Thin-Section CT of the Secondary Pulmonary Lobule

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REVIEW Thin-Section CT of the Ⅲ Secondary Pulmonary Lobule: Anatomy and the Image— The 2004 Fleischner Lecture1 REVIEWS AND COMMENTARY W. Richard Webb, MD The secondary pulmonary lobule is a fundamental unit of lung structure, and it reproduces the lung in miniature. Airways, pulmonary arteries, veins, lymphatics, and the lung interstitium are all represented at the level of the secondary lobule. Several of these components of the secondary lobule are normally visible on thin-section computed tomographic (CT) scans of the lung. The recognition of lung abnormalities relative to the structures of the secondary lobule is fundamental to the interpretation of thin- section CT scans. Pathologic alterations in secondary lobular anatomy visible on thin-section CT scans include interlobular septal thickening and diseases with peripheral lobular distribution, centrilobular abnormalities, and panlobular abnormalities. The differential diagnosis of lobular abnormalities is based on comparisons between lobular anatomy and lung pathology.

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1 From the Department of Radiology, University of Califor- nia San Francisco, 505 Parnassus Ave, San Francisco, CA 94143-0628. Received November 19, 2004; revision re- quested January 10, 2005; revision received February 16; accepted March 9; ﬁnal review by the author March 18. Address correspondence to the author (e-mail: [email protected]).

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322 Radiology: Volume 239: Number 2—May 2006 REVIEW: Thin-Section CT of Secondary Pulmonary Lobule Webb

he secondary pulmonary lobule is size, measuring from 1 to 2.5 cm in injecting mercury and other fluids into a fundamental unit of lung struc- diameter in most locations (8,11–14). the bronchi and pulmonary vessels. He Tture, and an understanding of In one study (14), the average diameter found that “little lobes” (ie, the lobules) lobular anatomy is essential to the inter- of secondary lobules measured in sev- arose from small branches of the tra- pretation of thin-section computed to- eral adults ranged from 11 to 17 mm. chea and were separated from each mographic (CT) scans of the lung. Thin- Airways, pulmonary arteries and other by a “membrane” (Fig 3). Bron- section CT can show many features of veins, lymphatics, and the various com- chioles entering the little lobes were de- the secondary pulmonary lobule in both ponents of the pulmonary interstitium scribed as dividing into a large number normal and abnormal lungs, and many are all represented at the level of the of fine branches, which led to minute lung diseases produce characteristic ab- secondary lobule (Figs 1, 2). Each sec- “bladders” or “vesicles.” normalities of lobular anatomy (1–7). ondary lobule is supplied by a small bron- Georg Rindfleisch (in 1875) first chiole and pulmonary artery branch and used the term acinus to indicate a sub- is variably marginated in different lung lobular lung unit. He described the sec- The Secondary Pulmonary Lobule and regions by connective tissue, the interlob- ondary lobule as supplied by a bronchi- Lung Acinus ular septa, that contains pulmonary veins ole, which divided into progressively The lung is made up of numerous ana- and lymphatics (15). Secondary lobular smaller bronchiolar branches, finally tomic units smaller than a lobe or seg- anatomy is easily visible on the surface of giving rise to arborizing alveolengange ment. The secondary pulmonary lobule the lung because of these interlobular (alveolar passages), which collectively and lung acinus are widely regarded to septa (8,11). formed a “lung acinus” (Fig 4). The aci- be the most important of these subseg- The pulmonary acinus is smaller nus, according to Rindfleisch, was a mental lung units. than the secondary lobule. It is defined much more consistent unit of lung struc- The secondary pulmonary lobule, as as the portion of lung distal to a terminal ture than was the secondary lobule be- defined by Miller, refers to the smallest bronchiole (the last purely conducting cause of variation in the size of lobules. unit of lung structure marginated by airway) and is supplied by a first-order On the other hand, he regarded the sec- connective tissue septa (8,9) (Figs 1, 2). respiratory bronchiole or bronchioles ondary lobule to be more important Secondary pulmonary lobules are irreg- (16). Since respiratory bronchioles are than the acinus pathologically, in that ularly polyhedral in shape and vary in the largest airways that have alveoli in disease processes tended to be limited their walls, an acinus is the largest lung by the connective tissue septa that mar- unit in which all airways participate in ginate the lobules. Essentials gas exchange. Acini are usually de- In 1881 Rudolph Kolliker, using the Ⅲ The secondary pulmonary lobule scribed as ranging from 6 to 10 mm in lung of an executed criminal, provided a is a fundamental unit of lung diameter (14,17) (Fig 1). more detailed analysis of the finer divi- structure, and an understanding Secondary pulmonary lobules are sions of the bronchial tree and de- of lobular anatomy is essential to usually made up of a dozen or fewer scribed respiratory bronchioles as air- the interpretation of thin-section acini, although the number varies con- ways that have both bronchiolar epithe- CT of the lung. siderably in different reports (18,19). In lium and alveoli in their walls. He Ⅲ Pulmonary disease occurring pre- a study by Itoh et al (10), the number of distinguished respiratory bronchioles dominantly in relation to interlob- acini counted in lobules of varying sizes from proximal airways that do not have ular septa and the periphery of ranged from three to 24. alveoli in their walls (ie, terminal bron- lobules is termed “perilobular”; chioles) and distal airways that have nu- this distribution of disease may merous alveoli in their walls (ie, alveo- reflect abnormalities of the inter- Historical Considerations lengange, subsequently termed alveolar lobular septa or peripheral alve- Concepts regarding the importance of ducts), thus providing the basis for de- oli. the secondary pulmonary lobule, aci- fining the lung acinus relative to airway Ⅲ Centrilobular abnormalities visi- nus, and smaller lung units have evolved anatomy. ble on thin-section CT scans may during the past 300 years in conjunction 1947, in his book entitled The Lung consist of nodular opacities; the with continued progress in the under- (21), William Snow Miller reviewed tree-in-bud appearance, which standing of lung anatomy, pathology, lung anatomy in detail. His definitions of usually indicates the presence of a and physiology. An excellent perspective small-airways abnormality; in- on the sequence of events and incremen- creased visibility of centrilobular tal discoveries made during this period Published online before print structures due to thickening or has been provided by Miller (20). 10.1148/radiol.2392041968 infiltration of the surrounding in- The earliest detailed description terstitium; or abnormal low-atten- (from 1676) of the secondary pulmo- Radiology 2006; 239:322–338 uation areas related to bronchio- nary lobule was provided by Thomas Originally presented at the 34th Annual Fleischner Society lar dilatation or emphysema. Willis, who studied lung structure by Conference on Chest Disease, Orlando, Fla, May 20, 2004.

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the secondary pulmonary lobule and ac- tailed in his book entitled The Lung: which extend inward from the pleural inus are still in use today (see above). Radiologic-Pathologic Correlations (22). surface. The interlobular septa are part However, he also considered the pri- Heitzman described the radiographic of the peripheral interstitial fiber sys- mary pulmonary lobule to be a funda- appearances of various lobular abnor- tem described by Weibel (12). The pe- mental unit of lung structure. He de- malities, as carefully correlated with in- ripheral interstitium extends over the fined the primary pulmonary lobule as flated and fixed lung specimens. In the surface of the lung beneath the visceral all the alveolar ducts, alveolar sacs, and initial articles (11,15), Heitzman et al pleura and envelopes the lung in a fi- alveoli distal to the last respiratory described the appearance of septal brous sac from which the connective- bronchiole, along with their associated thickening associated with fibrosis or tissue septa penetrate the lung paren- blood vessels, nerves, and connective lymphatic and pulmonary venous abnor- chyma. Pulmonary veins and lymphatics tissues (Fig 5). However, since the term malities, as well as panlobular consoli- lie within the connective-tissue interlob- “primary pulmonary lobule” is not in dation in pulmonary infarction and ular septa (Figs 1, 2). common use today, “secondary pulmo- bronchopneumonia. In the later and Secondary pulmonary lobules in the nary lobule”, “secondary lobule”, and more detailed descriptions, Heitzman lung periphery are relatively large and “lobule” are often used interchangeably; (22) further emphasized the radio- are marginated by interlobular septa in general, they should be considered as graphic appearances of the lobular that are thicker and better defined than synonymous. “core” structures and demonstrated the lobules in other parts of the lung In 1958, Reid suggested an alternate radiographic and pathologic findings of (15,23). Peripheral lobules tend to be definition of the secondary pulmonary peribronchiolar nodules and sublobular relatively uniform in appearance, often lobule based on the branching pattern opacities, which are now generally re- having a cuboidal or pyramidal shape of peripheral bronchioles identified ferred to by using the term “centrilobu- (15). Secondary lobules in the central bronchographically rather than on the lar.” lung zone are smaller and more irregu- presence and location of connective tis- lar in shape than those in the peripheral sue septa (16,19). On bronchographic lung and are marginated by interlobular images, small bronchioles can be seen Thin-Section CT Appearances of the septa that are thinner and less well de- to arise at intervals of 5–10 mm from Secondary Lobule fined. When visible, lobules in the cen- larger airways; these small bronchioles On thin-section CT images, the second- tral lung zone may appear hexagonal or show branching at approximately 2-mm ary pulmonary lobule may be thought of polygonal in shape. It should be kept in intervals, the so-called millimeter pat- as having three primary components: mind, however, that the size, shape, tern (16). Airways that show the milli- the interlobular septa and septal struc- and appearance of secondary lobules as meter pattern were considered by Reid tures, the centrilobular region and cen- seen on thin-section CT images are to be intralobular, with each branch trilobular structures, and the lobular markedly affected by their orientation corresponding to a terminal bronchiole parenchyma. relative to the scan plane. (19). She considered lobules to be the Interlobular septa are thickest and lung units supplied by three to five of Interlobular Septa and Septal Structures most numerous in the apical, anterior, the millimeter-pattern bronchioles. Al- Secondary lobules are marginated by and lateral aspects of the upper lobes, though Reid’s criteria delineate lung the connective-tissue interlobular septa, the anterior and lateral aspects of the units of approximately equal size, about 1 cm in diameter and containing three Figure 1 to five acini, it should be understood that this definition does not necessarily Figure 1: Diagram shows anat- describe lung units equivalent to the omy and dimensions of secondary secondary lobules as defined by Miller lobule and pulmonary acinus. Two and marginated by interlobular septa secondary pulmonary lobules in (10,19). Miller’s definition is most appli- the lung periphery are illustrated, cable to the interpretation of thin-sec- with approximate dimensions of tion CT studies and is widely accepted their components indicated. by both anatomists and pathologists because interlobular septa are visible on histologic sections (10). A foundation for our current understanding of secondary lobular anatomy and its importance in radiographic interpretation was provided by Heitzman and colleagues in two articles published in 1969 (11,15) and subsequently de-

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middle lobe and lingula, the anterior thickness in a subpleural location (1,4, chiole. It represents a preterminal bron- and diaphragmatic surfaces of the lower 5,12). chiole (a general term) and gives rise, in lobes, and along the mediastinal pleural Interlobular septa in the peripheral succeeding generations of branching, to surfaces (24); thus, secondary lobules lung are at the lower limit of thin-sec- smaller preterminal bronchioles, termi- are best defined in these regions. Septa tion CT resolution (5). In healthy pa- nal bronchioles, and respiratory bron- measure about 100 ␮m (0.1 mm) in tients, a few septa are often visible in chioles. The central portion of the sec- the lung periphery, but they tend to be ondary pulmonary lobule, or the centri- inconspicuous; normal septa are most lobular region, contains the pulmonary Figure 2 often seen in areas where they are best artery and bronchiolar branches (ie, developed; namely, in the apices anteri- preterminal, terminal, and respiratory orly and along the mediastinal pleural bronchioles) that supply the lobule, as surfaces (3,25). Occasionally, when in- well as lymphatics and supporting con- terlobular septa are not clearly visible, nective tissue (1,4,5,8,12) (Figs 1, 2). It their locations can be inferred by identi- is difficult to define lobules precisely in fying septal pulmonary vein branches, relation to the bronchial or arterial approximately 0.5 mm in diameter. trees; lobules do not arise at a specific Veins can sometimes be seen as linear, branching generation or from a specific arcuate, or branching structures 1.0– type of bronchiole or artery (8). 1.5 cm from the pleural surface or sur- Branching of the lobular bronchiole rounding centrilobular arteries and ap- and artery is irregularly dichotomous proximately 5–10 mm from the arteries. (10). Most often, bronchioles and arter- Figure 2: Radiograph of 1-mm lung slice taken Pulmonary veins may also be identified ies divide into two branches of different from peripheral lower lobe. Two well-defined sec- by their pattern of branching; it is com- sizes, one branch being nearly the same ondary pulmonary lobules are visible. Lobules are mon for small veins to arise at nearly right size as the one it arose from and the marginated by thin interlobular septa (S) contain- angles to a much larger main branch. ing pulmonary vein (V) branches. Bronchioles (B) and pulmonary arteries (A) are centrilobular. (Re- Centrilobular Region and Centrilobular Figure 5 printed, with permission, from reference 10.) Structures The bronchiole supplying a pulmonary lobule is best called the “lobular” bron-

Figure 3 Figure 4

Figure 5: Secondary pulmonary lobule, as shown by Miller. Diagram shows secondary pulmonary lobule from lung periphery surrounded by connective-tissue septa and pulmonary vein branches. Also shown is airway anatomy from the level of the lobular bronchiole to lung periphery. Large circle shows approximate size of an acinus. Figure 3: Secondary pulmonary lobules ac- Smaller circle shows approximate size of a primary cording to Thomas Willis (De respirationis organis Figure 4: Secondary pulmonary lobule and pulmonary lobule as deﬁned by Miller. Pulmonary et usu. In: Opera omnia. Geneva, Switzerland, acinus as shown by Georg Rindﬂeisch. The lobular artery branches are shown as thick black struc- 1676). Drawing shows a number of secondary bronchiole is shown dividing into smaller tures. (Reprinted, with permission, from reference lobules arising from small bronchial branches. branches, which supply the acini. 21.)

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Figure 6 Figure 6: Interlobular septal thickening in pulmonary edema. Transverse thin-section CT scan shows thickened septa (small arrows) in upper lobes. Smooth thickening of interlobular septa outline a number of secondary pulmonary lobules. Visible lobules vary in size, at least partly because of the position of lobules relative to the scan plane. Pulmonary veins (large arrows) in septa are visible as small rounded dots or linear or branching opacities. Septa are well developed in the apices, and septal thickening is often well depicted in this region.

other being smaller. Thus, on thin-sec- clinical scanners. It is important to re- nar artery both measure about 0.5 mm tion CT scans, there often appears to be member that with clinical thin-section in diameter; thus, intralobular acinar a single dominant bronchiole or artery CT, intralobular bronchioles are not arteries are large enough to be seen on in the center of the lobule, with smaller normally visible, and bronchi or bron- thin-section CT scans in some healthy branches emerging at intervals along its chioles are rarely seen within 1 cm of subjects (8,12,14,17). Murata et al (5) length. the pleural surface in most locations showed that pulmonary artery branches Secondary lobules are supplied by (26,27). as small as 0.2 mm in diameter, associ- arteries and bronchioles measuring ap- The peribronchovascular intersti- ated with a respiratory bronchiole and proximately 1 mm in diameter, while tium is a system of fibers that invests thus acinar in nature, are visible at thin- intralobular terminal bronchioles and bronchi and pulmonary arteries and section CT and that they can extend to arteries measure about 0.7 mm in diam- forms a strong connective-tissue sheath within 3–5 mm of the lobular margins or eter and acinar bronchioles and arteries that surrounds these structures in the pleural surface. range from 0.3 mm to 0.5 mm in diam- perihilar lung (28). The more periph- eter (Figs 1, 2). Arteries of this size can eral continuum of this interstitial fiber be easily resolved by using thin-section system surrounds small centrilobular Thin-Section CT Diagnosis of Lobular CT (4,5). On thin-section CT scans, a bronchioles and arteries. Taken to- Abnormalities linear, branching, or dotlike opacity gether, they correspond to the “axial Pathologic alternations in secondary seen in the center of a lobule or within 1 fiber system” described by Weibel (12), lobular anatomy visible on thin-section cm of the pleural surface represents the which extends peripherally from the CT scans may be described as perilobu- intralobular artery branch or its divi- pulmonary hila to the level of the alveolar (interlobular septal thickening and sions (1,4,5). The smallest arteries re- lar ducts and sacs. peripheral lobular diseases), centrilobu- solved extend to within 3–5 mm of the lar, and panlobular. pleural surface or lobular margin and Lobular Parenchyma and Lung Acini are as small as 0.2 mm in diameter The substance of the secondary lobule, Perilobular Pattern: Interlobular Septal (1,4,5). which surrounds the centrilobular re- Thickening and Peripheral Lobular The visibility of bronchioles in gion and is contained within the inter- Abnormalities healthy subjects depends on the wall lobular septa, consists of functioning Pulmonary disease occurring predomi- thickness of the bronchiole, rather than lung parenchyma—namely, alveoli and nantly in relation to interlobular septa its diameter. For a 1-mm bronchiole the associated pulmonary capillary bed and the periphery of lobules has been supplying a secondary lobule, the wall supplied by small airways and branches called “perilobular” (29,30), although thickness measures approximately 0.15 of the pulmonary arteries, veins, and this term is not in common use. Johkoh mm; this is at the lower limit of thin- lymphatics. This parenchyma is sup- et al (30,31) emphasized that a peri- section CT resolution. The wall of a ter- ported by a connective-tissue stroma, a lobular distribution of disease may re- minal bronchiole measures only 0.1 mm fine network of very thin fibers within flect abnormalities of the interlobular in thickness, and that of an acinar bron- the alveolar septa termed the “septal septa or peripheral alveoli. chiole is only 0.05 mm, both of which fibers” by Weibel and Taylor (8,12). On Septa easily seen on thin-section CT are below the resolution of thin-section thin-section CT scans, small intralobu- scans are abnormally thickened. In the CT for a tubular structure. In one in lar vascular branches are often visible peripheral lung, thickened septa 1.0– vitro study (5), only bronchioles with a within secondary lobules, but little else 2.5 cm in length may outline part of or diameter of 2 mm or more or a wall is visible in healthy subjects. an entire lobule and are usually seen thickness of more than 100 ␮m were Lung acini are not normally visible extending to the pleural surface (Fig 6) visible at thin-section CT, and resolu- on thin-section CT scans (10). First-or- (1,3,5,25,32–35). Lobules delineated by tion is certainly less than this for most der respiratory bronchioles and the aci- thickened septa commonly contain a

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Table 1 visible dotlike or branching centrilobu- Perilobular Pattern: Differential Diagnosis lar pulmonary artery. The characteristic relationship of the interlobular septa CT Finding Differential Diagnosis and centrilobular artery or arteries is Smooth interlobular septal thickening Pulmonary edema, hemorrhage, or veno-occlusive often of value for the identification of disease; lymphangitic spread of neoplasm; each of these structures (36). lymphangiomatosis; amyloidosis; pneumonia; Thickening of interlobular septa is alveoloar proteinosis commonly seen in patients with a vari- Nodular interlobular septal thickening Lymphangitic spread of neoplasm, lymphoproliferative ety of interstitial lung diseases, and the disease (eg, lymphocytic interstitial pneumonia), presence of a few thickened septa is of sarcoidosis, silicosis and coal worker’s little diagnostic value when other CT pneumoconiosis, amyloidosis abnormalities are also visible. When Irregular interlobular septal thickening End-stage lung disease, sarcoidosis, usual interstitial septal thickening is a predominant fea- pneumonia, asbestosis, hypersensitivity pneumonitis ture of disease, its differential diagnosis Peripheral lobular abnormalities Idiopathic pulmonary fibrosis, usual interstitial is based on its appearance. Septal thick- pneumonia, organizing pneumonia ening can be seen in the presence of interstitial fluid, cellular infiltration, or fibrosis and can have a smooth, nodu- Figure 7 lar, or irregular contour in different pathologic processes (Table 1) (1,37). Figure 7: Interlobular septal thickening in lymphangitic spread smooth septal thickening of carcinoma. (a) Transverse thin- section CT scan in patient with Smooth septal thickening is usually seen right lung carcinoma shows in association with venous, lymphatic, smooth thickening of interlobular or infiltrative diseases. Specifically, it may septa (small arrows) in the right reflect pulmonary edema (Fig 6) or hemor- upper lobe. Thickening of the rhage (38–40); pulmonary veno-occlusive peribronchovascular interstitium disease (38,40,41); lymphangitic spread results in apparent increased of carcinoma (Fig 7), lymphoma, or leu- thickness of right-sided bronchi kemia (33,35,42); lymphoproliferative (large arrow). Right pleural effu- disease; lymphangiomatosis (43,44); in- sion is also present. Left lung terstitial infiltration associated with amy- appears normal. (b) Cut surface of loidosis (45); and some pneumonias. lung in a different patient with Smooth septal thickening may also be lymphangitic spread of neoplasm. seen in association with ground-glass Smooth thickening of interlobular opacity, a pattern termed “crazy paving”; septa (small arrows) and peribron- this pattern is typical of alveolar proteino- chovascular interstitium (large sis but has an extensive differential diag- arrow) are seen. (Image courtesy nosis (31,46–49). of Martha Warnock, MD, Univer- sity of California, San Francisco.) nodular septal thickening Nodular or “beaded” septal thickening (42) typically occurs in lymphatic or infiltrative diseases, including lymphangitic spread of carcinoma or lymphoma (33,35,42), lymphoproliferative disease such as lymphocytic interstitial pneumonia (50–52), sarcoidosis (53–56), silicosis or coal worker’s pneumoconiosis (anthra- cosilicosis) (57), and amyloidosis (45,58) (Fig 8). The presence of septal nodules is often associated with a so-called perilymphatic or lymphatic distribution of nodules, in which abnormalities occur primarily in relation to pulmonary lym-

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Figure 8 phatics (36,44,54,59). In addition to has been termed a peripheral lobular, septal nodules, a perilymphatic pattern or perilobular, distribution. is associated with interstitial thickening A similar peripheral lobular (peri- or nodules involving (a) the subpleural lobular) distribution of abnormalities regions, (b) the peribronchovascular in- has been reported in as many as half of terstitium in a perihilar location, and patients with organizing pneumonia (c) the centrilobular peribronchovascu- (63). These abnormalities result in a lar interstitium. This pattern is most thin-section CT appearance of arcuate typical of patients with sarcoidosis, lym- or polygonal opacities, which are less phangitic spread of carcinoma or other well defined than thickened septa. Al- neoplasms, and lymphoproliferative dis- though the histologic correlates of this ease. pattern are unclear, it is likely related to organizing pneumonia involving the dis- irregular septal thickening tal airspaces. Although interlobular septal thickening can be seen on thin-section CT scans in Centrilobular Abnormalities association with fibrosis and honey- Centrilobular abnormalities generally combing (60), it is not usually a predom- may be classified as bronchiolocentric, inant feature (34,61,62). Generally angiocentric, perilymphatic, or intersti- speaking, in the presence of substantial tial. Centrilobular abnormalities visible fibrosis and honeycombing, distortion at thin-section CT may consist of of lung architecture makes the recogni- (a) nodular opacities, (b) an appearance tion of lobules and thickened septa diffi- termed “tree-in-bud” that usually indi- cult. Among patients with pulmonary fi- cates the presence of a small-airways brosis and end-stage lung disease, the abnormality, (c) increased visibility of presence of interlobular septal thicken- centrilobular structures due to thickening on thin-section CT scans is most fre- ing or infiltration of the interstitium sur- quent in patients with sarcoidosis and is rounding them, or (d) abnormal areas less common in those with usual inter- of low attenuation related to bronchio- stitial pneumonia of various causes, as- lar dilatation or emphysema. bestosis, or hypersensitivity pneumonitis (62). The frequency of septal thick- centrilobular nodules ening and fibrosis in patients with Centrilobular nodules can reflect the sarcoidosis reflects the tendency of ac- presence of either interstitial or air- tive sarcoid granulomas to involve the space abnormalities. The histologic cor- interlobular septa. In patients who have relates reported to occur in association interstitial fibrosis, septal thickening with centrilobular nodules vary with the visible on thin-section CT scans is often disease entity (64). irregular in appearance or associated On thin-section CT scans, centri- with marked distortion of lung struc- lobular nodules usually appear to be Figure 8: Nodular thickening of interlobular tures (4). separated from the pleural surfaces, fis- septa. (a) Transverse thin-section CT scan at level sures, and interlobular septa by a dis- of right lung base in a patient with sarcoidosis peripheral lobular abnormalities tance of at least several millimeters (Fig shows interlobular septal thickening associated In patients with idiopathic pulmonary 10). In the lung periphery, the nodules with several septal nodules (arrows). (b) Histo- fibrosis or usual interstitial pneumonia are usually centered 5–10 mm from the logic specimen in patient with lymphangitic of other cause, irregular reticular opac- pleural surface, a fact that reflects their spread of tumor shows secondary pulmonary ities are often visible on thin-section CT centrilobular origin. Although centri- lobule with nodules of tumor (large arrows) in the scans; these opacities appear to repre- lobular nodules, when large, may touch interlobular septa. Tumor (small arrow) is also sent thickened interlobular septa (Fig the pleural surface, they do not appear visible in centrilobular peribronchovascular re- 9). This finding usually correlates with to arise at the pleural surface. gion. (Hematoxylin-eosin stain; original magnifi- ϫ the presence of fibrosis that predomi- Centrilobular nodules may be dense cation, 10.) (Image courtesy of Kirk Jones, MD, nantly affects the periphery of acini and and of homogeneous attenuation or of University of California, San Francisco.) the secondary lobule rather than the ground-glass opacity. They may range septa themselves (Fig 9) (44,61). None- from a few millimeters to a centimeter theless, the CT appearance is similar to in size. Either a single centrilobular nod- that of irregular septal thickening. This ule or a centrilobular rosette of nodules

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Table 2 may be visible (5,65,66). Although cen- Centrilobular Nodules: Differential Diagnosis trilobular nodules are often ill defined, this is not always the case. Because of Cause Differential Diagnosis the similar size of secondary lobules, Bronchiolar infection Endobronchial spread of tuberculosis, nontuberculous mycobacteria or centrilobular nodules often appear to be other granulomatous infection, bronchopneumonia, infectious evenly spaced. They may appear patchy bronchiolitis, cystic fibrosis or diffuse in different diseases. Bronchioloar inflammation Hypersensitivity pneumonitis, diffuse panbronchiolitis, asthma, allergic The term centrilobular nodules is bronchopulmonary aspergillosis, Langerhans cell histiocytosis, best thought of as indicating that the organizing pneumonia, bronchiolitis obliterans, respiratory nodules are seen to be related to centri- bronchiolitis in smokers, asbestosis, follicular bronchiolitis lobular structures, even if they cannot Endobronchial spread of For example, bronchioloalveoloar carcinoma be precisely localized to the centers of tumor secondary lobules. Indeed, in many Angiocentric disease Pulmonary edema, pulmonary vasculitis, talcosis, pulmonary cases, centrilobular nodules can be hemorrhage or hemosiderosis, metastatic calcification, pulmonary identified by noting their association hypertension Perilymphatic disease Sarcoidosis, silicosis and coal worker’s pneumoconiosis, lymphangitic with small pulmonary artery branches. spread of neoplasm, lymphocytic interstitial pneumonia In occasional cases, an air-filled centrilobular bronchiole can be recognized as a rounded area of low attenuation within a centrilobular nodule (Fig 11). Centrilobular nodules are most commonly seen in patients with disease that primarily affects centrilobular bronchioles and results in inflammation, infiltra- Figure 9 tion, or fibrosis of the surrounding interstitium and alveoli (Table 2) (44,64). The differential diagnosis of this appearance is long, but most diseases resulting in centrilobular nodules are associated with so-called cellular bronchiolitis, defined histologically by the presence of inflammatory cell infiltrates involving the bronchiolar wall and lumen. Infec- tious diseases associated with cellular bronchiolitis and centrilobular nodules include endobronchial spread of tuberculosis, nontuberculous mycobacteria, or other granulomatous infections (5,29,66–69); bronchopneumonia; infectious bronchiolitis (70); and cystic fibrosis. Noninfectious inflammatory diseases of bronchioles associated with cellular bronchiolitis and centrilobular nodules include hypersensitivity pneumonitis (Fig 10) (71–74), diffuse panbronchiolitis (Fig 11) (75–77), asthma and allergic bronchopulmonary aspergillosis (78), Langerhans cell histiocytosis (79), organizing pneumonia (80,81), bronchiolitis obliterans (64,82), respiratory bronchiolitis in smokers (83–86), as- Figure 9: Peripheral lobular fibrosis in idiopathic pulmonary fibrosis. (a) Transverse thin-section CT scan bestosis (87), and follicular bronchiolitis through right upper lobe in a patient with idiopathic pulmonary fibrosis shows irregular reticular opacities (88–91). Endobronchial spread of neo- (arrows). (b) Histologic specimen from open lung biopsy in a different patient with idiopathic pulmonary fi- plasm, usually bronchioloalveolar carci- brosis shows irregular fibrosis (arrows) in periphery of secondary pulmonary lobules. (Hematoxylin-eosin noma may also result in this appearance stain; original magnification, ϫ4.) in some patients (92,93).

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Figure 10 Figure 11 Angiocentric diseases are less common than bronchiolitis as a cause of centrilobular nodules. Causes include pulmonary edema (39,66,94); pulmonary vasculitis, including that related to injected substances such as talc (64,95, 96); pulmonary hemorrhage or hemosiderosis (97,98); metastatic calcification (99,100); and vascular lesions associated with pulmonary hypertension (41,101). Centrilobular nodules also can be seen in diseases associated with a perilymphatic distribution of abnormalities; these diseases include sarcoidosis, silicosis, and lymphangitic spread of tumor (Fig 8) (29,53,54). In some cases, centrilobular clusters of granulomas are a predominant feature of sarcoidosis. Small centrilobular nodules are also characteristic of both silicosis and coal worker’s pneumoconiosis (57,96); this abnormality may be considered peribronchiolar as well as perilymphatic. In patients with lymphangitic spread of carcinoma (although interlobular septal thickening is usually a predominant feature of the disease), centrilobular peribronchovascular interstitial thickening or nodules is commonly seen (64). Lym- phocytic interstitial pneumonia can result in the presence of ill-defined centrilobular opacities (50,52). Figure 11: Centrilobular nodules and abnor- tree-in-bud sign mal airways in cellular bronchiolitis. (a) Trans- verse thin-section CT scan in a patient with follicu- The tree-in-bud sign usually reflects the Figure 10: Centrilobular nodules in hypersen- lar bronchiolitis shows small ill-defined centri- presence of dilated centrilobular bronchi- sitivity pneumonitis. (a) Transverse thin-section lobular nodules. In some locations (arrows), these oles with lumina that are impacted with CT scan shows small ill-defined centrilobular are seen to surround dilated centrilobular bronchi- mucus, fluid, or pus; it is often associated nodules separated from pleural surface and fissure oles. The cause of bronchiolitis in this patient was with peribronchiolar inflammation (Fig by several millimeters. The nodules arise in rela- not determined. (b) Histologic specimen from tion to centrilobular bronchioles and appear as 12) (64,67,82,102,103). Because of the open lung biopsy in a patient with diffuse panlobular rosettes (arrows). (b) Histologic specimen branching pattern of the dilated bronchi- bronchiolitis. Small arrows outline a secondary shows ill-defined peribronchiolar and alveolar ole and the presence of ill-defined nodules lobule. Peribronchiolar infiltrates (large arrow) infiltrates (large arrows) that predominate in center of peribronchiolar inflammation, its ap- predominate in centers of several secondary lob- of a secondary lobule. Interlobular septa (small pearance has been likened to a budding ules. Centrilobular bronchioles are dilated. (He- arrows) outline parts of three lobules. (Hematoxy- or fruiting tree (67,75) or to the child’s matoxylin-eosin stain; original magnification, lin-eosin stain; original magnification, ϫ15.) toy jacks (103). The term “budding tree” ϫ10.) has also been used to describe the ap- (Image courtesy of Martha Warnock, MD, Univer- pearance of small-airways filling at bron- sity of California, San Francisco.) chography (16). On thin-section CT scans, the tree- nodules, depending on the relationship in-bud finding is usually easy to recog- ing appearance, with the most periph- of the bronchiole to the plane of the nize, but several different appearances eral branches or nodular opacities being scan. If the centrilobular bronchiole is may be seen alone or in combination. In several millimeters from the pleural sur- sectioned across its axis, as is typical in the lung periphery, the tree-in-bud sign face (Fig 12). The tree-in-bud sign may the costophrenic angles, the impacted may be associated with a typical branch- also appear as a centrilobular cluster of bronchiole may appear to be a single

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Figure 12 well-defined centrilobular nodule a few Thus, in patients with a centrilobu- millimeters in diameter. lar distribution of nodules, if the tree-in- Abnormal bronchioles producing a bud sign can be recognized the differen- tree-in-bud pattern can usually be distin- tial diagnosis is limited: endobronchial guished from normal centrilobular vessels spread of tuberculosis (67) or nontuber- by their more irregular appearance, lack culous mycobacteria (64), bronchopneu- of tapering, and knobby or bulbous ap- monia, infectious bronchiolitis (70), cys- pearance at the tips of small branches. tic fibrosis (104), bronchiectasis of any Normal centrilobular arteries are consid- cause (64,82,102), diffuse panbronchiol- erably thinner than the branching bron- itis (75,76), asthma or allergic broncho- chioles seen in patients with the tree-in- pulmonary aspergillosis (82), constrictive bud sign and are much less conspicuous. bronchiolitis (82), follicular bronchiolitis, The tree-in-bud sign is usually asso- bronchioloalveolar carcinoma, and intra- ciated with other abnormal findings vis- vascular metastases. ible on thin-section CT scans. Bronchio- The tree-in-bud sign is less frequent lar dilatation and wall thickening can in airways diseases that result in the sometimes be seen in association with accumulation of mucus within small the tree-in-bud pattern if the dilated bronchi, such as asthma or allergic bronchioles are air filled; normal bron- bronchopulmonary aspergillosis, and it chioles should not be visible in the pe- is rarely seen in patients with constric- ripheral 1 cm of lung. The tree-in-bud tive bronchiolitis, which is presumably sign may also be associated with ill-de- related to impaction of bronchioles fined centrilobular nodules representing (82). Constrictive bronchiolitis is char- areas of inflammation. Large-airways acterized histologically by the presence abnormalities with bronchial wall thick- of concentric bronchiolar fibrosis with ening or bronchiectasis are also often narrowing or obliteration of the bron- present (64). In a study by Aquino et al chiolar lumen; it is associated with the (102), 26 (96%) of 27 patients with clinical syndrome referred to as bron- thin-section CT findings of the tree-in- chiolitis obliterans. bud pattern also showed bronchiectasis An appearance resembling the tree- or bronchial wall thickening. in-bud sign has also been reported in The tree-in-bud finding is usually indic- patients with follicular bronchiolitis, an ative of small-airways disease. Further- entity in which hyperplasia of lymphoid more, a tree-in-bud appearance is associ- follicles occurs in relation to centrilobu- ated with airways infection in the majority lar airways; it is seen in association with of cases, although it may also be seen in collagen-vascular disease or acquired im- patients with mucoid impaction or bron- munodeficiency syndrome (88). Bron- chiolar wall infiltration (88). In one study chioloalveolar carcinoma may occasion- Figure 12: Tree-in-bud sign associated with (102), 19 (25.6%) of 74 patients with bron- ally show the tree-in-bud pattern, al- bronchiolar infection. (a) Transverse thin-section chiectasis and six (17.6%) of 34 patients though nodules are more typical (93). In CT scan through right lower lobe in a patient with with infectious bronchitis showed the tree- some patients with sarcoidosis, nodules airways disease and bacterial infection related to in-bud sign, but this finding was not visible that occur in relation to centrilobular acquired immunodeficiency syndrome. Multiple in patients with other diseases that involve arteries may mimic the tree-in-bud ap- impacted centrilobular bronchioles result in tree- the small airways, such as emphysema, re- pearance, although other typical fea- in-bud appearance (arrowheads). Bronchiectasis spiratory bronchiolitis, bronchiolitis obliter- tures of sarcoidosis are usually present is also present. (b) Lung slice from patient with bronchopneumonia. Impacted mucus- and pus- ans, or hypersensitivity pneumonitis. Simi- (64,82). Recently, this appearance has filled bronchioles (arrows) are visible throughout larly, in 21 (72%) of 29 patients with active also been reported in patients with in- the lung; this is the pathologic examination equiv- tuberculosis, a tree-in-bud appearance was travascular metastases involving centri- alent of the tree-in-bud sign. (Image courtesy of visible (67), and it correlated with the pres- lobular arteries (105,106). Martha Warnock, MD, University of California, ence of caseous material in terminal and San Francisco.) respiratory bronchioles. In patients with prominent (increased thickness of) diffuse panbronchiolitis, prominent branch- centrilobular structures ing centrilobular opacities represent dilated Increased visibility or increased thickness bronchioles with inflammatory bronchiolar of otherwise normal-appearing centri- wall thickening and abundant intraluminal lobular structures, usually the centrilobu- secretions (75,76). lar artery, may be seen in conditions that

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Figure 13 result in centrilobular interstitial infiltration or thickening, such as occurs in pulmonary edema, lymphangitic spread of carcinoma, amyloidosis, or diseases associated with interstitial fibrosis. This appearance is nonspecific and is usually associated with other findings of interstitial infiltration, such as interlobular septal thickening, peribronchovascular interstitial thickening, or findings of lung fibrosis. centrilobular low attenuation Abnormal areas of low attenuation usually reflect bronchiolectasis or centrilobular emphysema. Cavitary centrilobular nodules may also be seen. Figure 13: Centrilobular emphysema. (a) Transverse thin-section CT scan through left upper lobe shows a Bronchiolectasis may be seen in pa- centrilobular artery (arrows) in many of the low-attenuating areas. (b) Histologic specimen shows areas of tients with airways disease or lung fi- lung destruction surrounding a small centrilobular artery (arrow). (Hematoxylin-eosin stain; original magnifi- ϫ brosis. Since normal centrilobular bron- cation, 10.) (Image courtesy of Martha Warnock, MD, University of California, San Francisco.) chioles are not visible at thin-section CT, the recognition of air-filled airways in the lung periphery usually means that Table 3 that the airways are both dilated and thick walled (Fig 11). This may be seen Panlobular Nodules: Differential Diagnosis in airways diseases such as those that CT Finding Differential Diagnosis cause the tree-in-bud pattern, or it may represent traction bronchiolectasis in Lobular consolidation Bronchopneumonia, organizing pneumonia, eosinophilic patients with lung fibrosis. In the latter pneumonia, bronchioloalveolar carcinoma case, an abnormal reticular pattern or Lobular ground-glass opacity Bronchopneumonia, viral infection, Pneumocystis carinii other findings of fibrosis will also be vis- pneumonia, Mycoplasma pneumoniae, pulmonary edema, ible. hypersensitivity pneumonitis, alveolar proteinosis, lipoid pneumonia Centrilobular (centriacinar) em- Lobular low attenuation Mosaic perfusion due to airways or vascular disease, emphysema physema is characterized histologi- (panlobular or paraseptal) cally by areas of lung destruction oc- Headcheese sign Hypersensitivity pneumonitis, desquamative interstitial curring in relation to centriacinar pneumonia, respiratory bronchiolitis–interstitial lung disease, bronchioles and, therefore, is located sarcoidosis, atypical infections with bronchiolitis (eg, M in the center of the secondary lobule pneumoniae) or surrounding the centrilobular region. On thin-section CT scans, low- attenuation areas of emphysema are adjacent lobules appear normal, giving ized by thick and tenacious secretions often visible in the centers of lobules the lung a mosaic appearance. This may and are spread through the airways and may be seen surrounding the cen- result from (a) lobular consolidation or rather than through the pores of Kohn. trilobular artery on good-quality scans infiltration with increased attenuation of Infected secretions are typically present (Fig 13). Multiple small areas of low lobules on thin-section CT scans or in bronchi and bronchioles. Consolida- attenuation predominate in the upper (b) lobular low attenuation due to de- tion of scattered lobules also may be lobes. In most cases, the areas of low creased perfusion, air trapping, or lobu- seen with pulmonary embolism, which attenuation seen on CT scans in pa- lar destruction (Table 3). results in hemorrhage or infarction. tients with centrilobular emphysema Chronic lung diseases that result in lack a visible wall, although very thin lobular consolidation consolidation often involve the lung in a walls are occasionally visible, and are Lobular consolidation with a patchy dis- patchy fashion. Patchy consolidation can related to areas of fibrosis. tribution is typical of lobular pneumo- show a nonanatomic and nonsegmental nia, also known as bronchopneumonia. distribution but can also be panlobular on Panlobular Abnormalities Pneumonias associated with this pat- thin-section CT scans (1,29,65,67). Eo- Some lung diseases result in abnormali- tern (eg, due to infection from staphylo- sinophilic pneumonia, organizing pneu- ties that involve individual lobules or cocci, Haemophilus species, pseudo- monia, and bronchioloalveolar carcinoma groups of lobules in their entirety while monads, M pneumoniae) are character- may show this appearance.

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lobular ground-glass opacity fibrosis, or a preponderance of an air- regional differences in lung perfusion in As with consolidation, a variety of acute space filling process at the periphery of patients with airways obstruction or and chronic lung diseases may result in lobules or acini (31). pulmonary vascular obstruction (104, lobular areas of ground-glass opacity, The differential diagnosis of the cra- 119,120). Because this phenomenon is which give the lung a mosaic appear- zy-paving pattern includes diseases con- often patchy or mosaic in distribution, ance. Lobular ground-glass opacity (Fig sidered to be primarily airspace or in- with adjacent areas of lung being of dif- 14) may be seen in patients with infec- terstitial and mixed conditions (31,49). fering attenuation, it has been termed tion (eg, bronchopneumonia, viral in- These include pulmonary alveolar proteino- “mosaic perfusion” (36,59). Areas of fections, P carinii pneumonia, or M sis (46,48); pulmonary edema (39); pulmo- relatively decreased lung opacity seen at pneumoniae) (107,108), pulmonary nary hemorrhage (97); adult respiratory thin-section CT can be of varying sizes edema (39), and chronic infiltrative dis- distress syndrome (49); acute interstitial but commonly appear to correspond to eases such hypersensitivity pneumoni- pneumonia; diffuse alveolar damage; pneu- lobules. tis, alveolar proteinosis (31,48,109, monias due to infection by P carinii, virus Mosaic perfusion is most frequent in 110), and lipoid pneumonia (111–114). (eg, cytomegalovirus), Mycoplasma spe- patients with airways diseases that re- In some patients with lobular cies, bacteria, and tuberculosis; organizing sult in focal air-trapping or poor ventila- ground-glass opacity visible on thin-sec- pneumonia; chronic eosinophilic pneumo- tion of lung parenchyma (104,119,120); tion CT scans, superimposition of a re- nia; acute eosinophilic pneumonia (115); in these patients, areas of poorly venti- ticular pattern results in the crazy-pav- Churg-Strauss syndrome (116); radiation lated lung are poorly perfused because ing appearance (46). This pattern was pneumonitis (117); drug-related pneumoni- of reflex vasoconstriction or a perma- first recognized in patients with pulmo- tis; bronchioloalveolar carcinoma (118); nent reduction in the pulmonary capil- nary alveolar proteinosis (46) and is and lipoid pneumonia (114). Clearly, the lary bed. This finding is most common in quite typical of this disease; however, differential diagnosis of a crazy-paving pat- patients with bronchiolitis obliterans, the crazy-paving pattern may also be tern must be based on a consideration of cystic fibrosis, and hypersensitivity seen in patients with a variety of other clinical as well as thin-section CT findings. pneumonitis (Fig 15) (121–123). Mo- diseases (31,49). In patients with the saic perfusion has also been reported in crazy-paving pattern, ground-glass opac- lobular low attenuation due to mosaic association with pulmonary vascular ob- ity may reflect the presence of airspace or perfusion struction such as that caused by chronic interstitial abnormalities; the reticular Lung attenuation is partially determined pulmonary embolism (124–126). How- opacities may represent thickening of in- by the amount of blood present in lung ever, areas of low attenuation are often terlobular septa, thickening of the in- tissue. On thin-section CT scans, inho- larger than lobules in patients with vas- tralobular interstitium, irregular areas of mogeneous lung opacity can result from cular abnormalities. In a study of 48 consecutive patients with lobular areas Figure 14 of low attenuation visible on thin-section CT scans (127), only one had isolated vascular disease; in the remain- der, airways disease was the likely cause. When mosaic perfusion is present, pulmonary vessels in the areas of decreased opacity often appear smaller than vessels in areas of relatively high attenuation in the lung (120,126). This difference reflects disparities in regional blood flow and can be quite helpful in distinguishing mosaic perfusion from lobular ground-glass opacity, which can otherwise have a similar mosaic appearance. In patients with ground-glass opacity, vessels usually appear equal in size throughout the lung. For example, in a series of 48 patients with mosaic perfusion primarily due to airway dis- Figure 14: Transverse thin-section CT of lobular ground-glass opacity. (a) Contrast material–enhanced ease, Im et al (127) observed smaller scan shows lobular pneumonia (bronchopneumonia), with lobular areas of ground-glass opacity (arrows) in vessels in areas of low attenuation in 45 left upper lobe. Centrilobular bronchioles and arteries are visible within some lobular opacities. (b) Lobular (93.8%) patients. It must be pointed .are also present (ء) ground-glass opacity in a patient with pulmonary edema. Pleural effusions out, however, that decreased vessel size

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Figure 15 Figure 16 may be subtle and difficult to observe in some patients with mosaic perfusion. In a study by Arakawa et al (128) of patients with inhomogeneous lung opacity of various causes, only 68% of patients with airways or vascular disease were thought to show small vessels in areas of low attenuation. Expiratory thin-section CT scans may be useful in the differentiation of lobular mosaic perfusion from lobular ground-glass opacity (128). In patients with ground-glass opacity, expiratory thin-section CT typically demonstrates a proportional increase in attenuation both in areas of increased opacity and in areas of decreased opacity. In patients with mosaic perfusion resulting from airways disease or pulmonary embolism, attenuation differences are often accentuated at expiration. Relatively high-attenuation areas increase in attenuation, while regions of lower atten- Figure 15: Lobular low attenuation in hyper- uation remain low attenuating (ie, air sensitivity pneumonitis. Transverse thin-section trapping is present) (120,129–132). CT scan shows low-attenuating regions (arrows), Figure 16: Headcheese sign in hypersensitivity which reflect mosaic perfusion due to air trapping. mixed disease and the headcheese sign pneumonitis. Transverse thin section CT scan Ground-glass opacity is also present. shows lung with a geographic appearance, which In some patients, thin-section CT shows represents a combination of patchy or lobular a patchy pattern of variable lung attenu- ground-glass opacity (small arrows) and mosaic ation. This pattern represents the com- solidation is due to lung infiltration, perfusion (large arrows). bination of lobular areas of ground-glass while the presence of mosaic perfusion opacity (or consolidation), normal lung, with decreased vessel size is usually due and lobular areas of reduced lung atten- to small-airways obstruction. uation indicating mosaic perfusion. This The most common causes of this pat- eas, which often share very thin walls combination of mixed abnormalities, in- tern are hypersensitivity pneumonitis, des- that are visible on thin-section CT cluding the presence of both ground- quamative interstitial pneumonia or respi- scans. Paraseptal emphysema reflects glass opacity and mosaic perfusion, of- ratory bronchiolitis–interstitial lung dis- the presence of destruction of subpleu- ten gives the lung a geographic appear- ease, sarcoidosis, and atypical infections ral secondary lobules marginated by in- ance and has been termed the with associated bronchiolitis, such as oc- terlobular septa. “headcheese sign” (Fig 16) because of curs with M pneumoniae (107,108,133). its resemblance to the variegated ap- Each of these diseases results in infiltra- Summary pearance of a sausage made from parts tive abnormalities and may be associated of the head of a hog (133). The head- with airways abnormalities. The secondary pulmonary lobule is a cheese sign is distinguished from mosaic fundamental unit of lung structure, and perfusion alone by the presence of areas lobular low attenuation due to the recognition of abnormalities relative of increased attenuation. It can be dis- emphysema to lobular anatomy is important in the tinguished from patchy ground-glass Panlobular emphysema results in uni- diagnosis and differential diagnosis of opacity or consolidation by the presence form destruction of the secondary lob- lung abnormalities by using thin-section of air trapping. Air trapping is com- ule, but lung involvement is usually dif- CT scans. monly visible on expiratory scans in pa- fuse and thin-section CT shows an over- tients with the headcheese sign. all decrease in lung attenuation and a The headcheese sign is indicative of reduction in size of pulmonary vessels, References mixed infiltrative and obstructive dis- without focal areas of lobular low atten- 1. Webb WR. High-resolution CT of the lung ease, usually associated with bronchioli- uation being seen. Paraseptal (distal parenchyma. Radiol Clin North Am 1989; tis. In patients with this appearance, the acinar) emphysema results in the pres- 27:1085–1097. presence of ground-glass opacity or con- ence of subpleural low-attenuation ar- 2. Zerhouni EA, Naidich DP, Stitik FP, Khouri

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NF, Siegelman SS. Computed tomography 16. Reid L, Simon G. The peripheral pattern in findings and pathologic correlation. J Tho- of the pulmonary parenchyma. II. Intersti- the normal bronchogram and its relation to rac Imaging 1999;14:172–177. tial disease. J Thorac Imaging 1985;1:54– peripheral pulmonary anatomy. Thorax 31. Johkoh T, Itoh H, Mu¨ller NL, et al. Crazy- 64. 1958;13:103–109. paving appearance at thin-section CT: spec- 3. Zerhouni E. Computed tomography of the 17. Gamsu G, Thurlbeck WM, Macklem PT, trum of disease and pathologic findings. Ra- pulmonary parenchyma: an overview. Fraser RG. Peripheral bronchographic diology 1999;211:155–160. Chest 1989;95:901–907. morphology in the normal human lung. In- 32. Swensen SJ, Aughenbaugh GL, Brown LR. vest Radiol 1971;6(3):161–170. 4. Webb WR, Stein MG, Finkbeiner WE, Im High-resolution computed tomography of JG, Lynch D, Gamsu G. Normal and dis- 18. Weibel ER. High resolution computed to- the lung. 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