Clinical Features

WG affects about 1 in every 3 million people in the United States¹¹ and 1 in 8.5 million people in the United Kingdom.¹² There is debate as to whether WG 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 WG 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 WG 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, as well as causing 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 WG. 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 WG is still being elucidated.^17,18 Genetic factors, toxic exposures, and deficient proteinase-3 clearance are also being explored as potential causes and contributing factors.^11,19

WG occurs at any age but typically is a disease of adults, with a mean age of 50 years.^20–22 A list of the clinical manifestations of WG is presented in Table 10-1. Body sites most commonly affected are the head and neck region, followed by the lung, kidney, and eye.^20,23 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.²⁴ Rarely WG may involve the salivary glands, pancreas, breast, mediastinum, gastrointestinal tract, prostate and urethra, vagina and cervix, heart, spleen, or peripheral or central nervous system.^2,25–27

Table 10-1 Wegener Granulomatosis: Clinical Manifestations

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.

The most frequent abnormality on pulmonary function testing is airflow obstruction, often associated with a reduced diffusing capacity for carbon monoxide (DLco), 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 WG. The most common of these include leukocytosis, thrombocytosis (>400,000 cells/μL), marked elevation of the erythrocyte sedimentation rate, and normochromic normocytic anemia. In the past decade, the diagnosis of WG has been dramatically aided by the discovery and use of serum ANCA.^28–32

Two major immunofluorescence patterns occur as expressions of ANCA (Fig. 10-4): the cytoplasmic or classic type (c-ANCA) and the perinuclear type (p-ANCA).³³ The c-ANCA pattern is associated with WG 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.³⁴ The p-ANCA pattern can be seen in a small percentage of patients with WG, but it is more characteristic of idiopathic necrotizing and crescentic glomerulonephritis, microscopic polyangiitis, polyarteritis nodosa, and CSS.³⁵

Figure 10-4 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, et al, eds. Non-Neoplastic Disorders of the Lower Respiratory Tract. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Figure 4-1.)

The ANCA immunofluorescence patterns have been shown to correspond to specific antigen immunoreactivities; c-ANCA typically has specificity for proteinase-3, while most p-ANCAs have a specificity for myeloperoxidase. Studies have shown no significant difference in the lung biopsy findings from WG patients with c-ANCAs versus those with p-ANCAs.^36,37 Levels of c-ANCA in the bronchoalveolar lavage fluid have not been shown to be a more specific predictor of WG or of the level of disease.³⁸ 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 WG, and c-ANCA may occasionally be encountered in patients with other vasculitic syndromes or infection.³⁹

Radiologic Features

Most patients with pulmonary disease have multiple opacities (Figs. 10-5 and 10-6) in the form of well-marginated nodules or masses of variable size (0.5–10 cm). Lesions may wax and wane over time. Most occur in the lower lobes.^40–42 Poorly defined or even spiculated nodules may also be seen.⁴³ 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.^42,44 WG 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.^42,45

Figure 10-5 Wegener granulomatosis (WG): radiographic features. Posteroanterior chest radiograph from a patient with WG. Note the multifocal nodules, some of which appear cavitated.

(From Travis WD, Colby TV, Koss MN, et al, eds. Non-Neoplastic Disorders of the Lower Respiratory Tract. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Figure 4-2.)

Figure 10-6 Wegener granulomatosis: 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, et al, eds. Non-Neoplastic Disorders of the Lower Respiratory Tract. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Figure 4-3.)

Patients with WG may present initially with pulmonary hemorrhage. In this setting, diffuse infiltrates on chest radiographs and diffuse air space opacities on computed tomograms are observed (see Fig. 10-6). In children, pulmonary hemorrhage is a common presentation of WG, while pulmonary nodules occur less frequently in pediatric patients.²²

Pleural effusion accompanies WG in 20% to 50% of cases, sometimes with focal pleural thickening. Hilar or mediastinal lymphadenopathy is an unusual finding in WG and, when significant, should raise concern for an alternate diagnosis. On rare occasions, WG occurs as a solitary pulmonary nodule (with or without cavitation), or as an isolated area of consolidation.⁴⁶

Computed tomography (CT) provides optimal visualization of the number, location, and morphologic characteristics of the pulmonary abnormalities in WG. Well-marginated nodules and masses, sometimes with spiculated borders, are typical findings. A “feeding” vessel is seen in 88% of nodules (see Fig. 10-6), consistent with the angiocentric nature of this disorder.⁴⁷ Cavitation is identified in 50% of cases. Another very common finding in WG 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).^47,48 Stenosis of the trachea or large airways may occur in short or long segments and may be complicated by partial or complete lobar collapse.^45,49,50

Pathologic Features

WG is characterized by the presence of multiple bilateral pulmonary nodules, often with cavitation⁵¹ (Fig. 10-7; see also Fig. 10-6). Solid nodular zones of consolidation with areas of punctate or geographic necrosis are typical findings (Figs. 10-8 and 10-9). WG can rarely present with a solitary lung lesion, but solitary granulomatous disease is more likely to be of infectious origin.⁵² When dealing with a solitary granulomatous lung nodule, a combination of both the classical histology and typical clinical or serologic findings of WG should be present before making a diagnosis.⁴⁶ 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 WG may predominantly involve bronchi. When acute lung hemorrhage is prominent, the cut surface of the lung is bloody and dark red.

Figure 10-7 Wegener granulomatosis: 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, et al, eds. Non-Neoplastic Disorders of the Lower Respiratory Tract. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Figure 4-5.)

At scanning magnification, the pulmonary lesions of WG simulate their radiologic appearance (see Fig. 10-8). The classic findings consist of nodular areas of consolidation with variable zones of necrosis. Major diagnostic criteria, presented in Box 10-2, include parenchymal necrosis (see Fig. 10-9), vasculitis (Fig. 10-10), and granulomatous inflammation (Fig. 10-11). Another important feature is a mixed inflammatory infiltrate composed of neutrophils, lymphocytes, plasma cells, macrophages, giant cells, and eosinophils (Fig. 10-12). Parenchymal necrosis can take the form of neutrophilic microabscesses (Fig. 10-13) or large zones of geographic necrosis (see Fig. 10-9). The neutrophilic microabscesses 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.⁵¹

Figure 10-8 Wegener granulomatosis: 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 10-9 Wegener granulomatosis: geographic necrosis. The basophilic necrosis can be appreciated at scanning magnification.

Figure 10-10 Wegener granulomatosis: vasculitis. The vasculitis of Wegener granulomatosis 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 10-11 Wegener granulomatosis (WG): granulomatous inflammation. A, The granulomatous inflammation of WG generally has a palisaded configuration. B, A closer view of palisaded histiocytes can be seen bordering basophilic necrosis with nuclear debris.

Figure 10-12 Wegener granulomatosis (WG): associated inflammation. Inflammatory infiltrate of WG is generally mixed with plasma cells, lymphocytes (A), and a variable number of eosinophils (B).

Figure 10-13 Wegener granulomatosis (WG): collagen necrosis. Collagen necrosis is thought to be the primary pathologic event in WG. Zones of collagen necrosis can be vague (A) or discrete and associated with giant cells and granulomatosis inflammation (B).

As illustrated in Figure 10-9, the classic geographic necrosis of WG is typically basophilic, owing to the presence of numerous necrotic neutrophils. The necrotic centers of WG lesions often lack the “ghosted” image of lung structure, a diagnostic clue useful in the case with atypical features (Fig. 10-14). This likely occurs because the necrotic zones of WG generally are not the result of “infarct-like” zonal parenchymal necrosis but rather occur by progressive expansion of collagen necrosis.

Figure 10-14 Wegener granulomatosis (WG): basophilic necrosis. A, The necrosis of WG 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 WG).

The “granulomatous” inflammation of WG typically includes giant cells scattered randomly or in loose aggregates.^10–15 Also commonly observed are palisaded histiocytes (Fig. 10-15), giant cells lining the border of geographic necrosis or microabscesses, and microgranulomas consisting of small foci of palisaded histiocytes arranged in acartwheel pattern around a central nidus of necrosis⁵¹ (Fig. 10-16). The presence of tightly cohesive, sarcoid-like granulomas is very rare in WG and suggests infection or necrotizing sarcoid. Also, the presence of granulomas without associated necrosis favors an infectious etiology over WG.

Figure 10-15 Wegener granulomatosis: 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).

Figure 10-16 Wegener granulomatosis: 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).

The vasculitis of WG 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. 10-17). Vasculitis in WG may comprise a variety of inflammatory cells including acute or chronic mural inflammation, necrotizing stellate granulomas, non-necrotizing stellate granulomas, and giant cells.⁵¹ 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. 10-18). Sometimes the inflammation is limited to the endothelium (endotheliolitis) 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 WG will be missed.

Figure 10-17 Wegener granulomatosis: 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 10-18 Wegener granulomatosis: 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.

As mentioned, all types of inflammatory cells may occur in WG, 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 WG from lymphomatoid granulomatosis may be difficult.

Another distinctive vascular manifestation of WG is capillaritis (Fig. 10-19). In many cases, capillaritis is only focally evident in the biopsy.⁵¹ When capillaritis is prominent, it is distinctive and easily recognized. In the rare case of WG dominated by capillaritis, a careful search throughout the rest of the biopsy should be made for more typical findings of WG such as granulomas, foci of necrosis (such as neutrophilic microabscesses), multinucleate giant cells, and vasculitis affecting arterioles or veins.

Figure 10-19 Wegener granulomatosis (WG): capillaritis. A, Capillaritis can be seen in WG 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.

In addition to these major histologic features, a variety of minor histologic features may be encountered (Box 10-3), including alveolar hemorrhage, interstitial fibrosis, lipoid pneumonia, organizing pneumonia, lymphoid hyperplasia, extravascular tissue eosinophils, and xanthomatous lesions. WG can also involve the airways, causing chronic bronchiolitis, acute bronchiolitis or bronchopneumonia, the histologic pattern of organizing pneumonia (see further on), bronchocentric granulomatosis, follicular bronchiolitis, and bronchial stenosis.^51,53 Occasionally one of these minor lesions may be the dominant lung biopsy finding.⁵¹ Diffuse pulmonary hemorrhage is a severe life-threatening manifestation of WG. The pattern of bronchocentric granulomatosis is another rare manifestation of WG encountered in 1% of cases.^51,53 Organizing pneumonia (Fig. 10-20) can be seen in 70% of lung biopsies from patients with WG⁵¹; rarely, it may be sufficiently dominant that some have referred to this manifestation as the “bronchiolitis obliterans organizing pneumonia” (BOOP) variant of WG.^51,54 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 WG.

Figure 10-20 Wegener granulomatosis (WG): organizing pneumonia. Organization may be prominent in WG 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.

The lung biopsy findings from patients with WG may not show classical histologic findings, especially if patients are either biopsied very early in the course of disease or following therapy.^51,55 Interstitial fibrosis (sometimes with scattered giant cells, but without necrosis)(Fig. 10-21), bronchial or bronchiolar scarring, and cicatricial vascular changes (Fig. 10-22) are common in lung biopsies from patients who have received therapy.^51,55 Wedge biopsies provide the best results for an accurate diagnosis of WG. 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 WG.

Figure 10-21 Wegener granulomatosis: 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.

Figure 10-22 Wegener granulomatosis: 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).

Differential Diagnosis

The differential diagnosis for WG based on lung biopsy tissue depends somewhat on the constellation of changes present and includes granulomatous infection,⁵² lymphomatoid granulomatosis,^56,57 CSS,^58–61 sarcoidosis, necrotizing sarcoid granulomatosis,^56,62,63 rheumatoid nodules,⁶³ bronchocentric granulomatosis,^53,63,64 and diffuse pulmonary hemorrhage syndromes.^65,66

Occasionally, a form of diffuse large B cell malignant lymphoma commonly referred to as lymphomatoid granulomatosis (see Chapter 15) can bear a striking resemblance to WG⁶ (Fig. 10-23). Like classic WG, 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. WG 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,^4,67 a finding not expected in WG. 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 WG).

Figure 10-23 Wegener granulomatosis (WG): prominent lymphoid infiltrates. A, WG 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 WG.

Prominent tissue eosinophilia occurs in approximately 5% of cases of WG (Fig. 10-24). With this finding, the differential diagnosis should include CSS (see later), along with fungal or parasitic infection.^58,61,68,69 Peripheral blood eosinophilia is characteristic of CSS and is uncommon in WG.⁷⁰ Also, asthma is not a characteristic feature of WG, although rarely, asthmatic individuals may develop WG, presumably at a rate similar to that seen in the general population. The distinction between WG and CSS is usually straightforward, but some cases may require careful assessment of all of the clinical, pathologic, and laboratory data (Table 10-2).

Figure 10-24 Wegener granulomatosis: prominent eosinophils. When eosinophils are a prominent histopathologic feature, the differential diagnosis will include Churg-Strauss syndrome. Here a vessel is obliterated by inflammation and fibroblastic proliferation, and eosinophils are abundant. Note multinucleate giant cell in upper left.

Table 10-2 Wegener Granulomatosis versus Churg-Strauss Syndrome: Distinguishing Features

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

* Eosinophilia may be fleeting and may be difficult to demonstrate during steroid therapy.

Perhaps the most important, and often problematic, consideration in the diagnosis of WG is the exclusion of infection. Mycobacteria and fungi can cause necrotizing granulomatous inflammation and vasculitis resembling that seen in WG. 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.⁴⁶ Second, WG does not tend to make granulomas without central necrosis,⁵¹ except in the rare occurrence of infection superimposed on the necrotic center of a WG lesion. Third, the necrosis of infection may show the “ghosted” outlines of underlying lung parenchyma, a finding uncharacteristic of WG. Fourth, the patient with infection, in whom a bilateral multiple-nodular appearance on radiologic studies may simulate that in WG, is typically quite ill, with generalized systemic symptoms. By contrast, the patient with WG 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 WG presents with a predominantly bronchocentric pattern of lung involvement, bronchocentric granulomatosis must be considered in the differential diagnosis.^51,53 Patients with bronchocentric WG should demonstrate other distinguishing features of WG, including renal or sinus involvement and a positive ANCA serology.

Diagnosis

The histologic features of WG 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 WG.⁷¹ Moreover, when all other clinical and histopathologic findings are compelling for WG, the diagnosis is still possible despite negative ANCA studies.³⁹

Treatment and Prognosis

WG 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.⁷² 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 WG.^20,73–75 Trimethoprim-sulfamethoxazole may reduce relapses for those patients who are in remission.⁷⁶ The mechanism of this protective action is unknown. Rituximab has more recently shown promise in treatment of WG, particularly limited disease refractory to standard therapy.⁷⁷ Initial trials of antagonists of tumor necrosis factor-alpha (TNF-α) 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.⁷⁸ The outcome with WG 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.

Clinical Features

Despite more than 40 years of study, the incidence and epidemiology of CSS remain unclear. Based on available (although limited) population-based studies, CSS is second only to WG as a major cause of systemic vasculitis, and CSS is the diagnosis in approximately 10% of patients who develop a major vasculitic syndrome.¹ The exact etiology of CSS is unknown, but an autoimmune etiology is most likely.

CSS affects both sexes equally. The mean age at diagnosis is 50 years, but the systemic vasculitic phase is frequently evident in patients in their late 30s. CSS mainly involves the upper respiratory tract, lungs, skin, and peripheral nerves.^59,61,69 Involvement of the heart and kidney also occurs and may be associated with a worse outcome.

CSS often progresses through three distinct phases. In the early or prodrome phase, the disease manifests as allergic rhinitis, asthma, peripheral eosinophilia, and/or eosinophilic infiltrative disease.^59,61,69,70 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.^58,59,61 In the prodrome phase, tissue infiltration by eosinophils can affect the lungs or the gastrointestinal tract. Pulmonary manifestations may take the form of Löffler syndrome, with fleeting pulmonary infiltrates or even chronic eosinophilic pneumonia.

The prodrome 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 p-ANCA assay are usually positive. The ACR criteria necessary for diagnosis are present only during this phase.⁶⁹ 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, CSS 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.^69,88 Proteinuria and gastrointestinal involvement are poor prognostic indicators.⁸⁹

A major difference between CSS and WG is the frequency of cardiac and renal involvement. Although the heart may be involved in both disorders, up to 47% of CSS patients develop cardiac disease.^61,69 CSS can cause cardiac failure, pericarditis, hypertension, and acute myocardial infarction.^58,59,61 Also, while renal disease is characteristic in WG, it is less frequent and less severe in patients with CSS.^59,61,90

Peripheral neuropathy, often in the form of mononeuritis multiplex, is seen in approximately two thirds of patients with CSS. The most common cutaneous manifestation is leukocytoclastic vasculitis.⁹¹ Sinonasal manifestations include nasal obstruction, nasal polyps, rhinnorhea, and thick intranasal crusts.⁹² Central nervous system involvement can occur in 25% of cases.^61,69,81 Gastrointestinal hemorrhage and perforation are potential complications.⁹³ Serologic studies usually show the p-ANCA pattern, although c-ANCA can also be seen (the inverse of ANCA types in WG).⁹⁴ Elevated serum IgE is also a characteristic finding in CSS.^59–61,69

A CSS-like syndrome develops as a rare complication in steroid-dependent asthmatics successfully treated with leukotriene receptor antagonists (e.g., pranlukast).^95–99 This complication probably is related to steroid withdrawal facilitated by the drugs, which unmasks underlying CSS, rather than a manifestation of the drugs. To this point, a similar unmasking of CSS has occurred in asthmatic patients whose withdrawal from oral steroids was facilitated by inhaled steroids.⁹⁹ Also, an unusual association between a CSS-like vasculitis and the illicit use of “free base” cocaine has been reported.¹⁰⁰

There are no laboratory tests specific for CSS. Peripheral blood eosinophilia (eosinophil counts usually 5000–9000/μL) 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.

Radiologic Features

CSS most commonly manifests radiologically as multifocal lung parenchymal infiltrates that change in location and size over time^42,58,101 (Fig. 10-25). The infiltrates may also exhibit a peripheral distribution, thereby mimicking those of chronic eosinophilic pneumonia. Lung involvement by pulmonary consolidation may be widespread. Diffuse miliary nodules have also been reported.^40,101 Cavitation of nodules is rare and when present should suggest superimposed infection.¹⁰² Eosinophilic pleural effusions may be seen in 29% of cases.^42,101 Hilar lymphadenopathy is infrequent. The chest radiograph can be normal in appearance in as many as 25% of patients.⁴²

Figure 10-25 Churg-Strauss syndrome (CSS): 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 CSS was confirmed at open lung biopsy.

(From Travis WD, Colby TV, Koss MN, et al, eds. Non-Neoplastic Disorders of the Lower Respiratory Tract. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Figure 4-18.)

High-resolution CT (HRCT) features of CSS 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.¹⁰³ 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.¹⁰⁴

Pathologic Features

The findings on lung biopsy depend on the stage of the disease during which the biopsy is obtained and whether or not the patient has received therapy, particularly steroids. Lung biopsies from CSS patients in the full blown vasculitic phase may show asthmatic bronchitis, eosinophilic pneumonia (Fig. 10-26), extravascular stellate granulomas (Fig. 10-27), and vasculitis^58,69 (Fig. 10-28). 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. 10-29) can be seen.^90,105 In patients who are partially treated, the pathologic (and clinical) features may be incomplete.¹⁰¹ Lung biopsy is not required for diagnosis, if pulmonary infiltrates are present in association with other systemic findings that fulfill the required diagnostic criteria.

Figure 10-26 Churg-Strauss syndrome (CSS): eosinophilic pneumonia. Eosinophilic pneumonia is the most consistent manifestation of CSS. Here, the triad of air space eosinophils, eosinophilic macrophages with fibrin, and atypical alveolar lining cells can be readily appreciated.

Figure 10-27 Churg-Strauss syndrome: 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 10-28 Churg-Strauss syndrome (CSS): vasculitis. Vasculitis is characteristic in CSS. 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.

Figure 10-29 Churg-Strauss syndrome (CSS): pulmonary hemorrhage. Diffuse pulmonary hemorrhage with capillaritis can occur in CSS. Capillaritis is demonstrated here, associated with aggregated air space fibrin and eosinophils.

Differential Diagnosis

The differential diagnosis of CSS includes eosinophilic pneumonia from any cause, WG,⁵¹ allergic bronchopulmonary fungal disease (ABPFD),¹⁰⁶ infection (especially parasitic and fungal),¹⁰⁷ Hodgkin disease, and drug-induced vasculitis.¹⁰⁸

Eosinophilic pneumonia and ABPFD lack systemic vasculitis, although some cases of eosinophilic pneumonia can show a mild non-necrotizing vasculitis, and “allergic granulomas” may be present. Features helpful in distinguishing CSS from WG are summarized in Table 4-5. Pathologic features similar to those of CSS can also be mimicked by certain parasitic infections, such as those caused by Strongyloides stercoralis¹⁰⁹ and Toxocara canis.¹⁰⁷ Therefore, parasitic infection should be carefully excluded when CSS 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 CSS. Drugs such as carbamazepine also can cause a CSS-like syndrome, so attention should be paid to the patient’s drug history.¹⁰⁸

Treatment and Prognosis

Most patients with CSS respond to systemic corticosteroids. In order to avoid irreversible organ injury, some authorities have favored treatment with cytotoxic immunosuppressive agents, such as cyclophosphamide, from the outset.⁶⁹ Azathioprine, interferon-α, 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 occasionally has been used but appears to have no added benefit to that observed with treatment with systemic corticosteroids, with or without the addition of cyclophosphamide.¹¹⁰

Patients who die from CSS 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.^69,111

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 10-4).^117,118 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).¹¹⁸ Onset of symptoms is rapid in most patients, but up to 28% may have symptoms for more than 1 year before diagnosis.

Table 10-4 Microscopic Polyangiitis: Clinical Features at Presentation

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.

Bronchoalveolar lavage fluid typically shows acute hemorrhage or hemosiderin-laden macrophages when the lungs are involved. Kidney biopsies may show a necrotizing glomerulonephritis.¹¹⁸ More than 80% of patients have a positive ANCA, most often demonstrating the perinuclear type (p-ANCA).¹¹⁷ Microscopic polyangiitis is the most common cause of so-called pulmonary hemorrhage renal syndrome.¹¹⁷

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.¹¹⁸

Pathologic Features

Surgical lung biopsies in microscopic polyangiitis typically show pulmonary hemorrhage, hemosiderin-laden macrophages in alveolar spaces, and neutrophilic capillaritis^37,117 (Fig. 10-30). At scanning magnification, neutrophilic capillaritis often appears as scattered foci of increased alveolar wall cellularity, in a background of alveolar hemorrhage (Fig. 10-31). 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. 10-32). 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. 10-33). As the lesions of capillaritis heal, polypoid plugs of organizing fibrosis may be seen, sometimes resulting in a organizing pneumonia pattern (Fig. 10-34) (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.

Figure 10-30 Microscopic polyangiitis: pulmonary hemorrhage. Alveolar hemorrhage with capillaritis is a common manifestation of this disorder.

Figure 10-31 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 hemosiderin-laden macrophages in adjacent air spaces (bottom left).

Figure 10-32 Microscopic polyangiitis: pseudobronchopneumonia. Capillaritis may result in shedding of neutrophils into air spaces. When this occurs, neutrophilic acute bronchopneumonia may be simulated.

Figure 10-33 Microscopic polyangiitis: classic features. Note the characteristic capillaritis with aggregated air space fibrin and hemosiderin-laden macrophages.

Figure 10-34 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.

Hyaline membranes (Fig. 10-35) identical to those of diffuse alveolar damage (DAD) may also be seen.^37,119 In some cases it may be difficult to distinguish hemorrhagic DAD from a diffuse pulmonary hemorrhage syndrome with capillaritis. Pulmonary fibrosis^36,37 and progressive obstructive airway disease with emphysematous features^120,121 have also been reported in patients with microscopic polyangiitis.

Figure 10-35 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.

Differential Diagnosis

The differential diagnosis for microscopic polyangiitis includes hemorrhagic lung infections, WG with prominent capillaritis, Goodpasture syndrome, certain systemic collagen vascular diseases (e.g., systemic lupus erythematosus [SLE]) and other small-vessel vasculitides, such as Henoch-Schönlein purpura and cryoglobulinemia, and even certain rare drug reactions (e.g., diphenylhydantoin).¹²²

WG typically has granulomatous inflammation often consisting of palisaded histiocytes surrounding necrosis. Pure capillaritis forms of WG cannot be reliably distinguished from microscopic polyangiitis on histologic grounds. In most of these instances, some areas of collagen necrosis will be present in WG. Unfortunately, granulomatous inflammation may not be included in the tissue sampled if a conservative approach is taken to obtaining tissue biopsies in patients with WG. Moreover, on occasion granulomas can be absent altogether in WG, 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 medium-sized arteries in microscopic polyangiitis, such as arterioles, venules, and capillaries¹¹⁷ (Table 10-5).

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 agents113–115,^122,123 (Box 10-4). Microscopic polyangiitis is not associated with immune deposits in lung as are some other types of small-vessel vasculitis, such as Henoch-Schönlein purpura, cryoglobulinemic vasculitis, serum sickness, and lupus vasculitis.^116,117 Other conditions known to produce small-vessel vasculitis (listed in Box 10-4) can typically be excluded on clinical and serologic grounds.

Treatment and Prognosis

Microscopic polyangiitis is treated with immunosuppressive agents.¹¹⁷ 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%).¹¹⁸ 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.¹¹⁸

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 10-6. The average age for patients who develop the disease is 50, but it can occur from adolescence to late adulthood.^25,79,125 Women are affected twice as often as men.^126,127 The usual presentation includes cough, fever, chest pain, dyspnea, malaise, and weight loss.^62,126,128 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.^63,129–131 Upper airway disease, glomerulonephritis, and systemic vasculitis are not expected findings. To date, positive ANCAs have not been reported in this disease.

Radiologic Features

Necrotizing sarcoid granulomatosis usually manifests as bilateral, multifocal parenchymal nodular opacities. Nodules may either be well marginated or have ill-defined borders (Fig. 10-36). 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.^{42,62,79,80,132} Solitary lesions and parenchymal consolidations may occur but are unusual manifestations.

Figure 10-36 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 mid lung 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, et al, eds. Non-Neoplastic Disorders of the Lower Respiratory Tract. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Figure 4-24.)

On CT scans, cavitation and heterogeneous contrast enhancement of the lesions may be seen (Fig. 10-37), correlating with intralesional necrosis.¹²⁹ Pleural involvement with thickening or effusion may also be observed.¹³² Hilar lymphadenopathy is variable and not seen as frequently as in sarcoidosis.⁵⁶

Figure 10-37 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, et al, eds. Non-Neoplastic Disorders of the Lower Respiratory Tract. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Figure 4-25.)

Pathologic Features

Confluent non-necrotizing granulomas form large nodules in the lung parenchyma (Fig. 10-38). Large zones of necrosis are present in the nodules (Fig. 10-39), and vasculitis (Fig. 10-40) 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. 10-41). One can also see a sarcoidal pattern of lung involvement with a lymphangitic distribution to the granulomas.^56,62,127 In addition to the large zones of necrosis, smaller foci of necrosis often are present.⁵⁶

Figure 10-38 Necrotizing sarcoid granulomatosis: large nodules with variable necrosis. Large parenchymal inflammatory nodules with necrosis are typically seen. A, Confluent non-necrotizing granulomas are a dominant feature. B, Elastic tissue stains help demonstrate vascular involvement within and around nodules (upper right, off center).

Figure 10-39 Necrotizing sarcoid granulomatosis: large zones of necrosis. Large zones of necrosis are seen at right.

Figure 10-40 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 adventitial fibrosis.

Figure 10-41 Necrotizing sarcoid granulomatosis: sarcoid-like granulomas. A, The granulomas in this disorder resemble those of sarcoidosis. B, Admixed multinucleate giant cells are typically seen.

The vasculitis of necrotizing sarcoid granulomatosis can affect both arteries and veins. Three patterns of vasculitis can be seen: necrotizing granulomas (Fig. 10-42), giant cell vasculitis (Fig. 10-43), and infiltration by chronic inflammatory cells.¹³³ Necrotizing granulomas may be present circumferentially along the vascular walls (Fig. 10-44).

Figure 10-42 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 10-43 Necrotizing sarcoid granulomatosis: giant cells in arteries. Giant cells may be a prominent component of the vasculitis.

Figure 10-44 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.

Differential Diagnosis

The differential diagnosis for necrotizing sarcoid granulomatosis includes granulomatous infection, nodular sarcoidosis, and WG. The most important of these entities, and the most difficult to exclude, is granulomatous infection,^56,61 especially because granulomatous infections caused by mycobacteria and fungi can produce both vasculitis and sarcoid-like granulomas.^51,52 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 WG are summarized in Table 10-7.

Table 10-7 Wegener Granulomatosis versus Necrotizing Sarcoidosis: Distinguishing Features

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

Treatment and Prognosis

The prognosis for patients with necrotizing sarcoid granulomatosis is excellent.^127,134 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^62,63 or will experience a relapse.^56,135 The only deaths reported in patients with necrotizing sarcoid granulomatosis have been due to opportunistic infections, so cytotoxic immunosuppression generally is not recommended.⁶²

Clinical Features

Takayasu arteritis most commonly affects women less than 40 years of age.¹⁵¹ Pulmonary arteries are involved in 12% to 86% of patients with the disease,^151–154 and rarely, pulmonary artery involvement may be the presenting manifestation.¹⁵⁵ Takayasu arteritis may affect the kidneys, heart, skin and gastrointestinal tract.¹⁵⁶ 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.^152,153,157 Fistulas between pulmonary arteries and systemic arteries may occur.¹⁵⁸

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.¹⁵⁹ Subpleural linear reticular changes and pleural thickening also occur.¹⁵⁹

Pathologic Features

Takayasu arteritis involves the adventitia, media, and intima of large elastic pulmonary arteries (Fig. 10-47). 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.^160,161 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.¹⁶¹

Figure 10-47 Takayasu arteritis. The wall of this pulmonary artery is infiltrated by lymphocytes and giant cells.

(From Travis WD, Colby TV, Koss MN, et al, eds. Non-Neoplastic Disorders of the Lower Respiratory Tract. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Figure 4-29.)

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.¹⁶²

Clinical Features

Behçet syndrome has a worldwide distribution but is most commonly a disease of the Mediterranean basin, the Middle East, and Japan.^164,165 The disease typically affects individuals between adolescence and middle age. The diagnosis is based primarily on clinical criteria (Box 10-5). 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 systemic lupus erythematosus.

Symptoms of pulmonary involvement include dyspnea, cough, chest pain, and hemoptysis.¹⁶⁵ Males are more likely to develop lung manifestations, particularly hemoptysis.^165,166 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.^166,167

Radiographic Features

Air space consolidation consistent with pulmonary hemorrhage, lung infarction, and pulmonary artery aneurysms may be seen when the lungs are involved.^168,169 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.^168,169 Pulmonary aneurysms and thromboses can be detected with angiography as well.¹⁶⁵

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. 10-48). Additional findings include aneurysms of elastic pulmonary arteries, arterial and venous thromboses(Fig. 10-49), pulmonary infarcts (Fig. 10-50), bronchial erosion by pulmonary artery aneurysms, and arteriobronchial fistulas.^165,170,171 Perivascular adventitial fibrosis may be prominent. Collateral vessels lacking elastic lamellae may develop in the periadventitial fibrous tissues around thrombosed arteries and aneurysms (Fig. 10-51). Hemorrhage¹⁷² and acute interstitial pneumonia¹⁷³ may occur as life-threatening pulmonary complications.

Figure 10-48 Behçet syndrome: vasculitis. The wall of this small artery is infiltrated by lymphocytes.

(From Travis WD, Colby TV, Koss MN, et al, eds. Non-Neoplastic Disorders of the Lower Respiratory Tract. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Figure 4-30.)

Figure 10-49 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, et al, eds. Non-Neoplastic Disorders of the Lower Respiratory Tract. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Figure 4-31.)

Figure 10-50 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).

Figure 10-51 Behçet syndrome: collateral vessels. The collateral vessels in the periadventitial tissues surrounding this large elastic artery lack elastic lamellae.

(From Travis WD, Colby TV, Koss MN, et al, eds. Non-Neoplastic Disorders of the Lower Respiratory Tract. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Figure 4-33.)

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.¹⁶⁶ Severe hemoptysis may require surgical intervention.¹⁷² The clinical course of Behçet syndrome is characterized by exacerbations and remissions. Over time, the disease may decrease in severity.

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.¹⁷⁸

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.¹⁷⁸