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CT OF NONINFECTIOUS GRANULOMATOUS LUNG DISEASE
HIGH-RESOLUTION CT OF THE LUNG
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CT OF NONINFECTIOUS GRANULOMATOUS LUNG DISEASE Steven E. Zinck, MD, Erich Schwartz, MD, Gerald J. Berry, MD, and Ann N. Leung, MD
The noninfectious granulomatous diseases of the lung can be divided into two groups based on the presence or absence of associated vasculitis on pathologic examination. Sarcoidosis and hypersensitivity pneumonitis (HP)are two relatively common infiltrative lung disorders belonging to the group without significant vascular inflammation. Berylliosis, the third entity of this group, is a pneumoconiosis that results from an immune-mediated hypersensitivity response to inhalation of beryllium metal alloys and ~ a l t s . ~ Pulmona y angiitis and gran~lomatosis~~ is the term traditionally used to describe the group of noninfectious granulomatous diseases that is associated with vasculitis. Five entities are recognized: (1) Wegener’s granulomatosis (WG), (2) Churg-Strauss syndrome (CSS), (3) bronchocentric granulomatosis (BCG), (4) necrotizing sarcoidosis (NSG), and (5) lymphomatoid granulomatosis (LYG). Of this group, only WG and CSS are true systemic vas~ulitides.~~, 49 SARCOIDOSIS
Sarcoidosis is a systemic disease of unknown cause that is characterized by the pres-
ence of noncaseating g r a n ~ l o m a sThoracic .~~ involvement occurs in up to 90% of affected individuals.22The disease is relatively common with an estimated prevalence of 3 to 50 per 100,00022and occurs worldwide, more frequently in temperate than tropical climates. Because approximately 50% of cases are asymptomatic, the true incidence of sarcoidosis likely is underestimated. There is no specific gender predilections5; in the United States, the disease is eight times more common in blacks than whites.92Age at presentation ranges from adolescence to the seventh decade with most patients under 40 years of age at time of initial presentati~n.~~ Symptoms of pulmonary involvement by sarcoidosis include dry cough, progressive dyspnea, and exertional intolerancez2,92; erythema nodosum and constitutional symptoms, such as fever, weight loss, and fatigue, may be associated.22, 92 The criteria for establishing the diagnosis of sarcoidosis are well established and include the following: (1) compatible clinical or radiologic findings or both; (2) histologic evidence of noncaseating granulomas; and ( 3 ) negative bacterial and fungal studies of tissue biopsy, sputum, or other body fluids.s2The characteristic pathologic lesion in sarcoidosis is the non-necrotiz-
From the Departments of Radiology (SEZ, ANL) and Pathology (ES, GJB), Stanford University Medical Center, Stanford. California
RADIOLOGIC CLINICS OF NORTH AMERICA VOLUME 39 NUMBER 6 * NOVEMBER 2001
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Figure 1. Sharply delineated noncaseating granuloma surrounded by collagenous stroma containing scattered chronic inflammatory cells (hematoxylin-eosin [H & El, original magnification x 400).
ing granuloma composed of tightly clustered aggregates of histiocytes and occasional multinucleated giant cells and sparse numbers of lymphocytes and other inflammatory cells (Fig. l).41 The granulomas are surrounded by hyalinized connective tissue containing a thin collar of chronic inflammatory cells. Intersti-
tial inflammation is generally absent. Granulomatous vasculitis may be seen and is characterized by mural intrusion by granulomas without fibrinoid necrosis of vessel walls. Most pulmonary granulomas are located in the interstitium along lymphatic pathways (bronchovascular bundles, interlobular septa,
Figure 2. Lymphatic distribution of sarcoidosis along bronchovascular bundles (asferisk), interlobular septa (arrow), and pleural tissues (arrowheads) (H&E, original magnification x 30).
CT OF NONINFECTIOUS GRANULOMATOUS LUNG DISEASE
and subpleural connective tissues) (Fig. 2):l~ 72 Because a number of different conditions including mycobacterial and fungal infections may have similar histologic featnres, ancillary procedures, such as bacteriologic culture and histochemical staining of tissue samples, are necessary to exclude these entities and confidently establish the diagnosis of sarcoidosis. The characteristic radiographic appearance of thoracic sarcoidosis consists of symmetric, bilateral hilar, and right paratracheal lymphadenopathy, with or without concomitant parenchymal abnormalities. Symmetry of nodal enlargement is an important feature differentiating sarcoidosis from other diseases, such as lymphoma, metastatic disease, or granulomatous infections, because unilateral lymphadenopathy occurs only in 5% of cases of sarcoidosis.88On CT, the most commonly involved nodal stations are right paratracheal, hilar, aortopulmonary window, subcarinal, and anterior mediastinum in decreasing order of frequency occurring in loo%, 92%, 88%, 64%, and 48% of patients, respectively, in one Nodal calcification (Fig. 3) is a late manifestation and when present, is usually associated with advanced disease. On high-resolution CT (HRCT), irregularly marginated nodules ranging from 1 to 10 mm in size are the predominant parenchymal ab-
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normality of sarcoidosis.6,62 The nodules typically have a perilymphatic distribution and are found along bronchovascular bundles, interlobular septa, and pleural surfaces (Fig. 4).62 Possible associated findings include ground-glass opacities, conglomerate masses, pleural thickening, architectural distortion, cysts, nonseptal lines, and traction bronchiectasis (Fig. 5)6,7, 64; the latter four features usually denote the presence of irreversible 64 An upper and middle lung zonal fibr~sis.~, predominance of parenchymal abnormalities is a distinguishing feature of sarcoidosis and is present in approximately two thirds of patients.6 Patients with sarcoidosis and abnormal lung function usually demonstrate a restrictive pattern with reduced lung volumes. Statistically significant but low correlations have been found between extent of parenchymal abnormalities identified on CT and measures of clinical and functional impairment, such as diffusing capacity (r = - 0.49 to - 0.62); vital capacity (r = -0.40 to -0.49); and total lung Both type and districapacity (r = - 0.48).63,76 bution of parenchymal abnormalities influence the degree of functional impairment; patients with predominantly nodular opacities have less severe dyspnea and higher volumes than those with predominantly irregular linear ~ p a c i t i e s .In ~ ~patients with fibrotic dis-
Figure 3. Sarcoidosis in a 48-year-old woman. High-resolution CT (HRCT) shows calcified nodes in the lower right paratracheal and bilateral hilar stations.
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Figure 4. Sarcoidosis in a 37-year-old woman. HRCT shows multiple, bilateral small irregularly marginated nodules distributed along the bronchovascular bundles, interlobular septae, and pleural surfaces.
Figure 5. Sarcoidosis in a 45-year-old woman. HRCT through the upper lobes shows confluent disease extending along bronchovascular bundles associated with scattered nodules. The presence of mild traction bronchiectasis within the areas of confluence suggests early fibrosis.
CT OF NONINFECTIOUS GRANULOMATOUS LUNG DISEASE
ease, honeycombing in a peripheral distribution is more commonly associated with restriction and reduced diffusing capacity than fibrotic patterns consisting primarily of central bronchial distortion or diffuse linear opacities. HYPERSENSITIVITY PNEUMONITIS Hypersensitivity pneumonitis, also known as extrinsic allergic ulveolitis, is an allergic inflammatory granulomatous reaction of the lungs caused by the inhalation of specific antigens contained in a number of organic dusts. Numerous inciting agents have been identified, but the more common include thermophilic actinomycetes, avian proteins, and fungi.3s The clinical, radiologic, and pathologic features of HP are classically divided into three stages: (1)acute, (2) subacute, and (3) chronic.*9,33, 38 These stages are not necessarily sequential, however, and features of each may coexist in the same patient.30,6o The acute phase is caused by overwhelming exposure to an inciting antigen. Patients present within 4 to 6 hours of exposure with symptoms of fever, chills, cough, dyspnea, chest tightness, and myalgia30,38, 83; symptoms usually subside over a few days. In subacute disease, intermittent exposure results in recurrent episodes of similar but less severe symptoms to those experienced in the acute phase that can continue for weeks to months.30,6o With prolonged exposure, a chronic stage with pulmonary fibrosis may develop. Affected patients often present with an insidious form of the disease with complaints of slowly increasing dyspnea, cough, weight loss, and fatigue.30,60, 83 Definitive diagnosis of HP requires demonstration of a direct temporal relationship between exposure to antigen and onset of symptoms, with resolution of symptoms when the inciting agent is removed or avoided.38,83 Clinical and radiologic features are often sufficient to suggest the diagnosis of HP, particularly when they develop in the context of a recognized sensitizing exposure. Serologic testing is often performed because demonstration of the presence of serum precipitins to a specific antigen serves as a marker of
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exposure and can further strengthen diagnostic confidence. In cases in which the clinical diagnosis remains uncertain, transbronchial or thoracoscopic biopsy may be necessary.38* 83 The histologic features of HI' vary according to the stage of disease with most biopsies performed in the subacute stage. The histologic triad that characterizes the subacute stage of HP consists of (1)a temporally uniform cellular peribronchiolitis with chronic inflammatory infiltrates around respiratory bronchioles (Fig. 6), (2) nonspecific cellular interstitial infiltrates of chronic inflammatory cells, and (3) scattered small loose non-necrotizing gran~lornas.'~ In contrast to sarcoidosis, the granulomas in HP are more poorly formed and are centered on the peribronchiolar interstitium rather than lymphatic spaces (Fig. 7).30,83 In the chronic stage, the granulomatous alveolitis is replaced by interstitial fibrosis and honeyc~mbing.~~ The CT findings of the acute stage of HP have been described in only two cases.86Diffuse, bilateral consolidation was the predominant finding with poorly marginated nodules measuring less than 3 mm associated in one patient.s6The characteristic HRCT findings of the subacute stage consist of diffuse, bilateral ground-glass opacities often seen in combination with poorly defined centrilobular nodules measuring between 1 and 5 mm in size (Fig. 8).31,57, n,86 The distribution of these parenchymal abnormalities may be n or have a middle to lower zonal predomin a n ~ e .86~ Focal ~, areas of decreased attenuation are a common associated finding in the subacute stage of diseases2,"; these sharply marginated areas are believed to represent air-trapping in obstructed secondary pulmonary lobules and may be accentuated by expiratory scanning.32 The chronic stage of HP on HRCT is characterized by findings of fibrosis with irregular linear opacities, architectural distortion, honeycombing, and traction bronchiectasis (Fig. 9).2,86 Fibrotic changes have been variably reported to be distributed evenly or to predominate in the middle and lower lung zones.2, Associated findings of subacute disease, such as ground-glass opacities and centrilobular nodules, are present in most patients2,8,86 and may aid in establishing the correct diagnosis.
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Figure 6. Scanning magnification of hypersensitivity pneumonitis showing patchy, chronic interstitial pneurnonitis in a peribronchiolar distribution (arrow). Scattered granulomas are present (arrowheads) (H&E, original magnification x 60).
Figure 7. Typical appearance of poorly formed granulomas of hypersensitivity pneumonitis composed of loosely arranged histiocytes admixed with mononuclear cells (H&E, original magnification x 400).
CT OF NONINFECTIOUS GRANULOMATOUS LUNG DISEASE
Figure 8. Subacute hypersensitivity pneumonitis in a 55-year-oldbird owner. HRCT shows innumerable poorly defined centrilobular nodules in a background of diffuse ground-glass opacity. Associated lobular areas of hyperlucency likely represent air-trapping.
Figure 9. Chronic hypersensitivity pneumonitis in a 71-year-old pigeon breeder. HRCT at the level of the bronchus intermedius shows diffuse nonseptal reticular opacities associated with mild architectural distortion and patchy areas of ground-glass attenuation.
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Lymphadenopathy and pleural disease are rare findings in any stage of HP.30,31 BERYLLIOSIS
opacities that are distributed diffusely in the 34, 7o Less lungs without zonal pred~minance.~, common parenchymal manifestations include linear scars; bulla, fibrosis predominantly involving the upper lobes, and conglomerate 34 masses similar to those seen in silic~sis.~, Hilar lymphadenopathy is present in up to one third of affected patients.70Pleural thickening may occur in advanced cases and can be associated with a reduction in vital capacity." Newman et a170 reviewed the HRCT findings of 28 patients with biopsy-proven CBD. Parenchymal nodules and interlobular septa1 thickening were the most common CT features found in 16 (57%) and 14 (50%) patients, respe~tively.~~ Nodules were typically welldefined and distributed along bronchovascular bundles and interlobular septa similar to the distribution of nodules associated with sarcoidosis (Fig. 10). Other CT findings of CBD include bronchial wall thickening, emphysema, ground-glass opacities, conglomerate masses, fibrosis, and pleural thickening.34,70 Hilar or mediastinal lymphadenopathy occurs in up to 40% of cases and similar to conglomerate masses, may contain 34 calcificati~n.~~,
Beryllium is a light weight metal with excellent thermal and electrical conductivity. Initially used in the manufacturing of fluorescent lamps, beryllium is now widely used in the ceramics, nuclear weapons, computer, and aerospace industries, and is a common component of many household appliance^.^, 79 Berylliosis is caused by exposure to aerosols, dusts, or fumes of beryllium metal or salts3 and can occur in acute and chronic forms. Acute disease follows an overwhelming airborne exposure, which causes a chemical pneumonitis and acute pulmonary edema; severe cases may be fatal. The histopathologic findings in this setting are primarily diffuse alveolar damage. Because of laws passed in 1950 regulating acceptable exposure levels? acute berylliosis now rarely occurs. Chronic beryllium disease (CBD) is a systemic granulomatous disease with histologic features identical to sarcoidosis and is thought to be caused by a specific, cell-mediated hypersensitivity response to long-term exposure to be68, 79 Although CBD may affect multirylli~m.~, WEGENER'S GRANULOMATOSIS ple organs, the lung usually is most severely in~olved.~,Exertional dyspnea is the most Wegener's granulomatosis is a systemic common presenting complaint, followed by disease of unknown cause characterized by cough and chest pain; less common sympthe triad of necrotizing granulomatous intoms include weakness, weight loss, fevers, flammation of the upper and lower respira61 and arthralgia~.~, tory tracts, glomerulonephritis, and disseminThe diagnosis of CBD may be suggested by a history of significant exposure to beryllium, ated small vessel vasculitis.13,25 In the United consistent radiographic findings, and abnorStates, the prevalence of WG is estimated to be 3 per 100,000 with a male to female ratio mal pulmonary function tests.34Confident diof about l:l.47Most affected patients are white agnosis, however, requires demonstration of granulomas in tissue, immunologic evidence and the mean age at diagnosis is 40 to 55 that granuloma formation is caused by berylyears.21,47 The onset and course of WG vary delium hypersensitivity, and a proliferative repending on the specific organ or organ syssponse of lymphocytes obtained by brontems involved. Patients may initially present choalveolar lavage to beryllium.79This latter with systemic symptoms, such as fever, test, known as the bronchoalveolar lymphocyte transformation test, is highly accuratesoand can weight loss, malaise, and myalgias.20,50 Over diagnose CBD before onset of clinical sympthe course of the disease, however, most detoms or pulmonary function abn~rmalities.~~velop localizing symptoms, such as sinusitis, otitis media, hearing loss, epistaxis, cough, The most common radiographic finding in dyspnea, and chest pain indicating the presCBD consists of small round and reticular
CT OF NONINFECTIOUS GRANULOMATOUS LUNG DISEASE
Figure 10. A 60-year-old man with berylliosis. A, HRCT through the right upper lung shows numerous micronodules with a preferential distribution along bronchi, vessels, interlobular septa, and pleura. There is a large conglomerate mass but no architectural distortion to suggest fibrosis. 13,CT at the level of carina shows multiple calcified and partially calcified nodes. The pattern is indistinguishable from sarcoidosis and was misdiagnosed as sarcoid for 10 years because the occupational history was not obtained.
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ence of upper airway or lung Renal disease is often asymptomatic, but may be associated with microscopic hematuria and proteinuria and can eventually result in renal failure.”, 36 Ocular involvement eventually develops in approximately 50% of patients and can cause proptosis, diplopia, and 36 Macules, papules, purpura, conjunctivitis.20, nodules, ulcers, vesicles, and rash are seen with cutaneous involvement.20,36 Neurologic disease occurs uncommonly, manifesting as peripheral or central neuropathy.20,36 Although previously considered a fatal disease, partial or complete remission of WG can be achieved in up to 90% of patients with combined cyclophosphamide and corticosteroid therapy.36,50 Accurate diagnosis of WG is critical because other vasculitides are treated with corticosteroids alone.50 The diagnostic criteria established by the American College of Rheumatology consist of (1) abnormal urinary sediment; (2) abnormal chest radiographic findings; (3) oral ulcers or nasal discharge; and (4)granulomatous inflammation on tissue biopsy (or hemoptysis if biopsy is una~ailable).~~ The presence of at least two of the four criteria is associated with a diagnostic sensitivity of 87% and specificity of 94%?O Measurement of serum antineutrophil cyto25, 36
plasmic antibody (ANCA) titers has also been shown to be helpful in the diagnosis and monitoring of disease activity.17,36 In particular, the c-AP\TCA form is elevated in approximately 90% of patients with active disease, and rising c-ANCA titers indicate disease relapse.17,36 The histologic findings of pulmonary WG are parenchymal granulomatous inflammation with a mixed cellular infiltrate associated with geographic basophilic necrosis and vasculitis of small and medium-sized arteries, veins, and capillarie~.~~ The presence of necrotizing vasculitis is required for pathologic diagnosis. Patterns include (1) granulomatous vasculitis (Fig. ll),(2) neutrophilic infiltration of vessel walls with cellular debris, and (3) acute and chronic inflammation with fibrinoid necrosis. In cases characterized by the presence of hemorrhage, histologic findings consist of a capillaritis with preservation of the normal lung architecture; filling of alveolar spaces with red blood cells is associated with hemosiderin-laden macrophages and foci of organizing fibrin exudate.67 On CT, the most common finding of pulmonary WG is multiple irregularly marginated nodules, which can range from 2 to 20 in number and from 2 to 90 mm in size.46,73, 96
Figure 11. Vasculitis in Wegener’s granulomatosis. The medial layer of this muscular pulmonary artery is incompletely preserved (arrows). Transmural infiltration by acute and chronic inflammatory cells and granulomatous elements result in necrosis of the vessel with marked luminal narrowing (H&E, original magnification x 400).
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Figure 12. Wegener’s granulomatosis in a 22-year-old man. HRCT shows bilateral nodules, some of which are peribronchovascularin distribution (small arrows). Air bronchograms (large arrow) and surrounding ground-glass attenuation (open arrows) are associated findings.
In the series of Weir et a1,96all nodules greater than 2 cm demonstrated cavitation; cavity walls may be thick and irregular or thin and 96 Nodules are typically bilateral and random in distrib~tion~~, 96 but may also occur in a predominantly subpleural or peribronchovascular location (Fig. l2).” Within nodules, an air bronchogram may occasionally be identified.46
Areas of opacification ranging from ground-glass attenuation to frank consolidation are the second most common CT pattern of pulmonary WG and often represent findings of pulmonary hemorrhage (Fig. 13).73,96 These areas of increased attenuation can occur as an isolated finding or in conjunction with pulmonary nodules; their distribution may be focal, patchy, or diffuse and occasion-
Figure 13. Wegener’s granulomatosis in a 55-year-old woman. CT shows diffuse, bilateral consolidation with air bronchograms secondary to extensive pulmonary hemorrhage.
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ally localizes to the ~ u b p l e u r a and l ~ ~ peribronchovascularZ4~ 73 regions. Tracheobronchial involvement by WG manifests on CT as mural thickening and narrowing of involved airways (Fig. 14). Screaton and colleagues81evaluated the CT findings in 10 patients with tracheal involvement and found that 90% of inflammatory lesions were located in the subglottic region; circumferential tracheal involvement and narrowing occurred in all patients with a length of involvement ranging from 5 to 45 mm. Associated findings in this study included mural thickening, mucosal irregularity and ulceration, and deformity of the cricoid or tracheal cartilage.81 Hilar or mediastinal lymphadenopathy in WG is believed to be rarez6but has been observed in up to 7% of patients evaluated with CT.73Pleural abnormalities, such as unilateral or bilateral effusions, thickening, and spontaneous hydropneumothorax, occur in a small percentage of patients.59,73,96
CHURG-STRAUSS SYNDROME Churg-Strauss syndrome, also known as allergic angiitis and granulomatosis, is an idiopathic multisystem disorder characterized
histologically by necrotizing vasculitis, extravascular granuloma formation, and tissue infiltration by eosinophils, which occurs almost exclusively-in patients with asthma or other allergic disease^.'^ CSS is the least common of the angiocentric granulomatoses with an estimated annual incidence of 3 per million.90 No gender predilection exists and mean age of onset ranges from 38 to 48 year^.^^,^^ The clinical course of CSS follows three distinct phases: (1) a prodromal phase of allergic rhinitis and asthma that may persist for years; (2) a second phase of peripheral and tissue eosinophilia resembling Loeffler 's syndrome, chronic eosinophilic pneumonia, or eosinophilic gastroenteritis that may recur for years; and (3) a third phase of severe, lifethreatening v a s c ~ l i t i sOnset . ~ ~ of the vasculitic phase may coincide with either a dramatic exacerbation or remission of asthma.48Systemic symptoms, such as fever, malaise, and profound weight loss, often occur in the early vasculitic phase.29,48 Although, any organ may be involved, the lungs, skin, gastrointestinal tract, and nervous system are the most frequently affected. Common presenting signs and symptoms include cough, dyspnea, palpable purpura, skin nodules, rash, abdominal pain, and mononeuritis multiplex.29, 48 The diagnostic criteria established by the
Figure 14. Wegener's granulomatosis in an 18-year-old woman. Volumerendered coronal CT image of the trachea and central airways shows severe narrowing of the left main stem bronchus (small arrows) and bronchus intermedius (large arrow).
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Figure 15. Churg-Strauss syndrome characterized by necrotizing vasculitis of pulmonary artery (arrows) by eosinophilic infiltrates with filling and expansion of adjacent alveolar airspaces and interstitum (H&E, original magnification x 400).
tive of chronic eosinophilic pneumonia may American College of Rheumatology consist of be seen.48Less common parenchymal findings (1) asthma, (2) eosinophilia of greater than include a diffuse interstitial pattern and bilat10% of the white blood cell differential count, eral noncavitary pulmonary nodules.12,48 (3) neuropathy, (4) migratory or transient pulmonary opacities, (5) paranasal sinus abnorPleural effusions may occur in up to 30% of mality, and (6) extravascular eosinophils on cases and lymphadenopathy is uncomtissue biopsy? The presence of at least four of m ~ n .48~ ~ , the six criteria is associated with a diagnostic Parenchymal opacification ranging from sensitivity of 85% and specificity of 99.7Y0.~~ ground-glass attenuation to consolidation is Histologically, CSS is characterized by a necthe most common HRCT finding found in rotizing vasculitis predominantly involving 73% (19 of 26) of patients with CSS evaluated medium- and small-sized arteries and veins in two series (Fig. 16).11,97 Distribution of the with mural infiltration by granulomatous inparenchymal opacities may be predominantly flammation, giant cells, or histiocytes and eosubpleural or patchy with no zonal sinophils (Fig. 15). Scattered well-formed predominance.", 97 Multiple pulmonary nodgranulomas with central foci of necrotic eoules ranging from less than 5 mm to 35 mm sinophils are often located adjacent to vessels in size are the second most common HRCT with patchy intra-alveolar and interstitial colfinding.", 97 Small centrilobular nodules can lections of eosinophils and macrophages reoccasionally be seen in areas of parenchymal sembling chronic eosinophilic p n e ~ m o n i a . ~ ~opacification.", 97 Larger nodules may contain The changes of chronic asthma can be seen in air bronchograms or demonstrate ~ a v i t a t i o n . ~ ~ bronchioles. An increased caliber of peripheral pulmonary Chest radiographs demonstrate abnormaliarteries relative to the accompanying bronchi ties in 27% to 100% of patients with CSS.lZ, has been described9," as an associated finding 42 Parenchymal abnormalities typically conand may correlate with eosinophilic infiltrasist of bilateral, migratory alveolar opacities tion of vessel walls9 Hilar or mediastinal without lobar or zonal predominance12,29, 42, 48; lymphadenopathy is identified in up to 40% occasionally, a peripheral distribution suggesof patients" and pleural effusions occur in the 297
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Figure 16. Churg-Strauss syndrome in a 46-year-old woman. HRCT shows bilateral patchy areas of ground-glass opacity.
minority of patients.", 97 Additional described findings, such as bronchial wall thickening and hyperinflation, likely reflect patients' underlying asthma.", 97 Occasionally, patients with documented CSS may have normal HRCT studies.97 BRONCHOCENTRIC GRANULOMATOSIS Bronchocentric granulomatosis is a rare disease of the lungs characterized by a necrotizing granulomatous reaction centered on the airways.53Rather than a specific disease, BCG represents a pattern of inflammatory response to a sustained and intense insult to the airways.16Affected patients can be divided into those with and those without concomitant asthma.40 Asthmatic patients with BCG typically present at a young age (childhood to early adulthood) and invariably have underlying allergic bronchopulmonary aspergillo~is.~~, 45 Nonasthmatic patients are usually older (mean age, 50 years) at time of presentation and may have associated conditions, such as granulomatous infections, rheumatoid arthritis, or prior organ transplantation.40,66,91 Asthmatic patients with BCG may present with symptoms of an asthma exacerbation or nonspecific complaints, such as fever, cough,
chest pain, hemoptysis, anorexia, and malaise.4O Nonasthmatic patients with BCG have a variable presentation; whereas some may have minimal symptoms or be completely asymptomatic, others present with fever, cough, wheezing, and malaise.40, 45 On gross pathologic inspection, the lesions of BCG consist of airways filled with mucoid or yellow-white cheesy material.40Histologically, necrotizing granulomatous inflammation replacing the mucosa and walls of bronchioles is present (Fig. 17) and is often associated with an interstitial infiltrate of eosinophils, particularly if the patient is asthmaScattered fungal hyphae can be found within luminal exudates. Unlike the other entities classified under pulmonary angiitis and granulomatosis, vasculitis is a minor component of BCG. Vascular involvement is usually an incidental finding and represents contiguous spread of inflammation from adjacent airways.4o Three radiographic patterns of disease have been described in BCG: (1)nodules, (2) alveolar opacities, and (3) reticulonodular opacities.78Nodules may range in size from 2 to 6 cm and are typically solitary but may be multiple.40,78 Nodule margins may be wellcircumscribed or ill-defined and associated cavitation is uncommon.78Like nodules, the alveolar opacities predominate in the upper lobes and are usually ~ n i l a t e r a l .78~ ~ , Diffuse
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Figure 17. Bronchocentric granulomatosis showing replacement of bronchiolar mucosa (white arrowheads) by necrotizing granulomatous inflammation (black arrows). ( M E , original magnification x 300).
reticulonodular opacities are the least common pattern, and on biopsy have been shown to represent diffuse involvement of smaller bronchi ole^.^^ Lymphadenopathy and pleural abnormalities are infrequent associated findings.78 Ward et a194described the CT findings in five patients with biopsy-proved BCG. Focal mass (Fig. 18) and lobar consolidation associ-
ated with volume loss were the most common findings occurring in three (60%) and two (40%) patients, respectively. Parenchymal abnormalities involved the upper lobes in four (80%) patients, and the superior segment of a lower lobe in one (20%) patient. Cavitation and central necrosis were identified in one patient with bilateral 2-cm nodules. Multilobar mucoid impaction was an associated
Figure 18. Bronchocentric granulomatosis in a 72-year-old nonasthmatic woman. CT shows a solitary 5-cm irregularly marginated mass in left upper lobe abutting the mediastinum.
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finding in one patient with the lobar consolidative pattern. Mediastinal nodal enlargement occurred in two (40%) patients. Geographic hyperlucency associated with bronchiectasis and septa1 thickening has been reported as the CT findings of BCG in one pediatric case.56
NECROTIZING SARCOID GRANULOMATOSIS
Necrotizing sarcoid granulomatosis is a rare disease of unknown cause that is characterized histologically by the presence of confluent sarcoid-like granulomas associated with variable amounts of parenchymal necrosis and v a s c ~ l i t i s Because .~~ of some shared similarities in clinical, immunologic, and histologic features, NSG has been postulated to represent a variant of classic sarc~idosis.'~, 89 Affected patients usually present between the third and seventh decades of life with women more than twice as frequently affected as men.10, 14. 43.52 Necrotizing sarcoidosis granulomatosis is usually limited to involvement of the thorax; common presenting symptoms include fever, malaise, weight loss, cough, chest pain, and dyspnea.lo,14, 43 Because the eye is the most
common site of extrathoracic involvement, patients may initially present with visual disturbances.& The histologic features of NSG consist of confluent granulomas composed of giant cells and epitheliod histiocytes interspersed with chronic inflammatory cells that replace lung parenchyma with zones of necrosis randomly distributed within the granulomas (Fig. 19).43 The vasculitic component primarily involves the muscular pulmonary arteries and veins and occurs in three different patterns: (1)nonnecrotizing granulomatous inflammation causing partial luminal narrowing, (2) giant cell reaction within vessel walls, and (3) transmural chronic inflammatory cell infiltrati~n.'~. 43 As with sarcoidosis, the diagnosis of NSG is one of exclusion and requires elimination of potential infectious causes that may produce similar clinical and histologic findings.14 The most common radiographic finding in patients with NSG is solitary or more commonly multiple pulmonary nodules.lo,14, 43, 52 Nodules range from 1 to 4 cm in size and may occasionally demonstrate ~avitation.'~, 43 A miliary pattern14 and reticulonodular infiltrates with a lower lobe predominancelo,43 have also been described. Nodal enlargement is found as an associated radiographic finding
Figure 19. Necrotizing sarcoidosis composed of multiple foci of central necrosis (*) within well-circumscribed granulomas (H&E, original magnification x 400).
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in 8% to 50% of cases.14,43 Pleural abnormalities may be seen in up to one half of pat i e n t ~Limited .~~ radiographic follow-up of patients with NSG has shown that garenchyma1 abnormalities may persist unchanged, decrease, or completely resolve with or without steroid therapy.14 On CT, multiple pulmonary nodules are the most common manifestation of NSG’O, 52; nodules are typically homogeneous, well-defined, and subpleural in location.1° Niimi et a17’ described three different HRCT patterns of parenchymal involvement in three patients with biopsy-proved NSG: (1) solitary, subpleural nodule; (2) multiple irregularly marginated nodules; and (3) patchy parenchymal opacification. The latter two patterns were associated with a subpleural and peribronchovascular distrib~tion.~~ Of a total of 13 patients with NSG and CT findings described in four different series? 10,52,71 9 (69%) patients had hilar or mediastinal lymphadenopathy and six (46%)patients had pleural abnormalities consisting of thickening or effusion. LYMPHOMATOID GRANULOMATOSIS
Lymphoma t oid granulomat osis, also known as angiocentric immunoproliferative le-
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sion (AIL), polymorphic reticulosis, or angiocentric lymphoma, refers to a group of disorders characterized histologically by a necrotizing angiocentric lymphoproliferative process that 39 Onset of disprimarily affects the ease is usually in the fifth or sixth decades of life with men affected approximately twice as frequently as women?9,65 Most patients with LYG present with respiratory symptoms, such as cough, dyspnea, and chest pain, often accompanied by systemic manifestations, such as fever, malaise and weight 44, 54 Extrathoracic involvement is common and most frequently affects 74 Cutaneous the skin and nervous lesions occur in up to one third of affected patients and include subcutaneous or dermal nodules, maculopapular eruptions, and macular erythema, which may be generalized or more frequently distributed on the lower e~tremities.3~~ 39 Neurologic disease occurs in approximately 30% of patients and most commonly involves the central nervous system.39 Patients may exhibit confusion, ataxia, hemiparesis, seizures, or cranial nerve defects.39, 74 Occasionally, asymptomatic patients are detected because of an abnormal screening chest radiograph.4 Definitive diagnosis of LYG requires tissue
Figure 20. High-grade lymphomatoid granulomatosis (AIULYG) characterized by the presence of infiltration and focal destruction of muscular artery (arrows) by atypical lymphoid infiltrate resembling large cell lymphoma (H&E, original magnification x 400).
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sampling. Grossly, the lung parenchyma contains white nodules measuring up to 10 cm in diameter with variable amounts of central yellowish necrosis. A variety of histopathologic classifications have been proposed but the authors prefer classifying these lesions as AIL-LYG. Immunophenotypic and molecular studies have shown that some cases represent T-cell proliferations whereas others are T-cellrich B-cell proliferations. The characteristic histologic triad consists of a heterogeneous mononuclear cell infiltrate with a variable degree of cytologic atypia and polymorphism; angiitis with transmural infiltration of arteries
and veins by lymphoid cells; and granulomatosis, indicating the presence of focal necrosis within lymphoid nodules rather than true is granulomatous i n f l a m m a t i ~ n AIL-LYG .~~ graded into three forms based on the relative proportion of atypical lymphoid cells and inf l a m m a t i ~ nLow-grade .~~ lesions consist predominantly of lymphocytes with minimal cytologic atypia and are believed to represent a lymphoproliferative disorder.55High-grade lesions are characterized by increasing numbers of atypical lymphocytes, necrosis, and represent angiocentric lymphomas (Fig. 20).*8,55
Figure 21. Lymphomatoid granulomatosis in a 65-year-old man. A, CT at the level of the aortic arch shows multiple, bilateral, poorly defined nodules. B, CT at the lung bases shows a cavitary mass in the right middle lobe and consolidation in the left lower lobe.
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The most common radiographic finding of LYG is multiple ill-defined pulmonary nodules that range in size from 0.5 to 10 cm and predominate in the lower lung zones.23,2x, 35, 39, 74, 75 Cavitation may be seen as an associated finding in larger nodules resulting in both thin- and thick-walled cavities.2x,74, 95 Parenchymal consolidation occurs in up to 50% of affected patients and manifests as either an isolated finding or in association with nodules.2x,75* 95 A subpleural distribution of parenchymal abnormalities suggestive of pulmonary infarction has also been described.74, 95 A diffuse bilateral reticulonodular pattern is the least common of the parenchymal patterns of disease23,39, 95 and occurs in approximately 4% of cases.39Associated pleural effusion or thickening occurs in 25”/bto 50% of patients74, 75, 95; radiographic evidence of hilar or mediastinal lymphadenopathy is rare.23,39, 75, 95 On sequential radiographic studies, parenchymal nodules may wax and wane in sizeMor demonstrate asynchronous evolution with concomitant increase and decrease in sizes of different Lee et al5I have described the CT features of LYG in five patients. Both well and poorly defined nodules distributed in a perilymphatic distribution and extending along bronchovascular bundles and interlobular septa were seen in all patients. Most nodules were less than 1 cm in size with a maximum nodule diameter of 6.5 cm (Fig. 21). The number of nodules ranged from five to more than 60. In four (SOY0) patients, coarse reticular opacities also distributed along the bronchovascular bundles were found in association with small nodules. Thin-walled cysts and mediastinal lymphadenopathy were present in three (60%) patients each.
References Abehsera M, Valeyre D, Grenier P, et a1 Sarcoidosis with pulmonary fibrosis: CT patterns and correlation with pulmonary function. AJR Am J Roentgenol 174:1751, 2000 Adler BD, Padley SP, Muller NL, et a1 Chronic hypersensitivity pneumonitis: High-resolution CT and radiographic features in 16 patients. Radiology 185:91, 1992 Aronchick JM: Chronic beryllium disease. Radio1 Clin North Am 301209, 1992
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4. Aronchick JM, Rossman MD, Miller WT Chronic beryllium disease: Diagnosis, radiographic findings, and correlation with pulmonary function tests. Radiology 163:677, 1987 5. Bouman KP, Slabbynck H, Cuykens JJ, et al: Necrotizing sarcoid granulomatosis with uveitis: A variant of sarcoidosis? Acta Clin Belg 52:367, 1997 6. Brauner MW, Grenier P, Mompoint D, et al: Pulmonary sarcoidosis: Evaluation with high-resolution CT. Radiology 172:467, 1989 7. Brauner MW, Lenoir S, Grenier P, et al: Pulmonary sarcoidosis: CT assessment of lesion reversibility. Radiology 182:349, 1992 8. Buschman DL, Gamsu G, Waldron JA Jr, et al: Chronic hypersensitivity pneumonitis: Use of CT in diagnosis. AJR Am J Roentgenol 159:957, 1992 9. Buschman DL, Waldron JA Jr, King TE Jr: ChurgStrauss pulmonary vasculitis: High-resolution computed tomography scanning and pathologic findings. Am Rev Respir Dis 142:458, 1990 10. Chittock DR, Joseph MG, Paterson NA, et al: Necrotizing sarcoid granulomatosis with pleural involvement: Clinical and radiographic features. Chest 106:672, 1994 11. Choi YH, Im JG, Han B K Churg-Strauss syndrome: Radiologic and clinical findings. Chest 117:117, 2000 12. Chumbley LC, Harrison EG Jr, DeRemee RA: Allergic granulomatosis and angiitis (Churg-Strauss syndrome): Report and analysis of 30 cases. Mayo Clin Proc 52:477, 1977 13. Churg A: Pulmonary angiitis and granulomatosis revisited. Hum Pathol 14:868, 1983 14. Churg A, Carrington CB, Gupta R Necrotizing sarcoid granulomatosis. Chest 76:406, 1979 15. Churg J, Strauss L: Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Pathol 27277, 1951 16. Clee MD, Lamb D, Clark RA: Bronchocentric granulomatosis: A review and thoughts on pathogenesis. Br J Dis Chest 77227, 1983 17. Cohen Terraert JW, Huitem MG, Hene RJ, et al: Prevention of relapses in Wegener’s granulomatosis by treatment based on anti-neutrophil cytoplasmic antibody titer. Lancet 336:709, 1990 18. Colby TV, Carrington CB: Pulmonary lymphomas simulating lymphomatoid granulomatosis. Am J Surg Pathol 6:19, 1982 19. Coleman A, Colby TV Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol 12514, 1988 20. Cordier JF, Valeyre D, Guillevin L, et al: Pulmonary Wegener ’s granulomatosis. A clinical and imaging study of 77 cases. Chest 97906, 1990 21. Cotch MF, Hoffman GS, Yerg DE, et al: The epidemiology of Wegener’s granulomatosis: Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from populationbased data sources. Arthritis Rheum 39537, 1996 22. Crystal RG, Bitterman PB, Rennard SI, et al: Interstitial lung diseases of unknown cause: Disorders characterized by chronic inflammation of the lower respiratory tract. N Engl J Med 310:235, 1984 23. Dee I‘M, Arora NS, Innes DJ Jr: The pulmonary manifestations of lymphomatoid granulomatosis. Radiology 143:613,1982 24. Foo SS, Weisbrod GL, Herman ST, et al: Weaener granulomatosis presenting on CT with atypical Ybronchovasocentric distribution. J Comput Assist Tomogr 14:1004, 1990 25. Fulmer JD, Kaltreider HB: The pulmonary vasculitides. Chest 82:615, 1982
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26. George TM, Cash JM, Farver C, et a1 Mediastinal mass and hilar adenopathy: Rare thoracic manifestations of Wegener ’s granulomatosis. Arthritis Rheum 40:1992, 1997 27. Gevenois PA, Weyer RV, DeVuyst P: Beryllium disease: Assessment with CT. Radiology 93:283, 1994 28. Glickstein M, Kornstein MJ, Pietra GG, et a1 Nonlymphomatous lymphoid disorders of the lung. AJR Am J Roentgenol 147227, 1986 29. Guillevin L, Cohen P, Gayraud M, et al: ChurgStrauss syndrome: Clinical study and long-term follow-up of 96 patients. Medicine (Baltimore) 78:26, 1999 30. Gurney JW: Hypersensitivity pneumonitis. Radiol Clin North Am 30:12, 1992 31. Hansell DM, Moskovic E: High-resolution computed tomography in extrinsic allergic alveolitis. Clin Radiol 43:8, 1991 32. Hansell DM, Wells AU, Padley SP, et al: Hypersensitivity pneumonitis: Correlation of individual CT patterns with functional abnormalities. Radiology 199:123, 1996 33. Hapke EJ, Seal RM, Thomas GO, et al: Farmer’s lung: A clinical, radiographic, functional, and serological correlation of a&ie and chronic stages. Thorax 23:451, 1968 34. Harris. KM, McConnochie K, Adams H The computed tomographic appearances in chronic berylliosis. Clin Radiol 4726, 1993 35. Hicken P, Dobie JC, Frew E: The radiology of lymphomatoid granulomatosis in the lung. Clin Radiol 30:661, 1979 36. Hoffman GS, Kerr GS, Leavitt RY, et al: Wegener granulomatosis: An analysis of 158 patients [see comments]. Ann Intern Med 116:488, 1992 37. Jaffe ES, Wilson WH: Lymphomatoid granulomatosis: Pathogenesis, pathology and clinical implications. Cancer Surv 30933, 1997 38. Kaltreider HB: Hypersensitivity pneumonitis [see comments]. West J Med 159:570, 1993 39. Katzenstein AL, Carrington CB, Liebow AA: Lymphomatoid granulomatosis: A clinicopathologic study of 152 cases. Cancer 43:360, 1979 40. Katzenstein AL, Liebow AA, Friedman PJ: Bronchocentric granulomatosis, mucoid impaction, and hypersensitivity reactions to fungi. Am Rev Respir Dis 111:497, 1975 41. Kitaichi M: Pathology of pulmonary sarcoidosis. Clin Dermatol 4:108, 1986 42. Koss MN, Antonovvch T, Hochholzer L: Allergic granulomatosis (Chirg-Strauss syndrome): PulGonary and renal morphologic findings. Am J Surg Pathol 5:21, 1981 43. Koss MN, Hochholzer L, Feigin DS, et al: Necrotizing sarcoid-like granulomatosis: Clinical, pathologic, and immunopathologic findings. Hum Pathol11:510,1980 44. Koss MN, Hochholzer L, Langloss JM, et al: Lymphomatoid granulomatosis: A clinicopathologic study of 42 patients. Pathology 18:283, 1986 45. Koss MN, Robinson RG, Hochholzer L: Bronchocentric granulomatosis. Hum Pathol 12:632, 1981 46. Kuhlman JE, Hruban RH, Fishman EK: Wegener granulomatosis: CT features of parenchymal lung disease. J Comput Assist Tomogr 15:948, 1991 47. Langford CA, Hoffman GS: Rare diseases 3: Wegener’s granulomatosis. Thorax 54:629, 1999 48. Lanham JG, Elkon KB, Pusey CD, et al: Systemic vasculitis with asthma and eosinophilia: A clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore) 63:65, 1984
49. Leavitt RY, Fauci AS: Pulmonary vasculitis. Am Rev Respir Dis 134:149, 1986 50. Leavitt RY, Fauci AS, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 33:1101, 1990 51. Lee JS, Tuder R, Lynch DA: Lymphomatoid granulomatosis: Radiologic features and pathologic correlations. AJR Am J Roentgenol 175:1335,2000 52. Le Gall F, Loeuillet L, Delaval P, et al: Necrotizing sarcoid granulomatosis with and without extrapulmonary involvement. Pathol Res Pract 192:306, 1996 53. Liebow A A The J. Bums Amberson lecture: Pulmonary angiitis and granulomatosis. Am Rev Respir Dis 108:1, 1973 54. Liebow AA, Carrington CR, Friedman PJ: Lymphomatoid granulomatosis. Hum Pathol 3:457, 1972 55. Lipford EH Jr, Margolick JB, Longo DL, et al: Angiocentric immunoproliferative lesions: A clinicopathologic spectrum of post-thymic T-cell proliferations. Blood 72:1674, 1988 56. Lynch DA, Hay T, Newell JD Jr, et al: Pediatric diffuse lung disease: Diagnosis and classification using high-resolution CT. AJR Am J Roentgenol 173:713, 1999 57. Lynch DA, Rose CS, Way D, et al: Hypersensitivity pneumonitis: Sensitivity of high-resolution CT in a population-based study. AJR Am J Roentgenol 159:469, 1992 58. Masi AT, Hunder GG, Lie JT, et al: The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 33:1094, 1990 59. Maskell GF, Lockwood CM, Flower C D Computed tomography of the lung in Wegener’s granulomatosis. Clin Radiol 48:377, 1993 60. Matar LD, McAdams HP, Spom TA Hypersensitivity pneumonitis. AJR Am J Roentgenol 174:1061, 2000 61 Meyer KC: Beryllium and lung disease. Chest 106:942, 1994 62. Muller NL, Kullnig P, Miller RR. The CT findings of pulmonary sarcoidosis: Analysis of 25 patients. AJR Am J Roentgenol 1521179, 1989 63. Muller NL, Mawson JB, Mathieson JR, et al: Sarcoidosis: Correlation of extent of disease at CT with clinical, functional, and radiographic findings. Radiology 171:613. 1989 64. Murdoch 1. Muller NL: Pulmonarv sarcoidosis: Changes o n follow-up CT examinatihn. AJR Am J Roentgenol 159:473, 1992 65. Myers JL: Lymphomatoid granulomatosis: Past, present, . . . future? [comment]. Mayo Clin Proc 65:274, 1990 66. Myers JL, Katzenstein AL: Granulomatous infection mimicking bronchocentric granulomatosis. Am J Surg Pathol 10:317, 1986 67. Myers JL, Katzenstein AL: Wegener’s granulomatosis presenting with massive pulmonary hemorrhage and capillaritis. Am J Surg Pathol 11:895, 1987 68. Newman L S Immunology, genetics, and epidemiology of beryllium disease. Chest 109:40S, 1996 69. Newman LS: Significance of the blood beryllium lymphocyte proliferation test. Environ Health Perspect 104 (suppl5):953, 1996 70. Newman LS, Buschman DL, Newell JD Jr, et al: Beryllium disease: Assessment with CT [see comments]. Radiology 1902335, 1994 71. Niimi H, Hartman TE, Muller N L Necrotizing sarcoid granulomatosis: Computed tomography and
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pathologic findings. J Comput Assist Tomogr 19:920, 1995 Nishimura K, Itoh H, Kitaichi M, et al: Pulmonary sarcoidosis: Correlation of CT and histopathologic findings [published erratum appears in Radiology 190:907, 19941. Radiology 189:105, 1993 Papiris SA, Manoussakis MN, Drosos AA, et al: Imaging of thoracic Wegener's granulomatosis: The computed tomographic appearance. Am J Med 93:529, 1992 Prenovault JM, Weisbrod GL, Herman SJ: Lymphomatoid granulomatosis: A review of 12 cases. Can Assoc Radiol J 39:263, 1988 Rabinowitz JG, Cohen BA, Mendelson DS: Lymphomatoid granulomatosis. JAMA 254:3458, 1985 Remy-Jardin M, Giraud F, Remy J, et al: Pulmonary sarcoidosis: Role of CT in the evaluation of disease activity and functional impairment and in prognosis assessment. Radiology 191:675, 1994 Remy-Jardin M, Remy J, Wallaert B, et al: Subacute and chronic bird breeder hypersensitivity pneumonitis: Sequential evaluation with CT and correlation with lung function tests and bronchoalveolar lavage. Radiology 189:111, 1993 Robinson RG, Wehunt WD, Tsou E, et al: Bronchocentric granulomatosis: Roentgenographic manifestations. Am Rev Respir Dis 125:751, 1982 Rossman M D Chronic beryllium disease: Diagnosis and management. Environ Health Perspect 104 (suppl 5):945, 1996 Rossman MD, Kern JA, Elias JA, et al: Proliferative . response of bronchoalveolar lymphocytes to beryllium. A test for chronic beryllium disease [published erratum appears in Ann Intern Med 110:672, 19891. Ann Intern Med 108:687, 1988 Screaton NJ, Sivasothy P, Flower CD, et al: Tracheal involvement in Wegener 's granulomatosis: Evaluation using spiral CT. Clin Radiol 53:809, 1998 Sharma OP: Sarcoidosis: Clinical, laboratory, and immunologic aspects. Semin Roentgenol 20340, 1985 Sharma OP, Fujimura N: Hypersensitivity pneumonitis: A noninfectious granulomatosis. Semin Respir Infect 10:96, 1995
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84. Sider L, Horton ES Jr: Hilar and mediastinal adenopathy in sarcoidosis as detected by computed tomography. J Thorac Imaging 5:77, 1990 85. Siltzbach LE, James DG, Neville E, et al: Course and prognosis of sarcoidosis around the world. Am J Med 57:847, 1974 86. Silver SF, Muller NL, Miller RR, et al: Hypersensitivity pneumonitis: Evaluation with CT. Radiology 173:441, 1989 87. Small JH, Flower CD, Trail1 ZC, et al: Air-trapping in extrinsic allergic alveolitis on computed tomography Clin Radiol 51:684, 1996 88. Spann RW, Rosenow EC, Miller WE: Unilateral hilar or paratracheal adenopathy in sarcoidosis: A study of 38 cases. Thorax 26:296, 1971 89. Spiteri MA, Gledhill A, Campbell D, et al: Necrotizing sarcoid granulomatosis. Br J Dis Chest 81:70,1987 90. Sullivan EJ, Hoffman GS: Pulmonary vasculitis. Clin Chest Med 19:759, 1998 91. Tazelaar HD, Baird AM, Mill M, et al: Bronchocentric mycosis occurring in transplant recipients [see comments]. Chest 96:92, 1989 92. Thomas PD, Hunninghake GW: Current concepts of the pathogenesis of sarcoidosis. Am Rev Respir Dis 135:747, 1987 93. Travis WD, Hoffman GS, Leavitt RY, et al: Surgical pathology of the lung in Wegener 's granulomatosis: Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol 15:315, 1991 94. Ward S, Heyneman LE, Flint JD, et al: Bronchocentric granulomatosis: Computed tomographic findings in five patients. Clin Radiol 55:296, 2000 95. Wechsler RJ, Steiner RM, Israel HL, et al: Chest radiograph in lymphomatoid granulomatosis: Comparison with Wegener granulomatosis. AJR Am J Roentgenol 142:79, 1984 96. Weir IH, Muller NL, Chiles C, et al: Wegener's granulomatosis: Findings from computed tomography of the chest in 10 patients. Can Assoc Radiol J 43:31, 1992 97. Worthy SA, Muller NL, Hansel1 DM, et al: ChurgStrauss syndrome: The spectrum of pulmonary CT findings in 17 patients. AJR Am J Roentgenol 170:297, 1998
Address reprint requests to Ann N. Leung, MD Department of Radiology, S072A Stanford University Medical Center Stanford, CA 94305-5105 e-mail: aleung8leland.stanford.edu
0033-8389/01 $15.00
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CT OF NONINFECTIOUS GRANULOMATOUS LUNG DISEASE Steven E. Zinck, MD, Erich Schwartz, MD, Gerald J. Berry, MD, and Ann N. Leung, MD
The noninfectious granulomatous diseases of the lung can be divided into two groups based on the presence or absence of associated vasculitis on pathologic examination. Sarcoidosis and hypersensitivity pneumonitis (HP)are two relatively common infiltrative lung disorders belonging to the group without significant vascular inflammation. Berylliosis, the third entity of this group, is a pneumoconiosis that results from an immune-mediated hypersensitivity response to inhalation of beryllium metal alloys and ~ a l t s . ~ Pulmona y angiitis and gran~lomatosis~~ is the term traditionally used to describe the group of noninfectious granulomatous diseases that is associated with vasculitis. Five entities are recognized: (1) Wegener’s granulomatosis (WG), (2) Churg-Strauss syndrome (CSS), (3) bronchocentric granulomatosis (BCG), (4) necrotizing sarcoidosis (NSG), and (5) lymphomatoid granulomatosis (LYG). Of this group, only WG and CSS are true systemic vas~ulitides.~~, 49 SARCOIDOSIS
Sarcoidosis is a systemic disease of unknown cause that is characterized by the pres-
ence of noncaseating g r a n ~ l o m a sThoracic .~~ involvement occurs in up to 90% of affected individuals.22The disease is relatively common with an estimated prevalence of 3 to 50 per 100,00022and occurs worldwide, more frequently in temperate than tropical climates. Because approximately 50% of cases are asymptomatic, the true incidence of sarcoidosis likely is underestimated. There is no specific gender predilections5; in the United States, the disease is eight times more common in blacks than whites.92Age at presentation ranges from adolescence to the seventh decade with most patients under 40 years of age at time of initial presentati~n.~~ Symptoms of pulmonary involvement by sarcoidosis include dry cough, progressive dyspnea, and exertional intolerancez2,92; erythema nodosum and constitutional symptoms, such as fever, weight loss, and fatigue, may be associated.22, 92 The criteria for establishing the diagnosis of sarcoidosis are well established and include the following: (1) compatible clinical or radiologic findings or both; (2) histologic evidence of noncaseating granulomas; and ( 3 ) negative bacterial and fungal studies of tissue biopsy, sputum, or other body fluids.s2The characteristic pathologic lesion in sarcoidosis is the non-necrotiz-
From the Departments of Radiology (SEZ, ANL) and Pathology (ES, GJB), Stanford University Medical Center, Stanford. California
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Figure 1. Sharply delineated noncaseating granuloma surrounded by collagenous stroma containing scattered chronic inflammatory cells (hematoxylin-eosin [H & El, original magnification x 400).
ing granuloma composed of tightly clustered aggregates of histiocytes and occasional multinucleated giant cells and sparse numbers of lymphocytes and other inflammatory cells (Fig. l).41 The granulomas are surrounded by hyalinized connective tissue containing a thin collar of chronic inflammatory cells. Intersti-
tial inflammation is generally absent. Granulomatous vasculitis may be seen and is characterized by mural intrusion by granulomas without fibrinoid necrosis of vessel walls. Most pulmonary granulomas are located in the interstitium along lymphatic pathways (bronchovascular bundles, interlobular septa,
Figure 2. Lymphatic distribution of sarcoidosis along bronchovascular bundles (asferisk), interlobular septa (arrow), and pleural tissues (arrowheads) (H&E, original magnification x 30).
CT OF NONINFECTIOUS GRANULOMATOUS LUNG DISEASE
and subpleural connective tissues) (Fig. 2):l~ 72 Because a number of different conditions including mycobacterial and fungal infections may have similar histologic featnres, ancillary procedures, such as bacteriologic culture and histochemical staining of tissue samples, are necessary to exclude these entities and confidently establish the diagnosis of sarcoidosis. The characteristic radiographic appearance of thoracic sarcoidosis consists of symmetric, bilateral hilar, and right paratracheal lymphadenopathy, with or without concomitant parenchymal abnormalities. Symmetry of nodal enlargement is an important feature differentiating sarcoidosis from other diseases, such as lymphoma, metastatic disease, or granulomatous infections, because unilateral lymphadenopathy occurs only in 5% of cases of sarcoidosis.88On CT, the most commonly involved nodal stations are right paratracheal, hilar, aortopulmonary window, subcarinal, and anterior mediastinum in decreasing order of frequency occurring in loo%, 92%, 88%, 64%, and 48% of patients, respectively, in one Nodal calcification (Fig. 3) is a late manifestation and when present, is usually associated with advanced disease. On high-resolution CT (HRCT), irregularly marginated nodules ranging from 1 to 10 mm in size are the predominant parenchymal ab-
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normality of sarcoidosis.6,62 The nodules typically have a perilymphatic distribution and are found along bronchovascular bundles, interlobular septa, and pleural surfaces (Fig. 4).62 Possible associated findings include ground-glass opacities, conglomerate masses, pleural thickening, architectural distortion, cysts, nonseptal lines, and traction bronchiectasis (Fig. 5)6,7, 64; the latter four features usually denote the presence of irreversible 64 An upper and middle lung zonal fibr~sis.~, predominance of parenchymal abnormalities is a distinguishing feature of sarcoidosis and is present in approximately two thirds of patients.6 Patients with sarcoidosis and abnormal lung function usually demonstrate a restrictive pattern with reduced lung volumes. Statistically significant but low correlations have been found between extent of parenchymal abnormalities identified on CT and measures of clinical and functional impairment, such as diffusing capacity (r = - 0.49 to - 0.62); vital capacity (r = -0.40 to -0.49); and total lung Both type and districapacity (r = - 0.48).63,76 bution of parenchymal abnormalities influence the degree of functional impairment; patients with predominantly nodular opacities have less severe dyspnea and higher volumes than those with predominantly irregular linear ~ p a c i t i e s .In ~ ~patients with fibrotic dis-
Figure 3. Sarcoidosis in a 48-year-old woman. High-resolution CT (HRCT) shows calcified nodes in the lower right paratracheal and bilateral hilar stations.
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Figure 4. Sarcoidosis in a 37-year-old woman. HRCT shows multiple, bilateral small irregularly marginated nodules distributed along the bronchovascular bundles, interlobular septae, and pleural surfaces.
Figure 5. Sarcoidosis in a 45-year-old woman. HRCT through the upper lobes shows confluent disease extending along bronchovascular bundles associated with scattered nodules. The presence of mild traction bronchiectasis within the areas of confluence suggests early fibrosis.
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ease, honeycombing in a peripheral distribution is more commonly associated with restriction and reduced diffusing capacity than fibrotic patterns consisting primarily of central bronchial distortion or diffuse linear opacities. HYPERSENSITIVITY PNEUMONITIS Hypersensitivity pneumonitis, also known as extrinsic allergic ulveolitis, is an allergic inflammatory granulomatous reaction of the lungs caused by the inhalation of specific antigens contained in a number of organic dusts. Numerous inciting agents have been identified, but the more common include thermophilic actinomycetes, avian proteins, and fungi.3s The clinical, radiologic, and pathologic features of HP are classically divided into three stages: (1)acute, (2) subacute, and (3) chronic.*9,33, 38 These stages are not necessarily sequential, however, and features of each may coexist in the same patient.30,6o The acute phase is caused by overwhelming exposure to an inciting antigen. Patients present within 4 to 6 hours of exposure with symptoms of fever, chills, cough, dyspnea, chest tightness, and myalgia30,38, 83; symptoms usually subside over a few days. In subacute disease, intermittent exposure results in recurrent episodes of similar but less severe symptoms to those experienced in the acute phase that can continue for weeks to months.30,6o With prolonged exposure, a chronic stage with pulmonary fibrosis may develop. Affected patients often present with an insidious form of the disease with complaints of slowly increasing dyspnea, cough, weight loss, and fatigue.30,60, 83 Definitive diagnosis of HP requires demonstration of a direct temporal relationship between exposure to antigen and onset of symptoms, with resolution of symptoms when the inciting agent is removed or avoided.38,83 Clinical and radiologic features are often sufficient to suggest the diagnosis of HP, particularly when they develop in the context of a recognized sensitizing exposure. Serologic testing is often performed because demonstration of the presence of serum precipitins to a specific antigen serves as a marker of
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exposure and can further strengthen diagnostic confidence. In cases in which the clinical diagnosis remains uncertain, transbronchial or thoracoscopic biopsy may be necessary.38* 83 The histologic features of HI' vary according to the stage of disease with most biopsies performed in the subacute stage. The histologic triad that characterizes the subacute stage of HP consists of (1)a temporally uniform cellular peribronchiolitis with chronic inflammatory infiltrates around respiratory bronchioles (Fig. 6), (2) nonspecific cellular interstitial infiltrates of chronic inflammatory cells, and (3) scattered small loose non-necrotizing gran~lornas.'~ In contrast to sarcoidosis, the granulomas in HP are more poorly formed and are centered on the peribronchiolar interstitium rather than lymphatic spaces (Fig. 7).30,83 In the chronic stage, the granulomatous alveolitis is replaced by interstitial fibrosis and honeyc~mbing.~~ The CT findings of the acute stage of HP have been described in only two cases.86Diffuse, bilateral consolidation was the predominant finding with poorly marginated nodules measuring less than 3 mm associated in one patient.s6The characteristic HRCT findings of the subacute stage consist of diffuse, bilateral ground-glass opacities often seen in combination with poorly defined centrilobular nodules measuring between 1 and 5 mm in size (Fig. 8).31,57, n,86 The distribution of these parenchymal abnormalities may be n or have a middle to lower zonal predomin a n ~ e .86~ Focal ~, areas of decreased attenuation are a common associated finding in the subacute stage of diseases2,"; these sharply marginated areas are believed to represent air-trapping in obstructed secondary pulmonary lobules and may be accentuated by expiratory scanning.32 The chronic stage of HP on HRCT is characterized by findings of fibrosis with irregular linear opacities, architectural distortion, honeycombing, and traction bronchiectasis (Fig. 9).2,86 Fibrotic changes have been variably reported to be distributed evenly or to predominate in the middle and lower lung zones.2, Associated findings of subacute disease, such as ground-glass opacities and centrilobular nodules, are present in most patients2,8,86 and may aid in establishing the correct diagnosis.
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Figure 6. Scanning magnification of hypersensitivity pneumonitis showing patchy, chronic interstitial pneurnonitis in a peribronchiolar distribution (arrow). Scattered granulomas are present (arrowheads) (H&E, original magnification x 60).
Figure 7. Typical appearance of poorly formed granulomas of hypersensitivity pneumonitis composed of loosely arranged histiocytes admixed with mononuclear cells (H&E, original magnification x 400).
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Figure 8. Subacute hypersensitivity pneumonitis in a 55-year-oldbird owner. HRCT shows innumerable poorly defined centrilobular nodules in a background of diffuse ground-glass opacity. Associated lobular areas of hyperlucency likely represent air-trapping.
Figure 9. Chronic hypersensitivity pneumonitis in a 71-year-old pigeon breeder. HRCT at the level of the bronchus intermedius shows diffuse nonseptal reticular opacities associated with mild architectural distortion and patchy areas of ground-glass attenuation.
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Lymphadenopathy and pleural disease are rare findings in any stage of HP.30,31 BERYLLIOSIS
opacities that are distributed diffusely in the 34, 7o Less lungs without zonal pred~minance.~, common parenchymal manifestations include linear scars; bulla, fibrosis predominantly involving the upper lobes, and conglomerate 34 masses similar to those seen in silic~sis.~, Hilar lymphadenopathy is present in up to one third of affected patients.70Pleural thickening may occur in advanced cases and can be associated with a reduction in vital capacity." Newman et a170 reviewed the HRCT findings of 28 patients with biopsy-proven CBD. Parenchymal nodules and interlobular septa1 thickening were the most common CT features found in 16 (57%) and 14 (50%) patients, respe~tively.~~ Nodules were typically welldefined and distributed along bronchovascular bundles and interlobular septa similar to the distribution of nodules associated with sarcoidosis (Fig. 10). Other CT findings of CBD include bronchial wall thickening, emphysema, ground-glass opacities, conglomerate masses, fibrosis, and pleural thickening.34,70 Hilar or mediastinal lymphadenopathy occurs in up to 40% of cases and similar to conglomerate masses, may contain 34 calcificati~n.~~,
Beryllium is a light weight metal with excellent thermal and electrical conductivity. Initially used in the manufacturing of fluorescent lamps, beryllium is now widely used in the ceramics, nuclear weapons, computer, and aerospace industries, and is a common component of many household appliance^.^, 79 Berylliosis is caused by exposure to aerosols, dusts, or fumes of beryllium metal or salts3 and can occur in acute and chronic forms. Acute disease follows an overwhelming airborne exposure, which causes a chemical pneumonitis and acute pulmonary edema; severe cases may be fatal. The histopathologic findings in this setting are primarily diffuse alveolar damage. Because of laws passed in 1950 regulating acceptable exposure levels? acute berylliosis now rarely occurs. Chronic beryllium disease (CBD) is a systemic granulomatous disease with histologic features identical to sarcoidosis and is thought to be caused by a specific, cell-mediated hypersensitivity response to long-term exposure to be68, 79 Although CBD may affect multirylli~m.~, WEGENER'S GRANULOMATOSIS ple organs, the lung usually is most severely in~olved.~,Exertional dyspnea is the most Wegener's granulomatosis is a systemic common presenting complaint, followed by disease of unknown cause characterized by cough and chest pain; less common sympthe triad of necrotizing granulomatous intoms include weakness, weight loss, fevers, flammation of the upper and lower respira61 and arthralgia~.~, tory tracts, glomerulonephritis, and disseminThe diagnosis of CBD may be suggested by a history of significant exposure to beryllium, ated small vessel vasculitis.13,25 In the United consistent radiographic findings, and abnorStates, the prevalence of WG is estimated to be 3 per 100,000 with a male to female ratio mal pulmonary function tests.34Confident diof about l:l.47Most affected patients are white agnosis, however, requires demonstration of granulomas in tissue, immunologic evidence and the mean age at diagnosis is 40 to 55 that granuloma formation is caused by berylyears.21,47 The onset and course of WG vary delium hypersensitivity, and a proliferative repending on the specific organ or organ syssponse of lymphocytes obtained by brontems involved. Patients may initially present choalveolar lavage to beryllium.79This latter with systemic symptoms, such as fever, test, known as the bronchoalveolar lymphocyte transformation test, is highly accuratesoand can weight loss, malaise, and myalgias.20,50 Over diagnose CBD before onset of clinical sympthe course of the disease, however, most detoms or pulmonary function abn~rmalities.~~velop localizing symptoms, such as sinusitis, otitis media, hearing loss, epistaxis, cough, The most common radiographic finding in dyspnea, and chest pain indicating the presCBD consists of small round and reticular
CT OF NONINFECTIOUS GRANULOMATOUS LUNG DISEASE
Figure 10. A 60-year-old man with berylliosis. A, HRCT through the right upper lung shows numerous micronodules with a preferential distribution along bronchi, vessels, interlobular septa, and pleura. There is a large conglomerate mass but no architectural distortion to suggest fibrosis. 13,CT at the level of carina shows multiple calcified and partially calcified nodes. The pattern is indistinguishable from sarcoidosis and was misdiagnosed as sarcoid for 10 years because the occupational history was not obtained.
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ence of upper airway or lung Renal disease is often asymptomatic, but may be associated with microscopic hematuria and proteinuria and can eventually result in renal failure.”, 36 Ocular involvement eventually develops in approximately 50% of patients and can cause proptosis, diplopia, and 36 Macules, papules, purpura, conjunctivitis.20, nodules, ulcers, vesicles, and rash are seen with cutaneous involvement.20,36 Neurologic disease occurs uncommonly, manifesting as peripheral or central neuropathy.20,36 Although previously considered a fatal disease, partial or complete remission of WG can be achieved in up to 90% of patients with combined cyclophosphamide and corticosteroid therapy.36,50 Accurate diagnosis of WG is critical because other vasculitides are treated with corticosteroids alone.50 The diagnostic criteria established by the American College of Rheumatology consist of (1) abnormal urinary sediment; (2) abnormal chest radiographic findings; (3) oral ulcers or nasal discharge; and (4)granulomatous inflammation on tissue biopsy (or hemoptysis if biopsy is una~ailable).~~ The presence of at least two of the four criteria is associated with a diagnostic sensitivity of 87% and specificity of 94%?O Measurement of serum antineutrophil cyto25, 36
plasmic antibody (ANCA) titers has also been shown to be helpful in the diagnosis and monitoring of disease activity.17,36 In particular, the c-AP\TCA form is elevated in approximately 90% of patients with active disease, and rising c-ANCA titers indicate disease relapse.17,36 The histologic findings of pulmonary WG are parenchymal granulomatous inflammation with a mixed cellular infiltrate associated with geographic basophilic necrosis and vasculitis of small and medium-sized arteries, veins, and capillarie~.~~ The presence of necrotizing vasculitis is required for pathologic diagnosis. Patterns include (1) granulomatous vasculitis (Fig. ll),(2) neutrophilic infiltration of vessel walls with cellular debris, and (3) acute and chronic inflammation with fibrinoid necrosis. In cases characterized by the presence of hemorrhage, histologic findings consist of a capillaritis with preservation of the normal lung architecture; filling of alveolar spaces with red blood cells is associated with hemosiderin-laden macrophages and foci of organizing fibrin exudate.67 On CT, the most common finding of pulmonary WG is multiple irregularly marginated nodules, which can range from 2 to 20 in number and from 2 to 90 mm in size.46,73, 96
Figure 11. Vasculitis in Wegener’s granulomatosis. The medial layer of this muscular pulmonary artery is incompletely preserved (arrows). Transmural infiltration by acute and chronic inflammatory cells and granulomatous elements result in necrosis of the vessel with marked luminal narrowing (H&E, original magnification x 400).
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Figure 12. Wegener’s granulomatosis in a 22-year-old man. HRCT shows bilateral nodules, some of which are peribronchovascularin distribution (small arrows). Air bronchograms (large arrow) and surrounding ground-glass attenuation (open arrows) are associated findings.
In the series of Weir et a1,96all nodules greater than 2 cm demonstrated cavitation; cavity walls may be thick and irregular or thin and 96 Nodules are typically bilateral and random in distrib~tion~~, 96 but may also occur in a predominantly subpleural or peribronchovascular location (Fig. l2).” Within nodules, an air bronchogram may occasionally be identified.46
Areas of opacification ranging from ground-glass attenuation to frank consolidation are the second most common CT pattern of pulmonary WG and often represent findings of pulmonary hemorrhage (Fig. 13).73,96 These areas of increased attenuation can occur as an isolated finding or in conjunction with pulmonary nodules; their distribution may be focal, patchy, or diffuse and occasion-
Figure 13. Wegener’s granulomatosis in a 55-year-old woman. CT shows diffuse, bilateral consolidation with air bronchograms secondary to extensive pulmonary hemorrhage.
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ally localizes to the ~ u b p l e u r a and l ~ ~ peribronchovascularZ4~ 73 regions. Tracheobronchial involvement by WG manifests on CT as mural thickening and narrowing of involved airways (Fig. 14). Screaton and colleagues81evaluated the CT findings in 10 patients with tracheal involvement and found that 90% of inflammatory lesions were located in the subglottic region; circumferential tracheal involvement and narrowing occurred in all patients with a length of involvement ranging from 5 to 45 mm. Associated findings in this study included mural thickening, mucosal irregularity and ulceration, and deformity of the cricoid or tracheal cartilage.81 Hilar or mediastinal lymphadenopathy in WG is believed to be rarez6but has been observed in up to 7% of patients evaluated with CT.73Pleural abnormalities, such as unilateral or bilateral effusions, thickening, and spontaneous hydropneumothorax, occur in a small percentage of patients.59,73,96
CHURG-STRAUSS SYNDROME Churg-Strauss syndrome, also known as allergic angiitis and granulomatosis, is an idiopathic multisystem disorder characterized
histologically by necrotizing vasculitis, extravascular granuloma formation, and tissue infiltration by eosinophils, which occurs almost exclusively-in patients with asthma or other allergic disease^.'^ CSS is the least common of the angiocentric granulomatoses with an estimated annual incidence of 3 per million.90 No gender predilection exists and mean age of onset ranges from 38 to 48 year^.^^,^^ The clinical course of CSS follows three distinct phases: (1) a prodromal phase of allergic rhinitis and asthma that may persist for years; (2) a second phase of peripheral and tissue eosinophilia resembling Loeffler 's syndrome, chronic eosinophilic pneumonia, or eosinophilic gastroenteritis that may recur for years; and (3) a third phase of severe, lifethreatening v a s c ~ l i t i sOnset . ~ ~ of the vasculitic phase may coincide with either a dramatic exacerbation or remission of asthma.48Systemic symptoms, such as fever, malaise, and profound weight loss, often occur in the early vasculitic phase.29,48 Although, any organ may be involved, the lungs, skin, gastrointestinal tract, and nervous system are the most frequently affected. Common presenting signs and symptoms include cough, dyspnea, palpable purpura, skin nodules, rash, abdominal pain, and mononeuritis multiplex.29, 48 The diagnostic criteria established by the
Figure 14. Wegener's granulomatosis in an 18-year-old woman. Volumerendered coronal CT image of the trachea and central airways shows severe narrowing of the left main stem bronchus (small arrows) and bronchus intermedius (large arrow).
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Figure 15. Churg-Strauss syndrome characterized by necrotizing vasculitis of pulmonary artery (arrows) by eosinophilic infiltrates with filling and expansion of adjacent alveolar airspaces and interstitum (H&E, original magnification x 400).
tive of chronic eosinophilic pneumonia may American College of Rheumatology consist of be seen.48Less common parenchymal findings (1) asthma, (2) eosinophilia of greater than include a diffuse interstitial pattern and bilat10% of the white blood cell differential count, eral noncavitary pulmonary nodules.12,48 (3) neuropathy, (4) migratory or transient pulmonary opacities, (5) paranasal sinus abnorPleural effusions may occur in up to 30% of mality, and (6) extravascular eosinophils on cases and lymphadenopathy is uncomtissue biopsy? The presence of at least four of m ~ n .48~ ~ , the six criteria is associated with a diagnostic Parenchymal opacification ranging from sensitivity of 85% and specificity of 99.7Y0.~~ ground-glass attenuation to consolidation is Histologically, CSS is characterized by a necthe most common HRCT finding found in rotizing vasculitis predominantly involving 73% (19 of 26) of patients with CSS evaluated medium- and small-sized arteries and veins in two series (Fig. 16).11,97 Distribution of the with mural infiltration by granulomatous inparenchymal opacities may be predominantly flammation, giant cells, or histiocytes and eosubpleural or patchy with no zonal sinophils (Fig. 15). Scattered well-formed predominance.", 97 Multiple pulmonary nodgranulomas with central foci of necrotic eoules ranging from less than 5 mm to 35 mm sinophils are often located adjacent to vessels in size are the second most common HRCT with patchy intra-alveolar and interstitial colfinding.", 97 Small centrilobular nodules can lections of eosinophils and macrophages reoccasionally be seen in areas of parenchymal sembling chronic eosinophilic p n e ~ m o n i a . ~ ~opacification.", 97 Larger nodules may contain The changes of chronic asthma can be seen in air bronchograms or demonstrate ~ a v i t a t i o n . ~ ~ bronchioles. An increased caliber of peripheral pulmonary Chest radiographs demonstrate abnormaliarteries relative to the accompanying bronchi ties in 27% to 100% of patients with CSS.lZ, has been described9," as an associated finding 42 Parenchymal abnormalities typically conand may correlate with eosinophilic infiltrasist of bilateral, migratory alveolar opacities tion of vessel walls9 Hilar or mediastinal without lobar or zonal predominance12,29, 42, 48; lymphadenopathy is identified in up to 40% occasionally, a peripheral distribution suggesof patients" and pleural effusions occur in the 297
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Figure 16. Churg-Strauss syndrome in a 46-year-old woman. HRCT shows bilateral patchy areas of ground-glass opacity.
minority of patients.", 97 Additional described findings, such as bronchial wall thickening and hyperinflation, likely reflect patients' underlying asthma.", 97 Occasionally, patients with documented CSS may have normal HRCT studies.97 BRONCHOCENTRIC GRANULOMATOSIS Bronchocentric granulomatosis is a rare disease of the lungs characterized by a necrotizing granulomatous reaction centered on the airways.53Rather than a specific disease, BCG represents a pattern of inflammatory response to a sustained and intense insult to the airways.16Affected patients can be divided into those with and those without concomitant asthma.40 Asthmatic patients with BCG typically present at a young age (childhood to early adulthood) and invariably have underlying allergic bronchopulmonary aspergillo~is.~~, 45 Nonasthmatic patients are usually older (mean age, 50 years) at time of presentation and may have associated conditions, such as granulomatous infections, rheumatoid arthritis, or prior organ transplantation.40,66,91 Asthmatic patients with BCG may present with symptoms of an asthma exacerbation or nonspecific complaints, such as fever, cough,
chest pain, hemoptysis, anorexia, and malaise.4O Nonasthmatic patients with BCG have a variable presentation; whereas some may have minimal symptoms or be completely asymptomatic, others present with fever, cough, wheezing, and malaise.40, 45 On gross pathologic inspection, the lesions of BCG consist of airways filled with mucoid or yellow-white cheesy material.40Histologically, necrotizing granulomatous inflammation replacing the mucosa and walls of bronchioles is present (Fig. 17) and is often associated with an interstitial infiltrate of eosinophils, particularly if the patient is asthmaScattered fungal hyphae can be found within luminal exudates. Unlike the other entities classified under pulmonary angiitis and granulomatosis, vasculitis is a minor component of BCG. Vascular involvement is usually an incidental finding and represents contiguous spread of inflammation from adjacent airways.4o Three radiographic patterns of disease have been described in BCG: (1)nodules, (2) alveolar opacities, and (3) reticulonodular opacities.78Nodules may range in size from 2 to 6 cm and are typically solitary but may be multiple.40,78 Nodule margins may be wellcircumscribed or ill-defined and associated cavitation is uncommon.78Like nodules, the alveolar opacities predominate in the upper lobes and are usually ~ n i l a t e r a l .78~ ~ , Diffuse
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Figure 17. Bronchocentric granulomatosis showing replacement of bronchiolar mucosa (white arrowheads) by necrotizing granulomatous inflammation (black arrows). ( M E , original magnification x 300).
reticulonodular opacities are the least common pattern, and on biopsy have been shown to represent diffuse involvement of smaller bronchi ole^.^^ Lymphadenopathy and pleural abnormalities are infrequent associated findings.78 Ward et a194described the CT findings in five patients with biopsy-proved BCG. Focal mass (Fig. 18) and lobar consolidation associ-
ated with volume loss were the most common findings occurring in three (60%) and two (40%) patients, respectively. Parenchymal abnormalities involved the upper lobes in four (80%) patients, and the superior segment of a lower lobe in one (20%) patient. Cavitation and central necrosis were identified in one patient with bilateral 2-cm nodules. Multilobar mucoid impaction was an associated
Figure 18. Bronchocentric granulomatosis in a 72-year-old nonasthmatic woman. CT shows a solitary 5-cm irregularly marginated mass in left upper lobe abutting the mediastinum.
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finding in one patient with the lobar consolidative pattern. Mediastinal nodal enlargement occurred in two (40%) patients. Geographic hyperlucency associated with bronchiectasis and septa1 thickening has been reported as the CT findings of BCG in one pediatric case.56
NECROTIZING SARCOID GRANULOMATOSIS
Necrotizing sarcoid granulomatosis is a rare disease of unknown cause that is characterized histologically by the presence of confluent sarcoid-like granulomas associated with variable amounts of parenchymal necrosis and v a s c ~ l i t i s Because .~~ of some shared similarities in clinical, immunologic, and histologic features, NSG has been postulated to represent a variant of classic sarc~idosis.'~, 89 Affected patients usually present between the third and seventh decades of life with women more than twice as frequently affected as men.10, 14. 43.52 Necrotizing sarcoidosis granulomatosis is usually limited to involvement of the thorax; common presenting symptoms include fever, malaise, weight loss, cough, chest pain, and dyspnea.lo,14, 43 Because the eye is the most
common site of extrathoracic involvement, patients may initially present with visual disturbances.& The histologic features of NSG consist of confluent granulomas composed of giant cells and epitheliod histiocytes interspersed with chronic inflammatory cells that replace lung parenchyma with zones of necrosis randomly distributed within the granulomas (Fig. 19).43 The vasculitic component primarily involves the muscular pulmonary arteries and veins and occurs in three different patterns: (1)nonnecrotizing granulomatous inflammation causing partial luminal narrowing, (2) giant cell reaction within vessel walls, and (3) transmural chronic inflammatory cell infiltrati~n.'~. 43 As with sarcoidosis, the diagnosis of NSG is one of exclusion and requires elimination of potential infectious causes that may produce similar clinical and histologic findings.14 The most common radiographic finding in patients with NSG is solitary or more commonly multiple pulmonary nodules.lo,14, 43, 52 Nodules range from 1 to 4 cm in size and may occasionally demonstrate ~avitation.'~, 43 A miliary pattern14 and reticulonodular infiltrates with a lower lobe predominancelo,43 have also been described. Nodal enlargement is found as an associated radiographic finding
Figure 19. Necrotizing sarcoidosis composed of multiple foci of central necrosis (*) within well-circumscribed granulomas (H&E, original magnification x 400).
CT OF NONINFECTIOUS GRANULOMATOUS LUNG DISEASE
in 8% to 50% of cases.14,43 Pleural abnormalities may be seen in up to one half of pat i e n t ~Limited .~~ radiographic follow-up of patients with NSG has shown that garenchyma1 abnormalities may persist unchanged, decrease, or completely resolve with or without steroid therapy.14 On CT, multiple pulmonary nodules are the most common manifestation of NSG’O, 52; nodules are typically homogeneous, well-defined, and subpleural in location.1° Niimi et a17’ described three different HRCT patterns of parenchymal involvement in three patients with biopsy-proved NSG: (1) solitary, subpleural nodule; (2) multiple irregularly marginated nodules; and (3) patchy parenchymal opacification. The latter two patterns were associated with a subpleural and peribronchovascular distrib~tion.~~ Of a total of 13 patients with NSG and CT findings described in four different series? 10,52,71 9 (69%) patients had hilar or mediastinal lymphadenopathy and six (46%)patients had pleural abnormalities consisting of thickening or effusion. LYMPHOMATOID GRANULOMATOSIS
Lymphoma t oid granulomat osis, also known as angiocentric immunoproliferative le-
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sion (AIL), polymorphic reticulosis, or angiocentric lymphoma, refers to a group of disorders characterized histologically by a necrotizing angiocentric lymphoproliferative process that 39 Onset of disprimarily affects the ease is usually in the fifth or sixth decades of life with men affected approximately twice as frequently as women?9,65 Most patients with LYG present with respiratory symptoms, such as cough, dyspnea, and chest pain, often accompanied by systemic manifestations, such as fever, malaise and weight 44, 54 Extrathoracic involvement is common and most frequently affects 74 Cutaneous the skin and nervous lesions occur in up to one third of affected patients and include subcutaneous or dermal nodules, maculopapular eruptions, and macular erythema, which may be generalized or more frequently distributed on the lower e~tremities.3~~ 39 Neurologic disease occurs in approximately 30% of patients and most commonly involves the central nervous system.39 Patients may exhibit confusion, ataxia, hemiparesis, seizures, or cranial nerve defects.39, 74 Occasionally, asymptomatic patients are detected because of an abnormal screening chest radiograph.4 Definitive diagnosis of LYG requires tissue
Figure 20. High-grade lymphomatoid granulomatosis (AIULYG) characterized by the presence of infiltration and focal destruction of muscular artery (arrows) by atypical lymphoid infiltrate resembling large cell lymphoma (H&E, original magnification x 400).
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sampling. Grossly, the lung parenchyma contains white nodules measuring up to 10 cm in diameter with variable amounts of central yellowish necrosis. A variety of histopathologic classifications have been proposed but the authors prefer classifying these lesions as AIL-LYG. Immunophenotypic and molecular studies have shown that some cases represent T-cell proliferations whereas others are T-cellrich B-cell proliferations. The characteristic histologic triad consists of a heterogeneous mononuclear cell infiltrate with a variable degree of cytologic atypia and polymorphism; angiitis with transmural infiltration of arteries
and veins by lymphoid cells; and granulomatosis, indicating the presence of focal necrosis within lymphoid nodules rather than true is granulomatous i n f l a m m a t i ~ n AIL-LYG .~~ graded into three forms based on the relative proportion of atypical lymphoid cells and inf l a m m a t i ~ nLow-grade .~~ lesions consist predominantly of lymphocytes with minimal cytologic atypia and are believed to represent a lymphoproliferative disorder.55High-grade lesions are characterized by increasing numbers of atypical lymphocytes, necrosis, and represent angiocentric lymphomas (Fig. 20).*8,55
Figure 21. Lymphomatoid granulomatosis in a 65-year-old man. A, CT at the level of the aortic arch shows multiple, bilateral, poorly defined nodules. B, CT at the lung bases shows a cavitary mass in the right middle lobe and consolidation in the left lower lobe.
CT OF NONINFECTIOUS GRANULOMATOUS LUNG DISEASE
The most common radiographic finding of LYG is multiple ill-defined pulmonary nodules that range in size from 0.5 to 10 cm and predominate in the lower lung zones.23,2x, 35, 39, 74, 75 Cavitation may be seen as an associated finding in larger nodules resulting in both thin- and thick-walled cavities.2x,74, 95 Parenchymal consolidation occurs in up to 50% of affected patients and manifests as either an isolated finding or in association with nodules.2x,75* 95 A subpleural distribution of parenchymal abnormalities suggestive of pulmonary infarction has also been described.74, 95 A diffuse bilateral reticulonodular pattern is the least common of the parenchymal patterns of disease23,39, 95 and occurs in approximately 4% of cases.39Associated pleural effusion or thickening occurs in 25”/bto 50% of patients74, 75, 95; radiographic evidence of hilar or mediastinal lymphadenopathy is rare.23,39, 75, 95 On sequential radiographic studies, parenchymal nodules may wax and wane in sizeMor demonstrate asynchronous evolution with concomitant increase and decrease in sizes of different Lee et al5I have described the CT features of LYG in five patients. Both well and poorly defined nodules distributed in a perilymphatic distribution and extending along bronchovascular bundles and interlobular septa were seen in all patients. Most nodules were less than 1 cm in size with a maximum nodule diameter of 6.5 cm (Fig. 21). The number of nodules ranged from five to more than 60. In four (SOY0) patients, coarse reticular opacities also distributed along the bronchovascular bundles were found in association with small nodules. Thin-walled cysts and mediastinal lymphadenopathy were present in three (60%) patients each.
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