Patients with lupus nephritis are at increased risk for DAH. The histopathology of DAH in SLE is similar to that of other pulmonary hemorrhage syndromes, including the presence of capillaritis (Fig. 11.61).

Table 11.8 Diffuse Alveolar Hemorrhage Manifestations in Major Pulmonary Vasculitis Syndromes

Feature	Vasculitic Syndrome
	EGPA	HSP	Goodpasture Syndrome	GPA	MPA	SLE	Isolated IPH
Laboratory Findings
Anti-GBM	No	No	Yes	No	No	No	No
c-ANCA	No	No	No	Usually	No	No	NA
p-ANCA	Usually	No	No	Rarely	Yes	No	NA
ANA	No	No	No	No	No	Yes	NA
Extrapulmonary Involvement
Kidney	Occasional	Often	Often	Often	Often	Often	No
Other organs	Often	Often	No	Sometimes	Sometimes	Sometimes	No
Histopathologic Findings
Necrotizing capillaritis	No	Sometimes	Sometimes	Yes	Yes	Yes	Yes
Immunofluorescence	No	No	Linear	No	No	No	No
Electron-dense	No	No	No	No	No	Yes	No

ANA, Antinuclear antibody; c-ANCA/p-ANCA, cytoplasmic/perinuclear antineutrophil cytoplasmic antibodies; EGPA, eosinophilic granulomatosis and polyangiitis (Churg-Strauss syndrome); GBM, glomerular basement membrane; GPA, granulomatosis and polyangiitis (Wegener granulomatosis); HSP, Henoch-Schonlein purpura; IPH, idiopathic pulmonary hemosiderosis; MPA, microscopic polyangiitis; NA, not available [insufficient data]; SLE, systemic lupus erythematosus.

Data from Lynch J, Leatherman J. Alveolar hemorrhage syndromes. In: Fishman A, Elias JA, Fishman JA, et al., eds. Fishmans Pulmonary Diseases and Disorders. 3rd ed. New York: McGraw-Hill; 1998:1193-1210; Schwarz M, Cherniak P, King T Diffuse alveolar hemorrhage and other rare infiltrative disorders. In: Murray J, Nadel J, eds. Textbook of Respiratory Medicine. Philadelphia: Saunders; 2000:1733-1755; Katzenstein A. Alveolar hemorrhage syndromes. In: Katzenstein A, Askin F, eds. Surgical Pathology of Non-neoplastic Lung Disease. Philadelphia: Saunders; 1997:153-159; and Jenne The J, Thomas D, Falk R. Microscopic polyangiitis (microscopic polyarteritis). Semin Diagn Pathol. 2001;18:3-13.

Figure 11.57 Goodpasture syndrome: diffuse alveolar hemorrhage with capillaritis. (A) Alveolar hemorrhage with capillaritis is a typical finding in Goodpasture syndrome. (B) In some cases, the capillaritis may be quite cellular and prominent.

Idiopathic Pulmonary Hemosiderosis

Idiopathic pulmonary hemosiderosis affects children more commonly than adults and is characterized by recurrent episodes of DAH with hemoptysis. Patients are frequently anemic. An immunologic mechanism for the disease has not yet emerged, and capillaritis is not seen. The histopathology of idiopathic pulmonary hemosiderosis is dominated by the presence of hemosiderin (Fig. 11.62). Interstitial widening with collagen deposition occurs over time.¹⁹⁵

Henoch-Schonlein Purpura (IgA Vasculitis)

Like idiopathic pulmonary hemosiderosis, Henoch-Schonlein purpura affects children more often than adults.¹²⁰’¹⁹²’¹⁹⁴’¹⁹⁶ Alveolar hemorrhage is rare and typically overshadowed by other systemic manifestations of the disease, such as involvement of the skin, joints, and kidneys. The histopathologic changes of pulmonary hemorrhage in Henoch-Schonlein purpura are nonspecific and resemble those of other pulmonary hemorrhage syndromes.

Figure 11.58 Goodpasture syndrome: hyaline membranes. As in other immune-mediated forms of alveolar hemorrhage, hyaline membranes may occur in Goodpasture syndrome.

Figure 11.59 Granulomatosis with polyangiitis (GPA): capillaritis. Diffuse alveolar hemorrhage with capillaritis indistinguishable from other hemorrhage syndromes can be seen in GPA. Here, air space hemorrhage, fibrin, hemosiderin-laden macrophages, and capillaritis are all evident.

Figure 11.60 Microscopic polyangiitis: capillaritis. (A) A case of microscopic polyangiitis showing air space fibrin and a cellular interstitium. (B) Another example showing neutrophils filling alveolar spaces, resembling acute bronchopneumonia.

Figure 11.61 Systemic lupus erythematosus (SLE): capillaritis. Alveolar hemorrhage with capillaritis can occur in SLE. Here, the picture is indistinguishable from that seen previously with Goodpasture syndrome, granulomatosis with polyangiitis, and microscopic polyangiitis.

Figure 11.62 Idiopathic pulmonary hemosiderosis: mild hemosiderosis to fibrosis. The hemosiderin deposition can be mild (A) or prominently associated with interstitial thickening and air space fibrin (B). Capillaritis and vasculitis are not expected findings in this disorder.

Isolated Pulmonary Capillaritis

Isolated pulmonary capillaritis is a rare form of DAH in which no associated immunologic or systemic manifestations are found. There may be overlap between this disorder, idiopathic pulmonary hemosiderosis in adults, and the group of diseases designated by Travis and coworkers as idiopathic pulmonary hemorrhage.⁶² the histopathology of isolated pulmonary capillaritis is similar to that in other alveolar hemorrhage syndromes that include capillaritis.

Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com.

References

1. Watts RA, Scott DG. Epidemiology of the vasculitides. Curr Opin Rheumatol. 2003;15(1):11-16.

2. Travis WD. Vasculitis. In: Tomashefski JF, Cagle PT, Farver CF, Fraire AE, eds. Dail and HammarS Pulmonary Pathology. 3rd ed. China: Springer; 2008:1088-1138.

3. Travis WD, Colby TV, Koss MN, et al. Pulmonary vasculitis. In: King DW, ed. Atlas of Non tumor Pathology. Washington, DC: American Registry of Pathology; 2002:233-264.

4. Guinee DJ, Jaffe E, Kingma D, et al. Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol. 1994;18:753-764.

5. Nicholson A, Wotherspoon A, Diss T, et al. Lymphomatoid granulomatosis: evidence that some cases represent Epstein-Barr virus-associated B-cell lymphoma. Histopathology. 1996;29:317-324.

6. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. Lyon: IARC Press; 2015:412.

7. Jenne The JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11.

8. DeRemee RA, McDonald TJ, Harrison EG, Coles DT Wegener’s granulomatosis. Anatomic correlates, a proposed classification. Mayo Clin Proc. 1976;51:777-781.

9. Carrington CB, Liebow AA. Limited forms of angiitis and granulomatosis of Wegener’s type. Am J Med. 1966;41:497-527.

10. Stone JH. Limited versus severe Wegener’s granulomatosis: baseline data on patients in the Wegener’s granulomatosis etanercept trial. Arthritis Rheum. 2003;48(8):2299-2309.

11. Cotch M, Hoffman G, Yerg D, et al. The epidemiology of Wegener’s granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources. Arthritis Rheum. 1996;39:87-92.

12. Carruthers D, Watts R, Symmons D, Scott D. Wegener’s granulomatosis—increased incidence or increased recognition. Br J Rheumatol. 1996;35:142-145.

13. Pallan L, Savage CO, Harper L. ANCA-associated vasculitis: from bench research to novel treatments. Nat Rev Nephrol. 2009;5(5):278-286.

14. Savage CO. The evolving pathogenesis of systemic vasculitis. Clin Med. 2002;2(5):458-464.

15. Kain R, Matsui K, Exner M, et al. A novel class of autoantigens of anti-neutrophil cytoplasmic antibodies in necrotizing and crescentic glomerulonephritis: the lysosomal membrane glycoprotein h-lamp-2 in neutrophil granulocytes and a related membrane protein in glomerular endothelial cells. J Exp Med. 1995;181(2):585-597.

16. Kain R, Exner M, Brandes R, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med. 2008;14(10):1088-1096.

17. Ludviksson BR, Sneller MC, Chua KS, et al. Active Wegener’s granulomatosis is associated with HLA-DR+ CD4+ T cells exhibiting an unbalanced Th1-type T cell cytokine pattern: reversal with IL-10. J Immunol. 1998;160(7):3602-3609.

18. Beaudreuil S, Lasfargues G, Laueriere L, et al. Occupational exposure in ANCA-positive patients: a case-control study. Kidney Int. 2005;67(5):1961-1966.

19. Hoffman G, Kerr G, Leavitt R, et al. Wegener’s granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488-498.

20. Wadsworth D, Siegel M, Day D. Wegener’s granulomatosis in children: chest radiographic manifestations. AJR Am J Roentgenol. 1994;163:901-904.

21. Langford C, Hoffman G. Wegener’s granulomatosis [In Process Citation]. Thorax. 1999;54:629-637.

22. Colby T, Specks U. Wegener’s granulomatosis in the 1990s—a pulmonary pathologists perspective. In: Churg A, Katzenstein A-L, eds. The Lung Current Concepts. Baltimore: Williams & Wilkins; 1993:195-218.

23. Travis W. Common and uncommon manifestations of Wegener’s granulomatosis. Cardiovasc Pathol. 1994;3:217-225.

24. Travis WD, Colby TV, Koss MN, et al. Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology; 2002.

25. Goulart R, Mark E, Rosen S. Tumefactions as an extravascular manifestation of Wegener’s granulomatosis. Am J Surg Pathol. 1995;19:145-153.

26. Gross W, Csernok E. Immunodiagnostic and pathophysiologic aspects of antineutrophil cytoplasmic antibodies in vasculitis. Curr Opin Rheumatol. 1995;7:11-19.

27. Jenne The J, Falk R, Wilkman A. Anti-neutrophilic antibodies—a serologic marker for vasculiti- des. Ann Acad Med Singapore. 1995;24:248-253.

28. Specks U. Pulmonary vasculitis. In: Schwarz M, King T, eds. Interstitial Lung Disease. 3rd ed. Hamilton: B.C. Decker, Inc; 1998:507-534.

29. Gross W, Schnabel A, Trabandt A. New perspectives in pulmonary angiitis. From pulmonary angiitis and granulomatosis to ANCA associated vasculitis [In Process Citation]. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17:33-52.

30. Schultz D, Diego J. Antineutrophil cytoplasmic antibodies (ANCA) and systemic vasculitis: update of assays, immunopathogenesis, controversies, and report of a novel de novo ANCA- associated vasculitis after kidney transplantation. Semin Arthritis Rheum. 2000;29:267-285.

31. Davenport A, Lock R, Wallington T. Clinical relevance of testing for antineutrophil cytoplasm antibodies (ANCA) with a standard indirect immunofluorescence ANCA test in patients with upper or lower respiratory tract symptoms. Thorax. 1994;49:213-217.

32. Nolle B, Specks U, Lüdemann J, et al. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener’s granulomatosis. Ann Intern Med. 1989;111:28-40.

33. Jenne The J, Charles L, Falk R. Anti-neutrophil cytoplasmic autoantibodies: disease associations, molecular biology, and pathophysiology. Int Rev Exp Pathol. 1991;32:193-221.

34. Gal A, Salinas F, Staton GJ. The clinical and pathological spectrum of antineutrophil cytoplasmic autoantibody-related pulmonary disease. A comparison between perinuclear and cytoplasmic antineutrophil cytoplasmic autoantibodies. Arch Pathol Lab Med. 1994;118:1209-1214.

35. Gaudin P, Askin F, Falk R, Jenne The J. The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic autoantibodies specific for anti-proteinase 3 and antimyeloperoxidase [see comments]. Am J Clin Pathol. 1995;104:7-16.

36. Schnabel A, Reuter M, Csernok E, Richter C, Gross WL. Subclinical alveolar bleeding in pulmonary vasculitides: correlation with indices of disease activity. Eur Respir J. 1999;14(1):118-124.

37. Jennings C, Jones N, Dugar J, et al. Wegener's granulomatosis—a review of diagnosis and treatment in 53 patients. Rhinoiogy. 1998;36(4):188-191.

38. Feigin D. Vasculitis in the lung. J Thorac Imaging. 1988;3:33-48.

39. Cordier J-F, Valeyre D, Guillevin L, Loire R, Brechot J-M. Pulmonary Wegener's granulomatosis. A clinical and imaging study of 77 cases. Chest. 1990;97:906-912.

40. Fraser RS, Pare J, Fraser R, Pare P. Diseases of altered immunologic activity. In: Fraser R, Pare J, Fraser R, Pare PS, eds. Synopsis of Diseases of the Chest 2nd ed. Philadelphia: W.B. Saunders, Co.; 1994:392-443.

41. Staples C. Pulmonary angiitis and granulomatosis. Radiol Clin North Am. 1991;29:973-982.

42. Farrelly C. Wegener's granulomatosis: a radiological review of the pulmonary manifestations at initial presentation and during relapse. Clin Radiol. 1982;33:545-551.

43. Aberle D, Gamsu G, Lynch D. Thoracic manifestations of Wegener granulomatosis: diagnosis and course. Radiology. 1990;174:703-709.

44. Katzenstein A, Locke W. Solitary lung lesions in Wegener's granulomatosis. Pathologic findings and clinical significance in 25 cases. Am J Surg Pathol. 1995;19:545-552.

45. Kuhlman J, Hruban R, Fishman E. Wegener granulomatosis: CT features of parenchymal lung disease. J Comput Assist Tomogr. 1991;15:948-952.

46. Primack S, Hartman T, Lee K, Muller N. Pulmonary nodules and the CT halo sign. Radiology. 1994;190:513-515.

47. Daum T, Specks U, Colby T, et al. Tracheobronchial involvement in Wegener's granulomatosis. Am J Respir Crit Care Med. 1995;151:522-526.

48. Maguire R, Fauci A, Doppman J, Wolff S. Unusual radiographic features of Wegener's granulomatosis. AJR Am J Roentgenol. 1978;130:233-238.

49. Travis W, Hoffman G, Leavitt RY, Pass H, Fauci A. Surgical pathology of the lung in Wegener's granulomatosis. Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol. 1991;15:315-333.

50. Ulbright T, Katzenstein A. Solitary necrotizing granulomas of the lung: differentiating features and etiology. Am J Surg Pathol. 1980;4:13-28.

51. Yousem SA. Bronchocentric injury in Wegener's granulomatosis: a report of five cases. Hum Pathol. 1991;22:535-540.

52. Uner A, Rozum-Slota B, Katzenstein A. Bronchiolitis obliterans-organizing pneumonia (BOOP)-like variant of Wegener's granulomatosis. A clinicopathologic study of 16 cases. Am J Surg Pathol. 1996;20:794-801.

53. Mark E, Flieder D, Matsubara O. Treated Wegener's granulomatosis: distinctive pathological findings in the lungs of 20 patients and what they tell us about the natural history of the disease. Hum Pathol. 1997;28:450-458.

54. Lipford E Jr, Margolick J, Longo D, Fauci A, Jaffe E. Angiocentric immunoproliferative lesions: a clinicopathologic spectrum of post-thymic T-cell proliferations. Blood. 1988;72:1674-1681.

55. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Pathol. 1951;27:277-294.

56. Chumbley L, Harrison E Jr, DeRemee R. Allergic granulomatosis and angiitis (Churg-Strauss syndrome). Report and analysis of 30 cases. Mayo Clin Proc. 1977;52:477-484.

57. Koss M, Antonovych T, Hochholzer L. Allergic granulomatosis (Churg-Strauss syndrome). Am J Surg Pathol. 1981;5:21-28.

58. Lanham J, Churg J. Churg-Strauss syndrome. In: Churg A, Churg J, eds. Systemic Vasculitides. 1st ed. New York: Igaku-Shoin; 1991:101-120.

59. Koss M, Hochholzer L, Feigin D, et al. Necrotizing sarcoid-like granulomatosis: clinical, pathologic, and immunopathologic findings. Hum Pathol. 1980;11(5 suppl):510-519.

60. Churg A, Carrington C, Gupta R. Necrotizing sarcoid granulomatosis. Chest 1979;76: 406-413.

61. Churg A. Pulmonary angiitis and granulomatosis revisited. Hum Pathol. 1983;14:868-883.

62. Travis W, Colby T, Lombard C, Carpenter H. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol. 1990;14:1112-1125.

63. Myers J, Kurtin P Katzenstein A, et al. Lymphomatoid granulomatosis. Evidence of immuno- phenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol. 1995;19:1300-1312.

64. Mark E, Ramirez J. Pulmonary capillaritis and hemorrhage in patients with systemic vasculitis. Arch Pathol Lab Med. 1985;109:413-418.

65. Lanham J, Elkon K, Pusey C, Hughes G. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore). 1984;63:65-81.

66. Churg J. Allergic granulomatosis and granulomatous-vascular syndromes. Ann Allergy. 1963;21:619-628.

67. Specks U, DeRemee R. Granulomatous vasculitis. Wegener's granulomatosis and Churg-Strauss syndrome. Rheum Dis Clin North Am. 1990;16:377-397.

68. Fienberg R, Mark E, Goodman M, McCluskey R, Niles J. Correlation of antineutrophil cytoplasmic antibodies with the extrarenal histopathology of Wegener's (pathergic) granulomatosis and related forms of vasculitis. Hum Pathol. 1993;24:160-168.

69. Fauci A, Haynes B, Katz P Wolff S. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients over 21 years. Ann Intern Med. 1983;98:76-85.

70. DeRemee R, McDonald T, Weiland L. Wegener's granulomatosis: observations on treatment with antimicrobial agents. Mayo Clin Proc. 1985;60:27-32.

71. Langford C, Sneller M. New developments in the treatment of Wegener's granulomatosis, polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome. Curr Opin Rheumatol. 1997;9:26-30.

72. Langford C, Sneller M. Update on the diagnosis and treatment of Wegener's granulomatosis. [In Process Citation]. Adv Intern Med. 2001;46:177-206.

73. Stegeman C, Tervaert J, de Jong P Kallengerg C. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group [see comments]. N Engl J Med. 1996;335:16-20.

74. Seo P, Specks U, Keogh KA. Efficacy of rituximab in limited Wegener's granulomatosis with refractory granulomatous manifestations. J Rheumatol. 2008;35(10):2017-2023.

75. Lee RW, D'Cruz DP Novel therapies for anti-neutrophil cytoplasmic antibody-associated vasculitis. Drugs. 2008;68(6):747-770.

76. Travis W, Koss M. Vasculitis. In: Dail D, Hammar S, eds. Pulmonary Pathology. 2nd ed. New York: Springer-Verlag; 1994:1027-1095.

77. Travis W, Koss M. Pulmonary angiitis and granulomatosis: necrotizing sarcoid granulomatosis and Churg-Strauss syndrome. In: Saldana M, ed. Pathology of Pulmonary Disease. 1st ed. Philadelphia: J.B. Lippincott, Co.; 1994:803-809.

78. Sehgal M, Swanson J, DeRemee R, Colby T. Neurologic manifestations of Churg-Strauss syndrome. Mayo Clin Proc. 1995;70:337-341.

79. Groh M, Pagnoux C, Baldini C, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) Consensus Task Force recommendations for evaluation and management. Eur J Intern Med. 2015;26(7):545-553.

80. Masi A, Hunder G, Lie J, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33:1094-1100.

81. Lie J. Illustrated histopathologic classification criteria for selected vasculitis syndromes. American College of Rheumatology Subcommittee on Classification of Vasculitis. Arthritis Rheum. 1990;33:1074-1087.

82. Sasaki A, Hasegawa M, Nakazato Y, Ishida Y, Saitoh S. Allergic granulomatosis and angiitis (Churg-Strauss syndrome). Report of an autopsy case in a nonasthmatic patient. Acta Pathol Jpn. 1988;38:761-768.

83. Gambari P, Ostuni P, Lazzarin P, Fassina A, Todesco S. Eosinophilic granuloma and necrotizing vasculitis (Churg-Strauss syndrome?) involving a parotid gland, lymph nodes, liver and spleen. Scand J Rheumatol. 1989;18:171-175.

84. Lipworth B, Slater D, Corrin B, Kesseler M, Haste A. Allergic granulomatosis without asthma: a rare "forme fruste" of the Churg-Strauss syndrome. Respir Med. 1989;83:249-250.

85. Greco A, Rizzo MI, De Virgilio A, et al. Churg-Strauss syndrome. Autoimmun Rev. 2015;14(4):341-348.

86. Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore). 1996;75:17-28.

87. Clutterbuck E, Pusey C. Severe alveolar hemorrhage in Churg-Strauss syndrome. Eur J Respir Dis. 1987;71:158-163.

88. Gibson L. Granulomatous vasculitides and the skin. Dermatol Clin. 1990;8:335-345.

89. Olsen KD, Neel HB 3rd, Deremee RA, Weiland LH. Nasal manifestations of allergic granulomatosis and angiitis (Churg-Strauss syndrome). Otolaryngol Head Neck Surg. 1980;88(1):85-89.

90. Fraioli P, Barberis M, Rizzato G. Gastrointestinal presentation of Churg Strauss syndrome. Sarcoidosis. 1994;11:42-45.

91. Harrison D, Simpson R, Kharbanda R, Abernethy V Nimmo G. Antibodies to neutrophil cytoplasmic antigens in Wegener's granulomatosis and other conditions. Thorax. 1989;44:373-377.

92. Churg J, Churg A. Zafirlukast and Churg-Strauss syndrome [letter; comment]. JAMA. 1998;279:1949-1950.

93. Green R, Vayonis A. Churg-Strauss syndrome after zafirlukast in two patients not receiving systemic steroid treatment [letter]. Lancet. 1999;353:725-726.

94. Holloway J, Ferriss J, Groff J, et al. Churg-Strauss syndrome associated with zafirlukast [published erratum appears in J Am Osteopath Assoc 1998 Dec;98(12):676]. J Am Osteopath Assoc. 1998;98:275-278.

95. Frosi A, Foresi A, Fozzoni M, Ubbiali A, Vezzoli F Churg-Strauss syndrome and antiasthma therapy [letter; comment]. Lancet. 1999;353:1102.

96. Wechsler M, Finn D, Gunawardena D, et al. Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma. Chest. 2000;117:708-713.

97. Orriols R, Munoz X, Ferrer J, Huget P Morell F Cocaine-induced Churg-Strauss vasculitis. Eur Respir J. 1996;9:175-177.

98. Churg A, Brallas M, Cronin S, Churg J. Formes frustes of Churg-Strauss syndrome. Chest. 1995;108:320-323.

99. Amundson D. Cavitary pulmonary cryptococcosis complicating Churg-Strauss vasculitis. South Med J. 1992;85:700-702.

100. Worthy S, Muller N, Hansell D, Flower C. Churg-Strauss syndrome: the spectrum of pulmonary CT findings in 17 patients. AJR Am J Roentgenol. 1998;170:297-300.

101. Buschman D, Waldron J Jr, King TJ. Churg-Strauss pulmonary vasculitis. High-resolution computed tomography scanning and pathologic findings. Am Rev Respir Dis. 1990; 142: 458-461.

102. Lai R, Lin S, Lai NS, Lee P. Churg-Strauss syndrome presenting with pulmonary capillaritis and diffuse alveolar hemorrhage. Scand J Rheumatol. 1998;27:230-232.

103. Travis W, Kwon-Chung K, Kleiner D, et al. Unusual aspects of allergic bronchopulmonary fungal disease: report of two cases due to Curvularia organisms associated with allergic fungal sinusitis. Hum Pathol. 1991;22:1240-1248.

104. Brill R, Churg J, Beaver P. Allergic granulomatosis associated with visceral larva migrans. Am J Clin Pathol. 1953;23:1208-1215.

105. Imai H, Nakamoto Y, Hirokawa M, Akihama T, Miura A. Carbamazepine-induced granulomatous necrotizing angiitis with acute renal failure. Nephron. 1989;51:405-408.

106. Strazzella W, Safirstein B. Asthma due to parasitic infestation. N J Med. 1989;89:947-949.

107. Guillevin L, Cohen P, Gayraud M, et al. Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients. Medicine (Baltimore). 1999;78:26-37.

108. Abu-Shakra M, Smy The H, Lewtas J, et al. Outcome of polyarteritis nodosa and Churg-Strauss syndrome. An analysis of twenty-five patients. Arthritis Rheum. 1994;37:1798-1803.

109. Calabrese L, Michel B, Bloch D, et al. The American College of Rheumatology 1990 criteria for the classification of hypersensitivity vasculitis. Arthritis Rheum. 1990;33:1108-1113.

110. Churg J. Nomenclature of vasculitic syndromes: a historical perspective. Am J Kidney Dis. 1991;18:148-153.

111. Leavitt R, Travis W, Fauci A. Vasculitis. In: Shelhamer J, Pizzo P, Parrillo J, Masur H, eds. Respiratory Disease in the Immunosuppressed Host. 1st ed. Philadelphia: J.B. Lippincott, Co; 1991:703-727.

112. Swerlick R, Lawley T Small-vessel vasculitis and cutaneous vasculitis. In: Churg A, Churg J, eds. Systemic Vascuiitides. 1st ed. New York: Igaku-Shoin; 1991:193-201.

113. Jenne The J, Falk R. Small-vessel vasculitis. N Engl J Med. 1997;337:1512-1523.

114. Jenne The J, Falk R, Andrassy K, et al. Nomenclature of systemic vasculitis. Arthitis Rheum. 1994;37:187-192.

115. Jenne The J, Thomas D, Falk R. Microscopic polyangiitis (microscopic polyarteritis). Semin Diagn Pathol. 2001;18:3-13.

116. Lauque D, Cadranel J, Lazor R, et al. Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature. Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P). Medicine (Baltimore). 2000;79:222-233.

117. Akikusa B, Kondo Y, Irabu N, Yamamoto S, Saiki S. Six cases of microscopic polyarteritis exhibiting acute interstitial pneumonia [published erratum appears in Pathol Int 1995 Nov;45(11):901]. Pathol Int. 1995;45:580-588.

118. Brugiere O, Raffy O, Sleiman C, et al. Progressive obstructive lung disease associated with microscopic polyangiitis. Am J Respir Crit Care Med. 1997;155:739-742.

119. Schwarz M, Mortenson R, Colby T, et al. Pulmonary capillaritis. The association with progressive irreversible airflow limitation and hyperinflation. Am Rev Respir Dis. 1993;148:507-511.

120. Green R, Ruoss S, Kraft S, et al. Pulmonary capillaritis and alveolar hemorrhage. Update on diagnosis and management. Chest. 1996;110(5):1305-1316.

121. Jennings C, King T, Tuder R, Cherniack R, Schwarz M. Diffuse alveolar hemorrhage with underlying isolated, pauciimmune pulmonary capillaritis. Am J Respir Crit Care Med. 1997;155:1101-1109.

122. Finnegan M, Hinchcliffe J, Russell-Jones D, et al. Vasculitis complicating cystic fibrosis. Q J Med. 1989;72:609-621.

123. Churg J, Churg A. Idiopathic and secondary vasculitis: a review. Mod Pathol. 1989;2:144-160.

124. Fortin P Esdaile J. Vasculitis and malignancy. In: Churg A, Churg J, eds. Systemic Vasculitides. 1st ed. New York: Igaku-Shoin; 1991:327-341.

125. Komadina K, Houck R. Polyarteritis nodosa presenting as recurrent pneumonia following splenectomy for hairy-cell leukemia. Semin Arthritis Rheum. 1989;18:252-257.

126. Fiegler W, Siemoneit K. Pulmonary manifestations in anaphylactoid purpura (Henoch-Schonlein Syndrome). Rofo. 1981;134:269-272.

127. Marandian M, Ezzati M, Behvad A, Moazzami P Rakhchan M. Pulmonary involvement in Schonlein-Henoch's purpura. Arch Fr Pediatr. 1982;39:255-257.

128. White R. Henoch-Schonlein purpura. In: Churg A, Churg J, eds. Systemic Vasculitides. 1st ed. New York: Igaku-Shoin; 1991:203-217.

129. Bombardieri S, Paoletti P Ferri C, et al. Lung involvement in essential mixed cryoglobulinemia. Am J Med. 1979;66:748-756.

130. Churg J. Cryoglobulinemic vasculitis. In: Churg A, Churg J, eds. Systemic Vasculitides. 1st ed. New York: Igaku-Shoin; 1991:293-298.

131. Monti G, Galli M, Cereda U, Cannatelli G, Invernizzi F. Mycosis fungoides with mixed cryoglobulinemia and pulmonary vasculitis. A case report. Boll Ist Sieroter Milan. 1987;66:324-328.

132. Nada A, Torres V, Ryu J, Lie J, Holley K. Pulmonary fibrosis as an unusual clinical manifestation of a pulmonary-renal vasculitis in elderly patients. Mayo Clin Proc. 1990;65:847-856.

133. Seiden M, O'Donnell W, Weinblatt M, Licht J. Vasculitis with recurrent pulmonary hemorrhage in a long-term survivor after autologous bone marrow transplantation. Bone Marrow Transplant. 1990;6:345-347.

134. Lazzarini LC, de Fatima do Amparo Teixeira M, Souza RR, Marcos Nunes Valiante P Necrotizing sarcoid granulomatosis in a family of patients with sarcoidosis reinforces the association between both entities. Respiration. 2008;76(3):356-360.

135. Tauber E, Wojnarowski C, Horcher E, Dekan G, Frischer T Necrotizing sarcoid granulomatosis in a 14-yr-old female. Eur Respir J. 1999;13:703-705.

136. Beach R, Corrin B, Scopes J, Graham E. Necrotizing sarcoid granulomatosis with neurologic lesions in a child. J Pediatr. 1980;97:950-953.

137. Singh N, Cole S, Krause P Conway M, Garcia L. Necrotizing sarcoid granulomatosis with extrapulmonary involvement. Clinical, pathologic, ultrastructural, and immunologic features. Am Rev Respir Dis. 1981;124:189-192.

138. Stephen J, Braimbridge M, Corrin B, et al. Necrotizing "sarcoidal" angiitis and granulomatosis of the lung. Thorax. 1976;31:356-360.

139. Niimi H, Hartman T, Muller N. Necrotizing sarcoid granulomatosis: computed tomography and pathologic findings. J Comput Assist Tomogr. 1995;19:920-923.

140. Le Gall F, Loeuillet L, Delaval P et al. Necrotizing sarcoid granulomatosis with and without extrapulmonary involvement. Pathol Res Pract. 1996;192:306-313.

141. Dykhuizen R, Smith C, Kennedy M, et al. Necrotizing sarcoid granulomatosis with extrapulmonary involvement. Eur Respir J. 1997;10:245-247.

142. Chittock D, Joseph M, Paterson N, McFadden R. Necrotizing sarcoid granulomatosis with pleural involvement. Clinical and radiographic features. Chest 1994;106:672-676.

143. Liebow A, the J. Burns Amberson lecture—pulmonary angiitis and granulomatosis. Am Rev Respir Dis. 1973;108:1-18.

144. Rolfes D, Weiss M, Sanders M. Necrotizing sarcoid granulomatosis with suppurative features. Am J Clin Pathol. 1984;82:602-607.

145. Spiteri M, Gledhill A, Campbell D, Clarke S. Necrotizing sarcoid granulomatosis. Br J Dis Chest. 1987;81:70-75.

146. Larson T, Hall S, Hepper N, Hunder G. Respiratory tract symptoms as a clue to giant cell arteritis. Ann Intern Med. 1984;101:594-597.

147. Rodat O, Buzelin F, Weber M, et al. Manifestations broncho-pulmonaires de la maladie de Horton: a propos d'une observation. Rev Med Interne. 1983;4:225-230.

148. Bradley J, Pinals R, Blumenfeld H, Poston W. Giant cell arteritis with pulmonary nodules. Am J Med. 1984;77:135-140.

149. Karam G, Fulmer J. Giant cell arteritis presenting as interstitial lung disease. Chest. 1982;82:781-789.

150. Ladanyi M, Fraser R. Pulmonary involvement in giant cell arteritis. Arch Pathol Lab Med. 1987;111:1178-1180.

151. Wagenaar S, van den Bosch J, Westermann C, Bosman H, Lie J. Isolated granulomatous giant cell vasculitis of the pulmonary elastic arteries. Arch Pathol Lab Med. 1986;110:962-964.

152. Wagenaar S, Westermann C, Corrin B. Giant cell arteritis limited to large elastic pulmonary arteries. Thorax. 1981;36:876-877.

153. Okubo S, Kuneida T, Ando M, Nakajima N, Yutani C. Idiopathic isolated pulmonary arteritis with chronic cor pulmonale. Chest. 1988;94:665-666.

154. Lie J. Disseminated visceral giant cell arteritis. Histopathologic description and differentiation from other granulomatous vasculitides. Am J Clin Pathol. 1978;69:299-305.

155. Morita T, Kamimura A, Koizumi F Disseminated visceral giant cell arteritis. Acta Pathol Jpn. 1987;37:863-870.

156. Marcussen N, Lund C. Combined sarcoidosis and disseminated visceral giant cell vasculitis. Path Res Pract. 1989;184:325-330.

157. Shintaku M, Mase K, Ohtsuki H, et al. Generalized sarcoidlike granulomas with systemic angiitis, crescentic glomerulonephritis, and pulmonary hemorrhage. Report of an autopsy case. Arch Pathol Lab Med. 1989;113:1295-1298.

158. Lie J. Combined sarcoidosis and disseminated visceral giant cell angiitis: a third opinion (letter). Arch Pathol Lab Med. 1991;115:210-211.

159. DeRemee R, Weiland L, McDonald T Respiratory vasculitis. Mayo Clin Proc. 1980;55:492-498.

160. Leavitt R, Fauci A. Pulmonary vasculitis. Am Rev Respir Dis. 1986;134:149-166.

161. Rosen S, Falk R, Jenne The J. Polyarteritis nodosa, including microscopic form and renal vasculitis. In: Churg A, Churg J, eds. Systemic Vasculitides. 1st ed. New York: Igaku-Shoin; 1991:57-77.

162. Arend W, Michel B, Bloch D, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum. 1990;33:1129-1134.

163. He N, Liu F, Wu E, et al. Pulmonary artery involvement in aorto-arteritis. An analysis of DSA. Chin Med J. 1990;103:666-672.

164. Sharma S, Kamalakar T, Rajani M, Talwar K, Shrivastava S. The incidence and patterns of pulmonary artery involvement in Takayasu's arteritis. Clin Radiol. 1990;42:177-181.

165. Sharma S, Rajani M, Shrivastava S, et al. Non-specific aorto-arteritis (Takayasu's disease) in children. Br J Radiol. 1991;64:690-698.

166. Nakabayashi K, Kurata N, Nangi N, Miyake H, Nagasawa T Pulmonary artery involvement as first manifestation in three cases of Takayasu arteritis. Int J Cardiol. 1997;54:S177-S183.

167. Sharma B, Jain S, Sagar S. Systemic manifestations of Takayasu arteritis: the expanding spectrum. Int J Cardiol. 1997;54(suppl):S149-S154.

168. Lie J. Takayasu's arteritis. In: Churg A, Churg J, eds. Systemic Vasculitides. 1st ed. New York: Igaku-Shoin; 1991:159-179.

169. Horimoto M, Igarashi K, Aoi K, Okamoto K, Takenaka T Unilateral diffuse pulmonary artery involvement in Takayasu's arteritis associated with coronary-pulmonary artery fistula and bronchial-pulmonary artery fistula: a case report. Angiology. 1991;42:73-80.

170. Takahashi K, Honda M, Furuse M, Yanagisawa M, Saitoh K. CT findings of pulmonary parenchyma in Takayasu arteritis. J Comput Assist Tomogr. 1996;20:742-748.

171. Rose A, Sinclair-Smith C. Takayasu's arteritis. A study of 16 autopsy cases. Arch Pathol Lab Med. 1980;104:231-237.

172. Matsubara O, Yoshimura N, Tamura A, et al. Pathological features of the pulmonary artery in Takayasu arteritis. Heart Vessels. 1992;7:18-25.

173. Jakob H, Volb R, Stangl G, et al. Surgical correction of a severely obstructed pulmonary artery bifurcation in Takayasu's arteritis. Eur J Cardiothorac Surg. 1990;4:456-458.

174. Direskeneli H. Behcet's disease: infectious aetiology, new autoantigens and HLA-B51. Ann Rheum Dis. 2001;60(11):996-1002.

175. Fairley C, Wilson J, Barraclough D. Pulmonary involvement in Behçet's syndrome. Chest. 1989;96:1428-1429.

176. Raz I, Okon E, Chajek-Shaul T Pulmonary manifestations in Behçet's syndrome. Chest. 1989;95:585-589.

177. Efthimiou J, Johnston C, Spiro S, Turner-Warwick M. Pulmonary disease in Behçet's syndrome. Q J Med. 1986;58:259-280.

178. Ahn J, Im J, Ryoo J, et al. Thoracic manifestations of Behcet syndrome: radiographic and CT findings in nine patients. Radiology. 1995;194:199-203.

179. Tunaci A, Berkmen Y, Gokmen E. Thoracic involvement in Behcet's disease: pathologic, clinical, and imaging features. AJRAm J Roentgenol. 1995;164:51-56.

180. Slavin R, de Groot W. Pathology of the lung in Behçet's disease. Case report and review of the literature. Am J Surg Pathol. 1981;5:779-788.

181. Lakhanpal S, Tani K, Lie J, et al. Pathologic features of Behçet's syndrome: a review of Japanese autopsy registry data. Hum Pathol. 1985;16:790-795.

182. Salamon F, Weinberger A, Nili M, et al. Massive hemoptysis complicating Behçet's syndrome: the importance of early pulmonary angiography and operation. Ann Thorac Surg. 1988;45:566-567.

183. Corren J. Acute interstitial pneumonia in a patient with Behcet's syndrome and common variable immunodeficiency [clinical conference]. Ann Allergy. 1990;64:15-20.

184. Soave R, Murray H, Litrenta M. Bacterial invasion of pulmonary vessels. Pseudomonas bacteremia mimicking pulmonary thromboembolism with infarction. Am J Med. 1978;65:864-867.

185. Winn W, Myerowitz R. The pathology of the Legionella pneumonias. A review of 74 cases and the literature. Hum Pathol. 1981;12:401-422.

186. Travis W, Pittaluga S, Lipschik G, et al. Atypical pathologic manifestations of Pneumocystis carinii pneumonia in the acquired immune deficiency syndrome. Review of 123 lung biopsies from 76 patients with emphasis on cysts, vascular invasion, vasculitis, and granulomas. Am J Surg Pathol. 1990;14:615-625.

187. Takemura T, Matsui Y, Saiki S, Mikami R. Pulmonary vascular involvement in sarcoidosis: a report of 40 autopsy cases. Hum Pathol. 1992;23:1216-1223.

188. Fernandes S, Singsen B, Hoffman G. Sarcoidosis and systemic vasculitis. Semin Arthritis Rheum. 2000;30:33-46.

189. Sweerts M, Nicholson AG, Goldstraw P Corrin B. Dieulafoy's disease of the bronchus. Thorax. 1995;50(6):697-698.

190. Kadokura M, Colby T, Myers J. Pathologic comparison of video-assisted thoracic surgical biopsy with traditional open lung biopsy. J Thorac Cardiovasc Surg. 1995;109:494-498.

191. Thompson G, Klecka M, Roden AC, Specks U, Cartin-Ceba R. Biopsy-proven pulmonary capillaritis: a retrospective study of aetiologies including an in-depth look at isolated pulmonary capillaritis. Respirology. 2016;21(4):734-738.

192. Lynch J, Leatherman J. Alveolar hemorrhage syndromes. In: Fishman A, ed. Fishman's Pulmonary Diseases and Disorders. 3rd ed. New York: McGraw Hill; 1998:1193-1210.

193. Lombard C, Colby T, Elliott C. Surgical pathology of the lung in antibasement membrane antibody-asociated Goodpasture's syndrome. Hum Pathol. 1989;20:445-451.

194. Specks U. Diffuse alveolar hemorrhage syndromes. Opin Rheumatol. 2001;13:12-17.

195. Cutz E. Idiopathic pulmonary hemosiderosis and related disorders in infancy and childhood. Perspect Pediatr Pathol. 1987;11:47-81.

196. Schwarz M, Cherniak R, King T Diffuse alveolar hemorrhage and other rare infiltrative disorders. In: Murray J, Nadel J, eds. Textbook of Respiratory Medicine. 3rd ed. Philadelphia: Saunders; 2000:1733-1755.

Multiple Choice Questions

1. Which of the following statements concerning pulmonary vasculitis is/are TRUE?

A. It should never be diagnosed casually.

B. It is most often a consequence of immune-mediated mechanisms.

C. Cases are treated aggressively, often with the addition of cytotoxic agents.

D. It requires clinicopathologic correlation for accurate diagnosis.

E. All of the above.

ANSWER: E

2. Which of the following statements about granulomatosis with polyangiitis/Wegener granulomatosis is FALSE?

A. It is an idiopathic pulmonary vasculitic syndrome.

B. It may involve the kidney, upper respiratory tract, and lower respiratory tract as a classic triad.

C. It is one of the vasculitic syndromes that commonly affects the lungs.

D. It occurs mainly in children.

E. It can have perinuclear antineutrophilic cytoplasmic antibody (p-ANCA)-positive serology.

ANSWER: D

3. Which of the following statements about the pathology of granulomatosis with polyangiitis/Wegener granulomatosis is TRUE?

A. It most commonly occurs as a solitary nodule with cavitation.

B. It characteristically has an associated background mixed inflammatory infiltrate.

C. It frequently has associated small sarcoid-like pulmonary granulomas, without necrosis.

D. It rarely ever occurs without renal involvement at presentation.

E. All of the above.

ANSWER: E

4. Which of the following findings favor eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) over granulomatosis with polyangiitis/Wegener granulomatosis?

A. Asthma

B. Fatal cardiac disease

C. Peripheral blood eosinophilia

D. Perinuclear antineutrophilic cytoplasmic antibody (p-ANCA) serology

E. All of the above ANSWER: E

5. The three most common clinical manifestations of patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) are:

A. Hemoptysis, arthralgias, mononeuritis multiplex

B. Pulmonary infiltrates, hemoptysis, arthralgias

C. Abdominal pain, arthralgia, skin nodules

D. Pulmonary infiltrates, mononeuritis multiplex, abdominal pain

E. Skin rash, pulmonary nodules, pulmonary infiltrates

ANSWER: D

6. Which of the following statements about eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) is FALSE?

A. This syndrome has an unknown etiology.

B. It is second only to granulomatosis with polyangiitis/Wegener granulomatosis as a known cause of systemic vasculitis.

C. It occurs most commonly in patients with asthma.

D. It often progresses through four distinct phases.

E. All of the above.

ANSWER: D

7. Which of the following sequences best describes the phases of disease progression in eosinophilic granulomatosis with polyangiitis (Churg- Strauss syndrome)?

A. Prodrome, prevasculitis, postvasculitis, resolution

B. Early, vasculitis, postvasculitis, resolution

C. Prodrome, vasculitis, postvasculitis

D. Prevasculitis, prodrome, postvasculitis

E. None of the above

ANSWER: C

8. All of the following statements about microscopic polyangiitis are correct EXCEPT:

A. It was previously known as hypersensitivity vasculitis.

B. It affects arterioles, capillaries, and venules exclusively.

C. It can be distinguished histopathologically from polyarteritis nodosa.

D. It affects the lung more than other organs.

E. All of the above.

ANSWER: D

9. Behçet syndrome includes which of the following?

A. Recurrent oral aphthosis

B. Uveitis

C. Recurrent genital aphthosis

D. Synovitis

E. A and B only

F. All of the above

ANSWER: E

10. Which of the following statements about necrotizing sarcoid granulomatosis is FALSE?

A. Sarcoid-like granulomas with necrosis are characteristic.

B. It is a disease of adults.

C. Interstitial fibrosis is common and is accompanied by honeycomb cysts.

D. It is a disease confined to the lungs.

E. All of the above.

ANSWER: C

11. True or false: Granulomatosis with polyangiitis/Wegener granulomatosis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), and microscopic polyangiitis are the three idiopathic vasculitides that commonly affect the lung.

A. True

B. False

ANSWER: A

12. True or false: Granulomatosis with polyangiitis/Wegener granulomatosis is characterized by the presence of proteinase-3-specific cytoplasmic antineutrophilic cytoplasmic antibody (c-ANCA) serology.

A. True

B. False

ANSWER: A

13. True or false: Eosinophilic pneumonia is the most common pulmonary manifestation of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

A. True

B. False

ANSWER: A

14. True or false: Knowledge of necrotizing sarcoid granulomatosis is based on large case studies that aggregate several thousand patients.

A. True

B. False

ANSWER: B

15. True or false: the pulmonary histopathology of Goodpasture syndrome is not specific for the disease.

A. True

B. False

ANSWER: A

16. What is this?

A. Acute bronchopneumonia

B. Necrotizing sarcoidosis

C. Capillaritis

D. Goodpasture syndrome

E. None of the above

ANSWER: C

17. What is this?

A. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

B. Eosinophilic pneumonia

C. Eosinophilic bronchopneumonia

D. Fibrinoid eosinophilia

E. None of the above

ANSWER: B

18. What is this?

A. Hemorrhage in granulomatosis with polyangiitis/Wegener granulomatosis

B. Hemorrhage in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

C. Hemorrhage in microscopic polyarteritis

D. Hemorrhage as artifact

E. None of the above

ANSWER: D

19. What is this?

A. Blue bodies

B. Behçet syndrome

C. Viral pneumonia

D. Siderosis

E. None of the above

ANSWER: D

20. What is this?

A. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

B. Microscopic polyangiitis

C. Granulomatosis with polyangiitis/Wegener granulomatosis

D. Eosinophilic pneumonia

E. None of the above

ANSWER: C

Case 1

eSlide 11.1

a. History

A 53-year-old female with clinical history of right lower lobe lung mass. Patient has positive cytoplasmic antineutrophilic cytoplasmic antibody (c-ANCA). Clinically suspicious for granulomatosis with polyangiitis.

b. Pathologic Findings

The biopsy shows necrotizing granulomatous inflammation and vasculitis. Within the granulomatous inflammation, there are prominent multinucleated giant cells, neutrophils, and some eosinophils. The necrosis has a basophilic appearance. Focal neutrophilic microabscesses are seen. Vasculitis is present, and the adjacent lung parenchyma reveals rare foci of neutrophilic capillaritis. Occasional hemosiderin-laden macrophages amidst red blood cells are seen. Chronic fibrous pleuritis with fibrinoid change is seen. No mycobacteria or fungi were seen on acid-fast bacilli (AFB), Fite, and Grocottmethenamine silver (GMS) stains.

c. Diagnosis

Necrotizing granulomatous inflammation and vasculitis, compatible with granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis).

d. Discussion

The biopsy shows necrotizing granulomatous inflammation and vasculitis. The differential diagnosis includes infection, drug toxicity, collagen vascular diseases, and vasculitis syndromes such as GPA and eosinophilic granulomatosis with polyangiitis (formerly Churg- Strauss syndrome). With the geographic necrosis, neutrophilic microabscesses, vasculitis, and the report of a positive c-ANCA, the diagnosis fits best for granulomatosis with polyangiitis. No history of head and neck or renal manifestations was provided.

Case 2

eSlide 11.2

a. History

A 51-year-old male with history of IgA nephropathy in 1996, now with end-stage renal disease on hemodialysis started 6 months ago. The patient has hypertension, gout, and a recent admission for skin rash that showed leukocyto clastic vasculitis. He presented at the hospital with dyspnea and hemoptysis but had joint pain and night sweats for a few months. He also lost 40 pounds. Initial serology markers showed increased antinuclear antibody (ANA), c-ANCA (93.74), and anticardiolipin antibody IgM (25.55), whereas perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) was negative. Double-strand antibodies are also elevated. The anti-basement membrane antibodies are negative.

b. Pathologic Findings

The biopsy shows diffuse alveolar hemorrhage (DAH) along with capillaritis. The sections show intraalveolar accumulation of blood and fibrin and hemosiderin-laden macrophages along with active capillaritis characterized by septal neutrophils infiltrate karyorrhectic debris and fibrinoid necrosis. There is also focal accumulation of intraalveolar neutrophils as well as foci of organizing pneumonia with intraalveolar plugs of loose connective tissue with entrapped red blood cells. No granulomas, foreign bodies, necrosis, infarcts, large vessel vasculitis, hyaline membranes, or tumor are seen.

c. Diagnosis

Diffuse pulmonary acute and organizing hemorrhage with neutrophilic capillaritis and focal acute and organizing pneumonia associated with IgA nephropathy.

d. Discussion

The biopsy shows diffuse pulmonary acute and organizing hemorrhage with neutrophilic capillaritis, which raises a wide variety of possible causes. The differential diagnoses include GPA, microscopic polyangiitis (MPA), Goodpasture syndrome, Henoch-Schonlein purpura (HSP), IgA nephropathy, collagen vascular diseases, and drug reaction. In the absence of any identifiable cause, the clinical term of idiopathic pulmonary hemorrhage would be appropriate. The presence of acute neutrophilic capillaritis and the increase in autoantibodies, including ANA, ds-DNA, and ANCAs favor a systemic vasculitis. Given the history of cutaneous leukocytoclastic vasculitis and the elevated ANCAs, the primary differential diagnoses are MPA and GPA. In the present case, the absence of necrotizing granulomatous inflammation of the lung or any history of such lesions in head and neck favors MPA over GPA. I would also consider systemic lupus erythematosus and HSP, but ANCAs are not typically increased in these conditions. IgA nephropathy has also been reported as a cause of pulmonary hemorrhage and neutrophilic capillaritis, but only rare cases are reported to have increased ANA and ANCAs. The absence of antibasement membrane antibodies is against Goodpasture syndrome. Although foci of intraalveolar accumulation of neutrophils raise the possibility of an infectious process, this can be seen when the capillaritis is so severe that the neutrophils spill over into the surrounding alveoli.

Case 3

eSlide 11.3

a. History

A 57-year old female with multiple incidental pulmonary nodules. Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA+). No evidence of sinus, renal, or skin disease.

b. Pathologic Findings

The lung shows alveolar hemorrhage, geographic necrosis, and granulomatous inflammation. Sections from the left lower lobe show prominent necrotizing granulomatous inflammation with an associated mixed inflammatory infiltrate consisting of lymphocytes, plasma cells, and eosinophils with prominent neutrophilic microabscesses. There is organizing pneumonia at the periphery. Foci of necrotizing vasculitis are noted. No fungi are seen on GMS. No mycobacteria are seen on AFB. The left upper lobe shows acute and chronic hemorrhage with prominent intraalveolar hemosiderin-laden macrophages and interstitial chronic inflammation with lymphoid hyperplasia. The alveolar septa show an infiltrate of lymphocytes and plasma cells; however, no active neutrophilic capillaritis is seen.

c. Diagnosis

Necrotizing granulomatous inflammation with necrotizing vasculitis. Acute and chronic alveolar hemorrhage. With positive p-ANCA and the histologic findings, the diagnosis fits best for granulomatosis with polyangiitis.

d. Discussion

In summary, these sections show a necrotizing granulomatous process with necrotizing vasculitis most suggestive of granulomatosis with polyangiitis. These changes are best appreciated in the left lower lobe. Although no necrotizing granulomatous inflammation or vasculitis are seen in the upper lobe, the presence of acute and chronic hemorrhage with interstitial and alveolar septal inflammation are consistent with granulomatosis with polyangiitis in which the acute changes, which may have represented neutrophilic capillaritis, have resolved. Although granulomatosis with polyangiitis is most often c-ANCA positive, approximately 10% of cases are p-ANCA positive.

Case 4

eSlide 11.4

a. History

A 34-year-old female with a history of Behçet disease and on immunosuppressants for 10 years including Infliximab, Mycophe- nolate, and Azathioprine. She came in with acute abdominal pain, leg pain, and shortness of breath. She quickly went into acute respiratory distress syndrome and is intubated now.

b. Pathologic Findings

The biopsy shows diffuse involvement by acute alveolar damage characterized by intraalveolar fibrin and hyaline membranes. There is focal alveolar septal thickening by a proliferation ofloose, organizing fibrous connective tissue, and prominent type 2 pneumocyte proliferations. There changes fit well for diffuse alveolar damage (DAD), acute and organizing patterns. In addition, there is lymphocytic and necrotizing vasculitis involving small and medium-sized vessels. Multiple thrombi and scattered small infarcts are also seen. No acute bronchopneumonia, diffuse hemorrhage, aneurysms, definite viral inclusions, granulomas, or tumor are identified. No fungi or mycobacteria are seen on GMS and AFB stains.

c. Diagnosis

DAD, acute and organizing pattern, etiology undetermined. Vasculitis with multiple infarcts and thrombi, consistent lung involvement by Behçet disease.

d. Discussion

In summary, the biopsy shows DAD and acute and organizing pattern mixed with lymphocytic and necrotizing vasculitis and infarcts. DAD can occur in many settings including collagen vascular disease, infection, drug toxicity, inhalational injury, and uremia, and it may be idiopathic. In the absence of any identifiable cause, the clinical term of acute interstitial pneumonia is appropriate. However, in this case despite the negative stains and cultures for organisms, infection is still in the differential diagnosis, especially given the long history of immunosuppression. Some viral infections such as influenza may not induce viral cytopathic changes visible under the microscope. In addition, some medications may cause lung injury with DAD pictures. In addition, the medications the patient was taking, such as Infliximab, Mycophenolate, and Azathioprine, have be reported to cause DAD. It is also possible the multiple small infarcts caused by Behçet vasculitis triggered the onset of DAD.

Case 5

eSlide 11.5

a. History

A 44-year-old female with a long history of asthma and recently developed a large mass in the left lower lobe. Her serum c-ANCA is 1 : 23 (nl range 1-9).

b. Pathologic Findings

The left lung sections show a mass consisting of inflammation, necrosis, and fibrosis. The infiltrate is composed of a mixture of inflammatory cells with lymphocytes, plasma cells, eosinophils, scattered giant cells, and neutrophils forming focal neutrophil microabscesses. The foci of necrosis are patchy without large geographic areas. There is focal vasculitis. No mycobacteria or fungi are seen on GMS and AFB stains.

c. Diagnosis

Necrotizing granulomatous inflammation and vasculitis, etiology undetermined. Consistent with granulomatous polyangiitis given morphology and positive c-ANCA.

d. Discussion

The biopsy shows necrotizing granulomatous inflammation and vasculitis. The differential diagnosis includes granulomatosis with polyangiitis, Hodgkin lymphoma, lymphomatoid granulomatosis, eosinophilic granulomatosis with polyangiitis (GPA), necrotizing sarcoid granulomatosis, rheumatoid nodules, bronchocentric

granulomatosis, and infection. In this case the constellation of histologic findings is compatible with GPA. This does not have the appearance of necrotizing sarcoid or bronchocentric granulomatosis. However, the diagnosis of GPA requires clinical, laboratory, and pathologic correlation. Increased serum c-ANCA is suggestive for GPA. No history of upper respiratory tract or kidney involvement was provided at the time of biopsy. Furthermore, no history of asthma or peripheral eosinophilia was provided to suggest eosinophilic granulomatosis and polyangiitis (EGPA).