Published online before print October 24, 2002, 10.1148/radiol.2253011490
(Radiology 2002;225:639-653.)
© RSNA, 2002
Small-Vessel Diseases of the Lung: CT-Pathologic Correlates1
David M. Hansell, MD, FRCP, FRCR
1 From the Department of Radiology, Royal Brompton Hospital, Sydney St, London SW3 6NP, England. Received September 6, 2001; revision requested November 8; revision received January 4, 2002; accepted January 22. Address correspondence to the author (e-mail: d.hansell@rbh.nthames.nhs.uk).
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ABSTRACT
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Diseases that primarily affect the small vessels of the lung are difficult to diagnose. Many conditions are characterized by involvement of small pulmonary vessels, and pathologically they can be conveniently divided into occluding and inflammatory types. The former, typified by chronic pulmonary thromboembolism and primary pulmonary hypertension, are relatively cryptic in terms of imaging. In contrast, inflammatory vasculitides, which often cause pulmonary hemorrhage and infarction, result in florid but nonspecific radiographic abnormalities. The spectrum of thin-section computed tomographic abnormalities encountered in the inflammatory vasculitides is wide: For example, in Wegener granulomatosis the pattern ranges from cavitating nodules to lobar consolidation to ground-glass opacity. This review highlights some of the less obvious imaging manifestations of occlusive and inflammatory diseases of the small pulmonary vessels.
© RSNA, 2002
Index terms: Hypertension, pulmonary, 944.723 • Lung, CT, 60.12111, 60.12112, 60.12118 • Lung, hemorrhage, 60.4123 • Lung, vascular disease, 50.781, 50.783, 50.788, 60.622, 60.623, 60.691, 60.692, 60.71 • State of the Art
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INTRODUCTION
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The imaging, and understanding, of conditions that affect the small vessels of the lung is a challenge. Many of the difficulties encountered in considering diseases of the small vessels are mirrored in small-airways diseases: Problems include the definition of anatomic criteria for what constitutes a "small vessel," the utility of clinical versus pathologic classification, the nonspecific and often late clinical manifestation of such diseases, the continuum between small- and large-vessel involvement, and, finally, the lack of specific radiographic findings in most of these diseases.
Although some diseases affecting the small vessels elude a precise clinical or histologic diagnosis, for reasons explored later, an increasing array of thin-section computed tomographic (CT) features can be used to corroborate small-vessel disease as the dominant pathologic process. While acknowledging the less-than-definitive diagnostic role of CT in diseases of the small vessels of the lung, this review will include discussion of those conditions in which an understanding of the pathology can be usefully brought to bear on the interpretation of thin-section CT findings in this difficult group of disorders.
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ANATOMIC AND HISTOLOGIC ASPECTS OF SMALL-VESSEL DISEASES
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The point at which pulmonary vessels, in particular pulmonary arteries, can be considered "small" is arguable but has a bearing on whether such vessels are within or below the spatial-resolution capability of thin-section CT. In addition to the size of pulmonary arteries, an important distinction can be made between elastic (larger arteries) versus muscular (smaller arteries) vessels. The larger pulmonary arteries and their intrapulmonary branches with an external diameter of 1 mm or larger have walls constructed of numerous parallel elastic laminae and are therefore termed elastic arteries. For both anatomic and pathologic classification, elastic tissue stains (eg, Verhoeff–van Gieson stain) are invaluable for enabling identification of arterial wall disruption in the inflammatory vasculitides. Pulmonary arteries smaller than 1 mm but larger than 100 µm are characterized by a thin smooth-muscle medial layer (providing less than 7% of the external diameter) bounded by internal and external elastic membranes. Vessels smaller than 100 µm in diameter are termed pulmonary arterioles and are composed of a single layer of endothelial cells on an elastic lamina. The morphologic diminution culminates in the pulmonary capillaries within the alveolar walls: These are smaller than 10 µm in diameter and consist simply of a layer of endothelial cells and basement membrane.
It should be appreciated that this simplified morphologic scheme (1) understates the gradual transition from elastic arteries to muscular arteries to arterioles. For example, because of the spiral configuration of muscular media, there will be some apparently "intermediate" arteries that in perpendicular section will have a muscular media in only part of the wall circumference. It is, therefore, probably inadvisable to categorize pulmonary arteries simply according to diameter, and one proposal has been to classify all precapillary pulmonary arteries as either muscular or nonmuscular (2), although the reality of "transitional" arteries remains. There are no morphologic characteristics on thin-section CT images, apart from size, that allow the distinction between these two fundamental types of pulmonary arteries. If the largely arbitrary definition of pulmonary arterioles as those vessels with a diameter of less than 100 µm is accepted and given the limits of spatial resolution of thin-section CT, which in the most optimal circumstances is approximately 200 µm (3), normal pulmonary arterioles are not directly visualized on standard thin-section CT images. Centrilobular pulmonary arteries, approximately 1 mm in diameter, can be readily recognized on thin-section CT images, particularly in the lung periphery (4).
The pulmonary arteries are accompanied by a similar-sized bronchus throughout their course, at least down to the size that these arteries are visible on thin-section CT images. Below this size, supernumerary arteries branch at right angles and penetrate the more peripheral lung parenchyma within an acinus; thus, there is a complex system of perfusion of the acinus, which receives arterial blood from the axial (central) and several supernumerary (peripheral) arteries (5). The postcapillary vessels converge to form the pulmonary veins, which are located within the interlobular septa; the small pulmonary venules are morphologically identical to arterioles and may only be identified confidently by demonstrating their continuity with a pulmonary vein (1).
Structural similarities between arterioles and venules are relevant to the difficulties that arise in distinguishing between precapillary and postcapillary vascular diseases. The walls of macroscopic pulmonary veins are much thinner than those of similar-sized pulmonary arteries and are composed of an inner elastic lamina and a less well organized peripheral layer of elastic fibers. The bronchial arteries are of systemic origin, and their smaller branches lie within bronchial walls; although there may be anastomotic links with the pulmonary circulation, there are no conditions that exclusively affect the small branches of the bronchial arteries, and the bronchial arterial circulation will not be considered further.
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CLASSIFICATION OF SMALL-VESSEL DISEASES
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The lack of a distinctive transitional zone between small and large pulmonary vessels means that any attempt to define "small-vessel disease" precisely is unrealistic; nevertheless, there are enough conditions that are predominantly confined to the smaller branches of the pulmonary vasculature to make this somewhat arbitrary categorization worthwhile. There are many classifications of diseases of the pulmonary vasculature, each with its own idiosyncrasies and problems. Most schemes are defined in terms of one of the following nosologies: (a) size of vessel predominantly involved (6) (eg, medium-sized vasculitis), (b) the predominant pathologic process (eg, granulomatous vasculitis), (c) cause or association (eg, toxic oil syndrome or systemic sclerosis–associated vasculopathy), (d) eponym (eg, Goodpasture syndrome), (e) mechanism (eg, embolic), and (f) constellation of clinical features (eg, antineutrophil cytoplasmic antibody [ANCA] vs non-ANCA). Some classifications of the pulmonary vasculitides can be regarded as a more or less complete list of pathologic conditions affecting the pulmonary vasculature (7) (Fig 1).
Pathologic classifications of diseases of the pulmonary vasculature are, in many respects, similar to those devised for the categorization of bronchial and bronchiolar diseases: Such classifications do not allow for situations in which various processes coexist (8–10), and, more important, there are not always obvious clinical and imaging correlates with the individual pathologic entities. Nevertheless, there is much to recommend the conceptual distinction between inflammatory and occlusive diseases of small vessels; while there is bound to be some overlap (eg, acute vasculitis of Wegener granulomatosis may ultimately result in scarring and occlusion of affected vessels), the clinical and imaging characteristics of the two ends of this notional spectrum are reasonably distinct and allow some sense to be made of the wide range of abnormalities seen on thin-section CT images.
The range of imaging abnormalities encountered in the inflammatory vasculitides is wide but in many ways predictable: Inflammatory involvement resulting in hemorrhagic leak and/or infarction results in florid radiographic changes. In contrast, the occlusive vasculitides, typified by chronic pulmonary thromboembolism and primary pulmonary hypertension, are characterized by relatively cryptic and usually indirect imaging signs. The conditions included under these two broad headings and discussed in this review are shown in Table 1.
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IMAGING TECHNIQUES
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CT Techniques
Standard thin-section CT technique is appropriate for demonstrating most of the features that characterize diseases of the small pulmonary vessels, particularly in advanced disease. The usual protocol (1.0–1.5-mm section thickness, 10–30-mm intervals) is usually adequate, with no benefit accruing from smaller intervals between images or contiguous images. Nevertheless, some modification to this basic technique may enhance the sometimes subtle signs of small-vessel disease. The two fundamental manifestations of occlusive small-vessel disease—alterations to the morphology and profusion of macroscopic vessels and a mosaic attenuation pattern—make different demands of the technique: For the former, adequate spatial resolution to depict small vessels is needed, whereas for the latter, appropriate contrast resolution is needed to demonstrate regional attenuation differences.
Alteration of window settings has a marked effect on the apparent size of structures (11), and, with specific reference to the pulmonary vasculature, smaller vessels are disproportionately and more adversely affected by inappropriate window settings than are larger vessels. Nonstandard window settings may either deemphasize the small vessels or, conversely, produce a nodular appearance in the lungs. Furthermore, subtle regional inhomogeneity in the attenuation of lung parenchyma may become invisible or inconspicuous if a wider than usual window setting is used; in general, a window level of -500 to -800 HU and a width of 900 to 1,500 HU is satisfactory, but a narrow window width of approximately 600 HU may be used to emphasize a subtle mosaic attenuation pattern. Although such latitude in the choice of window settings may be desirable, there is probably no substantial diagnostic gain in using freely adjustable window settings, provided the starting points are conventional width and level settings (12). Allowing for the few parameters that can be altered when performing a standard thin-section CT examination, the final appearance of the lungs obtained with different CT scanners, even when identical window settings are used, can be remarkably different; these differences may be particularly problematic in the context of identifying a mosaic attenuation pattern or assessing the abnormal paucity of small vessels.
The mosaic attenuation pattern on thin-section CT images is a nonspecific sign indicating patchy infiltrative, small-airways, or occlusive vascular disease (13–17). Enhancement of this regional inhomogeneity in the attenuation of the lung parenchyma on sections obtained at end expiration has led to the recommendation that expiratory sections be routinely obtained, irrespective of the findings on standard inspiratory thin-section CT images (18,19). In most cases, expiratory CT images will aid the identification of individuals with small-airways disease as the cause of a mosaic attenuation pattern (20); however, it is possible that the use of expiratory CT images to make the distinction between small-airways and small-vessel disease is not always reliable, particularly in the complex pathophysiologic situations in which airways and vessels are both abnormal (21).
The attenuation differences that characterize a mosaic attenuation pattern, when caused by occlusion of medium- and small-sized pulmonary arteries, may be subtle and close to the limit of visual detection. While optimization (narrowing) of window settings may increase the conspicuity of regional attenuation differences, it will also spuriously affect the apparent extent of abnormal versus normal lung. However, there are simple image-processing techniques that can be used to improve the detection of small attenuation differences within the lung parenchyma. The most widely used and simplest technique is the so-called minimum intensity projection technique, which has been shown to result in improved detection of subtle areas of low attenuation in the context of small-airways disease in emphysema (22,23). Conversely, maximum intensity projection images improve the delineation of medium and small vessels and may emphasize regional differences in their size (24) (Fig 2).
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Figure 2. Maximum intensity projection image comprising a slab of seven contiguous transverse 1.5-mm-thick CT sections shows to advantage the branching morphology of vessels in the upper lobes.
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Thin-Section CT Signs of Small-Vessel Diseases
The CT signs of small-vessel disease will depend on whether the pathologic process is inflammatory or occlusive. The spectrum of CT abnormalities encountered in various small-vessel diseases is not particularly wide and is encompassed in four main categories: (a) patchy ground-glass opacity, (b) consolidation, (c) nodules, and (d) interlobular septal thickening (14).
Parenchymal attenuation disturbances.—Patchy inhomogeneity in the attenuation of lung parenchyma (mosaic attenuation pattern) is a recognized sign of pulmonary vascular disease (13,14,25,26). In the specific context of a vascular cause for this nonspecific pattern, the original term mosaic oligemia (15) is semantically and mechanistically correct (Fig 3). However, the fact that three basic and fundamentally different types of disease (diffuse infiltrative, small-airways, and occlusive vascular diseases) can all cause a mosaic attenuation pattern may, on occasion, cause diagnostic difficulties (16,17).
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Figure 3. Transverse thin-section CT image through the upper lobes in a 64-year-old woman with chronic thromboembolic disease shows typical mosaic oligemia (mosaic attenuation pattern). Note the smaller caliber of vessels in the low-attenuating portion of (underperfused) lung, as compared with those in areas of increased attenuation (relatively overperfused lung). The proximal subsegmental and segmental pulmonary arteries are abnormally dilated.
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The major discriminating features that suggest a vascular origin for a mosaic attenuation pattern are the paucity and reduction in caliber of vessels within the areas of reduced attenuation (14) and the lack of air trapping on CT sections obtained at end expiration (16). Nevertheless, differentiation between the various causes of a mosaic attenuation pattern on CT images is not always straightforward: In one study (17), subjects with a vascular cause for the mosaic attenuation pattern were the least readily identified as such by two observers. Occasionally, coexisting small-airways and small-vessels disease may both contribute to a mosaic attenuation pattern (27) (Fig 4). Intriguingly, airways abnormalities have been demonstrated in patients with occlusive vascular disease, specifically dilatation of the segmental and subsegmental bronchi, seen in areas of lung affected by chronic thromboembolism (21). The mechanism is obscure, but a physiologic response to the hypoxic milieu of the underperfused lung (hypoxic bronchodilatation) is one of several postulated mechanisms (21); whatever the cause, it is as well to be aware of this phenomenon, which may lead to the erroneous conclusion that a case with thin-section CT features of mosaic attenuation pattern and dilatation of segmental and subsegmental bronchi is the result of small-airways disease (rather than occlusive vasculopathy) (Fig 5).
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Figure 4. Transverse thin-section CT image through the mid-lung zones in a 44-year-old woman with mixed small-airways and small-vessel disease. The patient had constrictive obliterative bronchiolitis secondary to a severe viral lower respiratory tract infection; she subsequently developed chronic thromboembolic disease. In this case, it is impossible to be certain what proportion of the mosaic attenuation pattern is ascribable to small-airways, as opposed to small-vessels, disease.
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Figure 5. Transverse thin-section CT image through the lower lobes in a patient with severe chronic thromboembolic disease and presumed hypoxic bronchodilatation. There are extensive areas of relatively underperfused lung. Peripheral subpleural opacification in the right lower lobe likely reflects previous pulmonary infarction (arrowheads). Note the mildly dilated segmental and subsegmental bronchi (arrow) in the lower lobes, which were also present on adjacent sections (not shown).
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Subtle perturbations of pulmonary perfusion as a consequence of small-vessel diseases may be inconspicuous or below the limits of visual detection without image enhancement by means of a technique such as minimum intensity projection. An interesting and invisible disturbance to the normal gravity-dependent attenuation gradient has been reported in patients with pulmonary hypertension associated with systemic sclerosis (28): In patients with pulmonary hypertension (but no evidence of interstitial lung disease), there was a diminution in the measurable attenuation difference between dependent and nondependent lung, suggesting that the normal gradient may in some way be disturbed, possibly reflecting a loss of compliance of the small pulmonary vessels.
Ground-glass opacity and consolidation.—In the context of small-vessel diseases, ground-glass opacity is most frequently seen as the increased-attenuation component (reflecting relative overperfusion) of the mosaic attenuation pattern and is encountered in chronic occlusive vascular disease. Nevertheless, other conditions affecting the small vessels may result in ground-glass opacity by other mechanisms: The commonest is diffuse pulmonary hemorrhage in which there is thickening of the interstitium and partial filling of the airspaces with blood (29). Other conditions affecting the small pulmonary vessels, characterized by ground-glass opacity, include pulmonary veno-occlusive disease (30), acute sickle cell disease (31), Churg-Strauss syndrome (32), and Wegener granulomatosis (33). The pathogenesis of ground-glass opacity will be considered in more detail for each specific disease.
Frank pulmonary consolidation is most often encountered in conditions in which there is pulmonary infarction with or without hemorrhage into the airspaces. The disposition of the consolidation (eg, focal wedge-shaped area in the periphery of the lower lobe) may be suggestive of an area of pulmonary infarction (Fig 6). It is not clear whether consolidation caused by an inflammatory granulomatous or neutrophilic vasculitis eventually results in a visible mosaic attenuation pattern in addition to residual scarring that may be ascribable to inflammatory pulmonary consolidation (34).
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Figure 6. Standard transverse CT section obtained after intravenous administration of contrast material in a 56-year-old woman with Wegener granulomatosis shows an area of consolidation in the medial segment of the right middle lobe (arrowheads), thought to be an area of organizing pneumonia. Histologic examination of a lung biopsy specimen revealed Wegener granulomatosis.
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Nodules and micronodules.—It is only relatively recently that nodules on thin-section CT images have been reported as a manifestation of small-vessel disease. In one study (35) of cases characterized by a diffuse micronodular pattern on thin-section CT images, only one case (foreign body–induced necrotizing vasculitis) was included in 40 consecutive patients with biopsy-proved micronodular disease of various origins (35).
On occasion, it may be difficult to discriminate between the numerous small but normal pulmonary vessels in dependent lung and an abnormal nodular pattern. However, this distinction can be made more easily with increased data sampling and viewing of the resultant thin sections in cine mode (36). Nevertheless, in specific circumstances, an apparent nodular pattern may indeed reflect an abnormal profusion of vessels, the most obvious example being the hepatopulmonary syndrome associated with liver cirrhosis, in which numerous peripheral minute arteriovenous malformations are seen as a nodular pattern (37). The micronodules associated with various occlusive vasculopathies are poorly defined and of relatively low attenuation (Fig 7) and may be encountered in primary pulmonary arterial hypertension (38), various forms of diffuse pulmonary hemorrhage (29,39), and pulmonary capillary hemangiomatosis (9,40).
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Figure 7. Transverse thin-section CT image through the upper lobes in a 39-year-old woman with severe primary pulmonary hypertension shows widespread subtle small nodules of relatively low attenuation throughout the lungs; these nodules correspond to focal extravasation of blood and/or cholesterol granuloma formation.
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Interlobular septal thickening.—Septal thickening may be seen in any condition characterized by capillary leak and is usually associated with peribronchovascular interstitial thickening and, sometimes, pleural effusions. In the context of small-vessel diseases, the most dramatic cause of widespread smooth thickening of the interlobular septa is veno-occlusive disease, in which the thickened septa reflect interstitial edema due to obstruction of venular drainage (30) (Fig 8).
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Figure 8. Transverse thin-section CT image through the upper lobes in a patient with veno-occlusive disease. Thickening of the interlobular septa is the most prominent feature, and there are some poorly defined centrilobular nodules. Bilateral dependent pleural effusions (arrows) are visible.
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Discernible abnormalities of the macroscopic vasculature.—A discrepancy in the size of the macroscopic pulmonary vessels is part of the constellation of features that reflect inhomogeneity of pulmonary perfusion, caused by either large- or small-vessel disease. Thromboembolic disease, demonstrable on a contrast material–enhanced study, is the most usual cause of abnormal regional variation in the size of the pulmonary vessels. On rare occasions, when tumor emboli are responsible for occlusive vascular disease, the affected vessels may show some varicosity and beading, particularly of the peripheral pulmonary arteries (41). In some cases, the tumor emboli excite a florid fibrocellular proliferation of the intima, with consequent thrombosis and obliteration of the vessel lumen; this so-called pulmonary tumor thrombotic microangiopathy (42) may result in particularly prominent peripheral pulmonary arteries resembling a tree-in-bud pattern (Fig 9).
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Figure 9a. Pulmonary tumor thrombotic microangiopathy. (a) Transverse thin-section CT image through the right lower lobe shows small branching opacities (arrows) representing enlarged peripheral arteries. (b) Cut surface of autopsy lung specimen shows pale nodules, which correspond to the pulmonary arteries thickened by the fibrotic reaction to tumor. (c) Photomicrograph demonstrates dense fibrocellular proliferation within an arteriolar lumen. The tumor emboli (arrows) are relatively small. (Image courtesy of Dr T. Franquet, Hospital Sant Pau, Barcelona, Spain.)
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Figure 9b. Pulmonary tumor thrombotic microangiopathy. (a) Transverse thin-section CT image through the right lower lobe shows small branching opacities (arrows) representing enlarged peripheral arteries. (b) Cut surface of autopsy lung specimen shows pale nodules, which correspond to the pulmonary arteries thickened by the fibrotic reaction to tumor. (c) Photomicrograph demonstrates dense fibrocellular proliferation within an arteriolar lumen. The tumor emboli (arrows) are relatively small. (Image courtesy of Dr T. Franquet, Hospital Sant Pau, Barcelona, Spain.)
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Figure 9c. Pulmonary tumor thrombotic microangiopathy. (a) Transverse thin-section CT image through the right lower lobe shows small branching opacities (arrows) representing enlarged peripheral arteries. (b) Cut surface of autopsy lung specimen shows pale nodules, which correspond to the pulmonary arteries thickened by the fibrotic reaction to tumor. (c) Photomicrograph demonstrates dense fibrocellular proliferation within an arteriolar lumen. The tumor emboli (arrows) are relatively small. (Image courtesy of Dr T. Franquet, Hospital Sant Pau, Barcelona, Spain.)
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Other nonthrombotic emboli (eg, intravenously injected materials such as particulate cellulose) may also be characterized by a tree-in-bud pattern (43). There are numerous potential materials, iatrogenic and otherwise, that can lodge within the small vessels of the lungs, and these have been elegantly reviewed by Rossi et al (44). If profuse enough, microvascular arteriovenous malformations may be visible as minute peripheral serpiginous opacities, usually associated with dilatation of the segmental and subsegmental pulmonary arteries (37).
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OCCLUSIVE SMALL-VESSEL DISEASES
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Primary Pulmonary Hypertension
Primary pulmonary hypertension is the occlusive small-vessel disease par excellence. The pathologic changes are largely confined to the muscular pulmonary arteries (those less than 1 mm in diameter that contain a medial layer of muscle). Changes seen in the macroscopic and large pulmonary arteries (eg, dilatation of the main pulmonary arteries seen on a chest radiograph) are a response to the pulmonary hypertension, rather than muscle hypertrophy per se, which characterizes primary pulmonary hypertension (45). Primary (idiopathic) pulmonary hypertension is a rare and often overlooked diagnosis, and, given the numerous conditions that can cause pulmonary hypertension (at least 30 causes in the World Health Organization classification of pulmonary hypertension [46,47]), the diagnosis is usually one of exhaustive exclusion.
The histologic grading of pulmonary hypertension (1) ranges from minor changes of hypertrophy of the muscular media of the small pulmonary arteries, to subendothelial fibrous proliferation, to the development of "plexiform lesions" (nothing more than aneurysmal expansion of a sclerotic damaged vessel with associated minute abnormal vascular channels in the wall [48]) (Fig 10). This spectrum of pathologic features is found with similar frequency in primary pulmonary (more properly, "unexplained" [49]) hypertension and in cases of pulmonary hypertension with a known cause or association. Many attempts have been made to classify pulmonary hypertension in terms of functional consequences or clinical risk factors, the most comprehensive of these being one developed at a World Health Organization symposium on primary pulmonary hypertension (46).
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Figure 10a. Histopathologic features of pulmonary hypertension. (a) Photomicrograph shows muscular hypertrophy and subendothelial fibrosis in two small pulmonary arteries. (Original magnification, x400.) (b) Photomicrograph shows typical plexiform lesion, with several abnormal vascular channels (arrows) in the damaged wall of a small pulmonary artery. (Original magnification, x200.)
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Figure 10b. Histopathologic features of pulmonary hypertension. (a) Photomicrograph shows muscular hypertrophy and subendothelial fibrosis in two small pulmonary arteries. (Original magnification, x400.) (b) Photomicrograph shows typical plexiform lesion, with several abnormal vascular channels (arrows) in the damaged wall of a small pulmonary artery. (Original magnification, x200.)
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The lack of thin-section CT literature on the effects of pulmonary hypertension on the appearances of lung parenchyma reflects both the rarity of the condition and the nonspecific and subtle changes that occur. In most cases, by the time a patient presents with symptoms attributable to pulmonary hypertension, there will be indirect radiographic signs of pulmonary hypertension (ie, dilatation of the main pulmonary arteries and pruning of the peripheral vasculature on chest radiographs [50]). These appearances will be reflected on CT images by manifestations of right ventricular hypertrophy and dilatation of the main pulmonary arteries (51–54) and, intriguingly, the development of pericardial fluid or thickening in some patients with markedly raised pulmonary arterial pressure (55) (Fig 11).
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Figure 11. Transverse thin-section CT image (soft-tissue window settings) in a patient with primary pulmonary hypertension. In this patient with a mean pulmonary artery pressure of more than 35 mm Hg, the main pulmonary artery (pa) is dilated and there is fluid within the anterior (double-headed arrow) and posterior (arrowhead) superior pericardial recesses. A pericardial effusion was evident on more caudal sections (not shown).
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While the mosaic attenuation pattern on thin-section CT images is an expected feature of chronic thromboembolic disease (56,57), there is little in the literature to indicate the prevalence of a mosaic attenuation pattern in nonthromboembolic pulmonary hypertension. In a single study (13), patients with a "vascular" origin of pulmonary hypertension were more likely to have mosaic attenuation on thin-section CT images than were those with either cardiac or lung disease as the cause of pulmonary hypertension; in the 64 patients included in that study, only four had primary pulmonary hypertension but all of these four patients had some regional inhomogeneity of the attenuation of lung parenchyma (similarly, 13 of 15 patients with thromboembolic disease had a mosaic attenuation pattern).
Whether the distribution of the pathologic process in primary pulmonary hypertension (relatively uniform involvement of the small muscular pulmonary arteries, in comparison with patchy thrombotic occlusion of larger generations of pulmonary arteries in thromboembolic disease) is responsible for different manifestations—that is, loss of the normal gravity-dependent attenuation gradient in nonthromboembolic pulmonary hypertension (28) rather than a conspicuous mosaic attenuation pattern in thromboembolic disease (58)—has not yet been determined. The pathophysiology of chronic occlusive vascular disease may be complex. In some patients with advanced primary pulmonary hypertension, there is scintigraphic evidence of reversed mismatching (ie, pulmonary perfusion of areas of lung showing little or no ventilation); CT studies have shown that such areas show normal or engorged pulmonary vasculature, with areas of increased parenchymal attenuation that are shown to have ventilatory defects at scintigraphy (59).
There is the fascinating report (38) of small, poorly defined, low-attenuating centrilobular nodules in patients with pulmonary arterial hypertension of various causes. These nodules resemble those found in hypersensitivity pneumonitis, and at histologic examination are seen to consist mainly of cholesterol granulomas, possibly formed as a consequence of macrophage ingestion of red blood cells after repeated pulmonary hemorrhage (Fig 12). Two of the five patients included in that report (38) had primary pulmonary hypertension; the presence of a widespread nodular pattern on thin-section CT images clearly raises the possibility of a secondary (diffuse parenchymal) cause for pulmonary hypertension (eg, conditions characterized by a nodular pattern with a propensity to cause pulmonary hypertension, such as primary capillary hemangiomatosis [40] or Langerhans cell histiocytosis [10]). Because of the lack of specific features ascribable to most causes of pulmonary hypertension, these conditions (summarized in Table 2) will not be covered in any detail. However, two conditions that specifically affect the small vessels of the lungs—namely, pulmonary capillary hemangiomatosis and veno-occlusive disease—will be discussed.
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Figure 12a. Severe small-vessel vasculopathy thought to be a variant of veno-occlusive disease at histologic examination. (a) Transverse thin-section CT image through the lower lobes shows numerous poorly defined nodules (arrows) ranging from 1 to 4 mm in diameter, with a generalized increase in attenuation of lung parenchyma. (b) Low-power photomicrograph shows that nodules seen at CT correspond to small, scattered, focal areas of hemorrhage, most obvious in the bottom right-hand corner. (Original magnification, x20.)
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Figure 12b. Severe small-vessel vasculopathy thought to be a variant of veno-occlusive disease at histologic examination. (a) Transverse thin-section CT image through the lower lobes shows numerous poorly defined nodules (arrows) ranging from 1 to 4 mm in diameter, with a generalized increase in attenuation of lung parenchyma. (b) Low-power photomicrograph shows that nodules seen at CT correspond to small, scattered, focal areas of hemorrhage, most obvious in the bottom right-hand corner. (Original magnification, x20.)
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Pulmonary capillary hemangiomatosis is characterized by an abnormal proliferation of thin-walled capillary channels throughout the interstitium (Fig 13); there is associated obstruction of small venules (so that the histologic picture in some ways resembles that of pulmonary veno-occlusive disease), resulting in pulmonary hypertension (60,61). This gross proliferation of capillary-sized vessels is responsible for the CT features of poorly defined small nodular opacities, thickened interlobular septa, and areas of ground-glass opacity (9,40). The authors of one study (9) stated that, in contrast, nodules were not seen in patients with primary pulmonary hypertension, although only five patients were evaluated; nevertheless, similar nodules (representing cholesterol granulomas) are an occasional feature in primary pulmonary hypertension (38).
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Figure 13a. Capillary hemangiomatosis. (a) Transverse thin-section CT image shows mosaic attenuation pattern in the lower lobes, with clear demarcation between areas of lung of differing attenuation. More cephalic sections (not shown) demonstrated marked dilatation of the proximal pulmonary arteries. (Image courtesy of Dr L. Mitchell, Freeman Hospital, Newcastle upon Tyne, England.) (b) Low-power photomicrograph of lung biopsy specimen shows clear demarcation between abnormal capillary proliferation causing thickening of interstitium (on the left), as compared with relatively normal lung (on the right). Small pulmonary arteries (arrowheads) at top of field show features of pulmonary hypertension; the patient was initially thought to have primary pulmonary hypertension. (Original magnification, x40.)
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Figure 13b. Capillary hemangiomatosis. (a) Transverse thin-section CT image shows mosaic attenuation pattern in the lower lobes, with clear demarcation between areas of lung of differing attenuation. More cephalic sections (not shown) demonstrated marked dilatation of the proximal pulmonary arteries. (Image courtesy of Dr L. Mitchell, Freeman Hospital, Newcastle upon Tyne, England.) (b) Low-power photomicrograph of lung biopsy specimen shows clear demarcation between abnormal capillary proliferation causing thickening of interstitium (on the left), as compared with relatively normal lung (on the right). Small pulmonary arteries (arrowheads) at top of field show features of pulmonary hypertension; the patient was initially thought to have primary pulmonary hypertension. (Original magnification, x40.)
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There is some overlap between the thin-section CT–pathologic features of capillary hemangiomatosis and pulmonary veno-occlusive disease (9,45), simply because of the size and site of the pulmonary vessels involved (capillaries and adjoining venules, respectively). In pulmonary veno-occlusive disease, the imaging features are essentially those of pulmonary venous congestion, with thickened interlobular septa, ground-glass opacity, and, sometimes, pleural effusions (30) (Fig 14); an obvious mosaic attenuation pattern is a less frequent finding. At the time of presentation, there is usually some dilatation of the proximal pulmonary arteries, which reflects back pressure from the obstructed venular side of the pulmonary circulation. A nodular pattern, similar to that seen in capillary hemangiomatosis (9) and in some cases of primary pulmonary hypertension (38), is an occasional finding, highlighting the overlap between these two entities.
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Figure 14. Transverse thin-section CT image through the lower lobes in a patient with veno-occlusive disease shows combination of thickening of interlobular septa (arrows), ground-glass opacity, and pleural effusions. Fluid is seen tracking into the right oblique fissure (arrowheads). (Image courtesy of Dr S. Swensen, Mayo Clinic, Rochester, Minn.)
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Other Examples of Occlusive Small-Vessel Disease
Microvascular occlusion due to sickle cell disease.—Sickle cell disease represents an idiosyncratic model of occlusion of the small pulmonary vessels. In the acute chest syndrome there is widespread capillary obstruction by sickle cells and accompanying in situ thrombosis (62,63). As might be anticipated, the most frequent finding on CT images in patients with acute chest syndrome is areas of "hypoperfusion" (31); that is, areas of decreased attenuation within which there are fewer pulmonary vessels than expected (Fig 15). In addition, there may be areas of ground-glass opacity; in the study by Bhalla et al (31), these areas of ground-glass opacity were identified only in segments that showed features of "hypoperfusion," and they represented areas of hemorrhagic edema caused by reversible ischemia or, possibly, areas of relative overperfusion. In contrast, denser areas of consolidation reflect either true tissue infarction or, less likely, infective consolidation responsible for precipitation of the acute chest syndrome. Chronic changes are seen in individuals with repeated acute episodes, with approximately half showing evidence of interstitial disease, most probably reflecting scarring from small pulmonary infarcts (Fig 16) (64). The nature of the chronic changes seen on thin-section CT images, such as diffuse uniform ground-glass opacity (Fig 16), has not been characterized at a histologic level. Ultimately, if there is sufficient and permanent occlusion of the microvascular bed, cor pulmonale develops, with dilatation of the central pulmonary arteries and evidence of right ventricular hypertrophy.
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Figure 15a. (a) Transverse thin-section CT image through the upper lobes in a ventilated 27-year-old woman with acute sickle cell crisis shows mosaic attenuation pattern. Vessels within areas of reduced attenuation are of decreased caliber (arrowheads). Combined dependent atelectasis and pleural effusions can be seen. (b) Photomicrograph of open lung biopsy specimen shows engorgement of alveolar capillaries resulting from sludging and occlusion by sickle cells, most obvious on the left-hand side of the image. (Original magnification, x200.)
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Figure 15b. (a) Transverse thin-section CT image through the upper lobes in a ventilated 27-year-old woman with acute sickle cell crisis shows mosaic attenuation pattern. Vessels within areas of reduced attenuation are of decreased caliber (arrowheads). Combined dependent atelectasis and pleural effusions can be seen. (b) Photomicrograph of open lung biopsy specimen shows engorgement of alveolar capillaries resulting from sludging and occlusion by sickle cells, most obvious on the left-hand side of the image. (Original magnification, x200.)
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Figure 16a. Transverse thin-section CT images through the lower zones of two patients with chronic changes of sickle cell anemia. (a) Irregular linear subpleural opacities in the lower lobes (arrowheads), with associated distortion of the lung architecture, indicate interstitial fibrosis in a patient with repeated sickle cell crises. (b) The striking abnormality is diffuse ground-glass opacity: The pathologic correlate of this pattern in chronic sickle cell disease is uncertain. (Images courtesy of Dr S. Desai, King’s College Hospital, London, England.)
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Figure 16b. Transverse thin-section CT images through the lower zones of two patients with chronic changes of sickle cell anemia. (a) Irregular linear subpleural opacities in the lower lobes (arrowheads), with associated distortion of the lung architecture, indicate interstitial fibrosis in a patient with repeated sickle cell crises. (b) The striking abnormality is diffuse ground-glass opacity: The pathologic correlate of this pattern in chronic sickle cell disease is uncertain. (Images courtesy of Dr S. Desai, King’s College Hospital, London, England.)
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Postirradiation vascular obliteration.—The injurious effects of radiation therapy on the pulmonary vasculature have long been recognized (65), and more recently it has been suggested that such damage is more severe in the venules and veins than in the arteries, possibly because of the generation of a higher concentration of free radicals within the milieu of oxygenated blood on the venous side of the circulation (66). Despite the obvious vascular component in radiation-induced lung damage, most CT studies have concentrated on the acute (exudative) and later fibroproliferative manifestations (67–72). Morphologic features suggestive of microvascular obliteration (in the form of regional attenuation differences and discrepancies in the size of macroscopic vessels) have not been evaluated.
Bronchopulmonary dysplasia.—There are two potential causes of extensive obliteration of the small pulmonary vessels in early life. The first is the exceedingly rare condition of congenital alveolar capillary dysplasia, in which there is a paucity of capillaries and abnormal pulmonary veins accompanying the pulmonary arteries within bronchovascular bundles (73). This dysplasia of the small pulmonary vessels causes pulmonary hypertension in the neonate.
An increasingly frequently encountered acquired cause of widespread obliteration of the small pulmonary vessels is found in individuals with bronchopulmonary dysplasia. Since the condition was first defined in 1967 (as oxygen dependency at 28 days of age with an accompanying abnormal chest radiograph) (74), there has been a dramatic increase in the number of premature neonates surviving into adulthood, with the consequences of early and prolonged ventilation (that contribute to bronchopulmonary dysplasia). From the relatively limited information available, it seems that all elements of the lungs—that is, the vasculature, airways, and lung parenchyma—are affected to a greater or lesser extent (75,76). The cardinal CT features of bronchopulmonary dysplasia in surviving adults are extensive areas of reduced lung attenuation, within which the size and number of vessels are reduced; widespread bronchial wall thickening; and a decreased bronchus-to–pulmonary artery diameter ratio (such that the airways may appear to be of strikingly reduced caliber). Some individuals show distortion of the lung parenchyma, with linear opacities and multiple bullae. Given that the histologic features of "healed" bronchopulmonary dysplasia include bronchial abnormalities, arrest of acinar development, and pulmonary arteriolar involvement (77), it is difficult in an individual case to confidently assign the areas of decreased attenuation on thin-section CT images to the consequences of parenchymal, bronchial, or vascular dysplasia. The morphologic sequelae of the similar situation in adults surviving acute respiratory distress syndrome are different: Thrombotic and fibroproliferative vascular occlusion occurs in the acute phase of disease (78,79); however, a mosaic attenuation pattern, indicating chronic occlusive vascular disease, is not a common feature in long-term survivors (80).
Miscellaneous causes.—As Table 2 shows, there are numerous potential causes of pulmonary hypertension, several of which can be regarded as having truly occlusive features. The thin-section CT findings for each cause will vary and be modulated by the exact nature of the underlying pathologic condition. For example, two recently reported causes of an occlusive vasculopathy include Langerhans cell histiocytosis (Fig 17) (10), with its characteristic cavitating nodular pattern, and microvascular emboli of precipitated crystals from parenteral nutrition (81), in which a granulomatous response to the intravascular particulate matter results in a micronodular appearance with a predominantly lower-zone distribution. There are other more or less exotic nonthrombotic embolic materials that may cause extensive occlusion of small pulmonary vessels, ranging from microscopic tumor emboli (82,83) to a variety of substances introduced intravenously by drug users (44).
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Figure 17a. Langerhans cell histiocytosis. (a) Transverse thin-section CT image shows fine reticulonodular pattern in the upper lobes, with relative sparing of the lower lobes. (b) Transverse contrast-enhanced CT image shows marked dilatation of the main pulmonary artery (arrowheads) relative to the ascending aorta (a), indicating severe pulmonary hypertension. (c) Photomicrograph of biopsy specimen in another patient shows Langerhans cell histiocytosis nodule involving and partly obliterating a pulmonary artery (arrowheads). (Original magnification, x20.) (Fig 17c courtesy of Dr F. Capron, Assistance Hôpitaux Publique de Paris, France.)
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Figure 17b. Langerhans cell histiocytosis. (a) Transverse thin-section CT image shows fine reticulonodular pattern in the upper lobes, with relative sparing of the lower lobes. (b) Transverse contrast-enhanced CT image shows marked dilatation of the main pulmonary artery (arrowheads) relative to the ascending aorta (a), indicating severe pulmonary hypertension. (c) Photomicrograph of biopsy specimen in another patient shows Langerhans cell histiocytosis nodule involving and partly obliterating a pulmonary artery (arrowheads). (Original magnification, x20.) (Fig 17c courtesy of Dr F. Capron, Assistance Hôpitaux Publique de Paris, France.)
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Figure 17c. Langerhans cell histiocytosis. (a) Transverse thin-section CT image shows fine reticulonodular pattern in the upper lobes, with relative sparing of the lower lobes. (b) Transverse contrast-enhanced CT image shows marked dilatation of the main pulmonary artery (arrowheads) relative to the ascending aorta (a), indicating severe pulmonary hypertension. (c) Photomicrograph of biopsy specimen in another patient shows Langerhans cell histiocytosis nodule involving and partly obliterating a pulmonary artery (arrowheads). (Original magnification, x20.) (Fig 17c courtesy of Dr F. Capron, Assistance Hôpitaux Publique de Paris, France.)
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INFLAMMATORY SMALL-VESSEL DISEASE
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Terminology and Scope
In pulmonary vasculitis there is, by definition, acute or chronic inflammation within vessel walls. In contrast to the occlusive vasculopathies affecting the lung, inflammatory pulmonary vasculitis is almost invariably accompanied by systemic vasculitis. The type of inflammation (eg, neutrophilic vs granulomatous) may be used to further classify the pulmonary vasculitides. The term pulmonary angiitis and granulomatosis was originally used by Liebow and included the main entities that cause inflammatory and granulomatous destruction of the pulmonary arteries (notably Wegener granulomatosis, Churg-Strauss syndrome, and necrotizing sarcoid granulomatosis) (84,85); however, such disorders are generally considered to affect the medium- and larger-sized pulmonary arteries, and some difficulties arise when inflammatory vasculitides are classified in terms of vessel size. While some authorities regard exclusive small pulmonary vessel vasculitis as a rarity occurring in a limited number of situations (7), others include many causes within the ambit of "small-vessel vasculitis" (6,86). As has been mentioned earlier, the categorization of pulmonary vascular diseases according to size, particularly in inflammatory conditions, is largely arbitrary. Nevertheless, Wegener granulomatosis can, on occasion be confined to the small vessels. An inflammatory capillaritis, resulting in diffuse pulmonary hemorrhage, may be considered the purest form of inflammatory small-vessel disease. Because of the obvious overlap in terms of pathology and vessel-size involvement (to say nothing of the nonspecificity of clinical and functional abnormalities), it is not surprising that the CT features of inflammatory vasculitides are largely nonspecific, and any attempt to categorize the imaging findings of this heterogeneous group of conditions is for convenience rather than for diagnostic utility (14,87).
Selected Inflammatory Small-Vessel Diseases
Pulmonary capillaritis.—The pathologic feature of capillaritis is simply that of a neutrophilic infiltrate (Fig 18), with consequent necrosis, intraalveolar hemorrhage, and subsequent hemosiderin deposition (84). The situations in which this entity occurs and the associations with other clinically defined syndromes are not straightforward. In the past, cases of acute capillaritis (resulting in diffuse pulmonary hemorrhage with a clinical manifestation of hemoptysis, dyspnea, iron deficiency anemia, and widespread airspace shadowing on chest radiographs) were classified clinically. When there was no obvious cause, the label of idiopathic pulmonary hemorrhage (or hemosiderosis) was used. The conditions generally considered to be associated with neutrophilic capillaritis include various autoimmune diseases (including systemic lupus erythematosus [88] and Goodpasture syndrome), Henoch-Schönlein purpura (89) (a hypersensitivity vasculitis), cryoglobulinemia, acute pulmonary allograft rejection (90), and Wegener granulomatosis (only rarely is capillaritis the sole manifestation of Wegener granulomatosis). Of these, Goodpasture syndrome (antiglomerular basement membrane antibody disease) is probably the commonest cause of diffuse pulmonary hemorrhage (29,91). In addition, there is an increasing appreciation that there are many variations of immune-mediated capillaritis (86). So-called isolated pauciimmune pulmonary capillaritis is a recently described entity in which there is no obviously associated systemic disease, but, confusingly, patients may be positive for perinuclear ANCA (92,93).
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Figure 18. Pulmonary capillaritis. Photomicrograph shows intense neutrophilic infiltration within the wall (arrowheads) of a small pulmonary artery (neutrophilic vasculitis), with some extravasation of red blood cells into surrounding airspaces. (Original magnification, x400.)
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Whatever the underlying cause of pulmonary capillaritis, the resultant hemorrhagic filling of the airspaces causes widespread radiographic shadowing ranging in intensity from vague ground-glass opacity to extensive intense consolidation (29). The corresponding findings on thin-section CT images are equally nonspecific, with ground-glass opacity as the cardinal feature. There is no characteristic distribution, and the opacities may be patchy or uniform. In more fulminant and acute disease, areas of ground-glass opacity merge with denser consolidation representing complete filling of the alveoli with blood (Fig 19). In view of the nonspecificity of these CT features, it is perhaps surprising that in one study of pediatric interstitial lung disease (94), observers were able to correctly render the diagnosis of idiopathic pulmonary hemosiderosis (hemorrhage) on the basis of thin-section CT appearances alone.
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Figure 19. Transverse thin-section CT image through the lower lobes in a 31-year-old patient with Goodpasture syndrome shows combination of widespread areas of ground-glass opacity, with poorly defined nodular elements and more intense opacification within the right middle lobe (arrowheads), reflecting extravasation of blood into the airspaces.
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There is always the concern in a patient with hemoptysis and widespread ground-glass opacity and/or consolidation on CT images that there is a focal source of bleeding (eg, an inconspicuous endobronchial tumor) responsible for the widespread aspiration of blood (95–98). Thus, the diagnosis of small-vessel disease is one of exclusion, and, ultimately, histologic confirmation is required. Most individuals with a capillaritis severe enough to cause widespread ground-glass opacities on thin-section CT images will experience hemoptysis (but this is not always so [99]), such that the combination of the clinical presentation and CT appearances suggests the diagnosis of diffuse pulmonary hemorrhage. An additional pointer is the rapidity with which intraalveolar blood can be resorbed (with sometimes dramatic radiographic clearing within 48 hours), matched only by that associated with pulmonary edema; otherwise, there are no CT features to indicate hemorrhage as the cause. After repeated episodes of pulmonary hemorrhage, hemosiderin-laden macrophages may become increasingly profuse, and on thin-section CT images a faint nodular pattern may be become evident, possibly reflecting the incorporation of whorls of fibrous tissue (39). Thickening of the interlobular septa is also an occasional feature, particularly in individuals with recurrent pulmonary hemorrhage (100).
Wegener granulomatosis.—Wegener granulomatosis is a necrotizing granulomatous vasculitis that affects the upper respiratory tract, lungs, and kidneys. At least 90% of patients have pulmonary involvement, and the typical radiographic findings are of bilateral multiple opacities, some of which show cavitation, ranging from less than 1 cm to 10 cm in diameter. Other frequent findings include larger masslike lesions and wedge-shaped areas of consolidation abutting the pleura (33,87,101,102). The histologic diagnosis requires positive identification of necrotizing vasculitis, and the predominant vessels affected are the medium-sized muscular arteries, although veins are also involved (84). It is probably the necrosis and obliteration of these larger vessels that account for the radiographic appearances of pulmonary infarcts. Nevertheless, a small-vessel vasculitis sited mainly in alveolar septal capillaries and small arterioles and venules is also encountered in Wegener granulomatosis (86).
At a histologic level, capillary involvement is usually found at the edges of more typical granulomatous vasculitis, but occasion
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ABSTRACT
INTRODUCTION
