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Pictorial Essay: Multinodular Disease
CHEST
Chest Imaging for Clinicians
Pictorial Essay: Multinodular Disease* A High-Resolution CT Scan Diagnostic Algorithm Suhail Raoof, MD, FCCP; Alexey Amchentsev, MD; Ioannis Vlahos, MD; Ajay Goud, MD; and David P. Naidich, MD, FCCP
The evaluation of patients presenting with multinodular pulmonary disease provides an important clinical challenge for physicians. The differential diagnosis includes an extensive list of benign and malignant processes making the management of these cases frequently problematic. With the introduction of high-resolution CT (HRCT) scanning, the ability to assess various patterns of diffuse multinodular disease has evolved into an essential part of the diagnostic process. The purpose of this article is to develop an approach to the diagnosis of multinodular parenchymal disease using HRCT scan pattern recognition as a point of departure. (CHEST 2006; 129:805– 815) Key words: algorithm; multinodular; multiple nodules Abbreviations: HP ⫽ hypersensitivity pneumonitis; HRCT ⫽ high-resolution CT; ILD ⫽ interstitial lung disease; LCH ⫽ Langerhans cell histiocytosis; LIP ⫽ lymphocytic interstitial pneumonitis; RB ⫽ respiratory bronchiolitis
the purposes of this report, multinodular F ordisease will be defined in a patient in which there are too many nodules to easily count on routine CT scan studies, with most of these nodules measuring ⬍ 1 cm in diameter. While the most common cause of multiple pulmonary nodules is metastatic disease, it is apparent that this definition encompasses a wide range of lung diseases, both benign and malignant. It is our contention that use of a dedicated diagnostic algorithm1 based on characteristic high-resolution CT (HRCT) scan features coupled with clinical findings can provide either a specific *From the Division of Pulmonary and Critical Care Medicine (Drs. Raoof and Amchentsev), New York Methodist Hospital, Brooklyn, NY; the Department of Radiology (Drs. Vlahos and Naidich), Tisch Hospital, New York University Medical Center, New York, NY; and the Department of Radiology (Dr. Goud), Brigham and Women’s Hospital, Boston, MA. No financial or other potential conflicts of interest exist for any of the authors. Manuscript received January 9, 2006; revision accepted January 14, 2006. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Suhail Raoof, MD, FCCP, Chief, Pulmonary and Critical Care Medicine, Medical Director, Respiratory Therapy Department, New York Methodist Hospital, Pulmonary Division, 506 Sixth St, Brooklyn, NY 11215; e-mail: [email protected] www.chestjournal.org
diagnosis or a markedly shortened list of differential diagnoses in a majority of patients presenting with diffuse lung nodules.
Algorithm Overview Due to its ability to evaluate the lung parenchyma in cross-section, eliminating the superimposition of densities, CT scanning offers a unique opportunity to evaluate lung nodules in exquisite detail.2 This includes first the ability to assess lesions by anatomic distribution, and second by morphology.3–5 Anatomic Localization This includes the consideration of the following patterns: diffuse vs focal or clustered; central (peribronchovascular) vs peripheral (subpleural or perifissural); and upper vs lower lung distribution. Most importantly, nodules also need to be characterized by their relation to secondary lobular anatomy allowing a distinction between centrilobular nodules and those that predominantly involve the lobular periphery, including the interlobular septa3–5 (Fig 1). For example, diseases such as sarcoidosis that localize within or adjacent to lymphatics predomiCHEST / 129 / 3 / MARCH, 2006
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Figure 1. Secondary lobular anatomy. A side-by-side diagrammatic representation of two normal secondary pulmonary lobules. Secondary lobules represent fundamental anatomic units of the lung and are defined by centrilobular structures, including pulmonary arteries/arterioles and their accompanying bronchi/ bronchioles, and peripheral structures, including the pulmonary veins and lymphatics within the interlobular septae. As shown, most of these structures are ⬍ 1 mm in size and therefore, with the exception of the centrilobular arteries, lie below the resolution of even HRCT scans. Most importantly, note that centrilobular structures do not extend to the pleural or interlobular septal surfaces. As will be illustrated, knowledge of basic lobular anatomy is the key to differentiating between different etiologies of diffuse pulmonary nodules.
nate in those regions in which lymphatics are most extensive, specifically along the pleural and fissural surfaces, within the interlobular septae, and along the peribronchovascular axial interstitium (Fig 2). Diseases that are primarily hematogenous in origin, such as miliary infections or hematogenous metastases, give rise to nodules that are randomly distributed throughout the secondary lobule, with the greatest profusion in the lung bases (Fig 3). These patterns are clearly separate from nodules that result from inhalational disorders such as occur in patients with endobronchial spread of infection or hypersensitivity pneumonitis (HP), in which nodules are predominantly centrilobular in distribution, sparing the lobular periphery (Fig 4, 5). Morphologic Characterization This includes assessing a number of characteristics including whether nodules are as follows: uniform or variable in size; sharply or poorly marginated6 – 8; solid or subsolid in density (so-called ground-glass opacities) [Fig 5]5; or have a so-called tree-in-bud appearance (Fig 4).9 Additionally, nodules may either be calcified, as occurs in fungal disease, or cavitary, as is seen, for example, in patients with septic emboli, metastatic disease, or Langerhans cell histiocytosis (LCH).10 806
Figure 2. Perilymphatic disease. A diagrammatic representation of the characteristic distribution of lung nodules in patients with perilymphatic disease. Note that nodules are preferentially subpleural, peribronchovascular within the axial interstitium, or along lobular septae. While this appearance is especially characteristic of nodular sarcoidosis, less commonly a similar pattern may also be seen in patients with silicosis or coal-workers pneumoconiosis.
It should be emphasized that many of these characteristics are best evaluated on high-resolution CT scan images. With the introduction of multidetector CT scanners, it is now possible to routinely, prospectively reconstruct both thick and thin sections through the lungs after a single breathhold, provided that the initial data are acquired using appropriately thin collimation. This approach also enables the use of high-definition, multiplanar reconstructions, the use of which may be of value in further characterizing lung nodules.11
Multinodular HRCT Algorithm: A StepWise Approach The use of this algorithm begins by dividing CT scans into two broad arms based on the presence (group 1) or absence (group 2) of pleural or perifissural involvement (Table 1). Step 1 Group 1: Those cases in which a striking proportion of nodules demonstrate pleural or perifissural involvement characterize nodules as predominantly perilymphatic or lymphohematogenous in origin, constituting a separate arm of the algorithm (Table 1). The explanation for this pattern lies in the greater density of lymphatic channels seen in the interlobuChest Imaging for Clinicians
Figure 3. Random nodules. A diagrammatic representation of the characteristic distribution of randomly distributed nodules in patients with lymphohematogenous disease. Note that in distinction with patients having predominantly perilymphatic disease, random nodules may been seen adjacent to all secondary lobular structures. Some nodules may also appear to be attached to pulmonary arterial branches (so-called feeding vessels). Random nodules are most commonly due to metastatic disease, and may vary considerably in size and edge characteristics. The differential diagnosis most importantly includes miliary infection. Lymphangitic carcinomatosis, while hematogenous in origin, is easily distinguished from random metastatic nodules by the presence of characteristically thickened interlobular septae, preferentially involving the lung bases, and usually associated with asymmetric hilar adenopathy and pleural effusions.
Figure 5. Centrilobular disease. A diagrammatic representation of the distribution of diseases that predominantly affect the centrilobular portion of secondary lobules, excluding those diseases that result in predominantly mucoid impaction due to infected secretions. The most common cause of diffuse centrilobular disease is subacute HP. This characteristically results in poorly defined, poorly marginated ground-glass opacities. Similar to tree-in-bud opacities, these rarely involve the pleural or fissural surfaces. While a number of different entities may result in predominantly centrilobular opacities, the differential diagnosis most often includes RB/RB-ILD. In distinction with subacute HP, RB in particular is less extensive, typically upper lobe in distribution, and almost always occurs in smokers.
lar septa and subpleural regions, including along the fissures. Step 2 Once nodules are characterized as predominantly perilymphatic or lymphohematogenous in origin, further assessment requires determining whether or not nodules are distributed diffusely or are patchy or clustered, with particular attention paid to the presence or absence of the extent of axial interstitial involvement. It is recalled that the axial interstitium envelops the main pulmonary vessels and bronchi extending from the hilum outward toward the lung periphery.12 Step 3
Figure 4. Bronchiolar disease. A diagrammatic representation of the typical appearance of bronchiolar inflammation resulting in so-called tree-in-bud opacities. These characteristically result in clusters of ill-defined nodules “attached” to adjacent branching or tubular structures due to extensive bronchiolar mucoid impaction. Most importantly, note that, unlike the situation in patients with either perilymphatic disease or random nodules, mucoid impacted bronchioles do not extend to the pleural, fissural, or septal surface. This pattern is nearly always due to infected secretions resulting from virtually any cause of acute or subacute bronchiolar infection. www.chestjournal.org
If nodules prove to be clustered in a predominantly subpleural/axial distribution, they are deemed to be perilymphatic in distribution (Fig 2). In this category, the main disease to be considered is sarcoidosis (Fig 6, 7).2,13,14 This diagnosis is further suggested by nodules that are typically ill-defined, frequently measuring only a few millimeters in size. Clusters of these nodules often have a “grainy” appearance and when sufficiently profuse may result in an appearance of poorly defined nodules or masses on corresponding chest radiographs (soCHEST / 129 / 3 / MARCH, 2006
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Table 1—HRCT Algorithm for Multinodular Disease*
* CWP ⫽ coal workers pneumoconiosis; MAI ⫽ M avium intracellulare; MTB ⫽ M tuberculosis; PMF ⫽ progressive massive fibrosis.
called alveolar sarcoid). When coalescent, these may simulate progressive massive fibrosis. Ancillary findings include a predominant upper lobe distribution, focal air-trapping due to bronchiolar obstruction, and diffuse adenopathy, often calcified. Calcified nodules may also be present in later stages of the disease.
The most important differential diagnoses for this pattern of disease are silicosis and coal worker pneumoconiosis.15,16 In both of these occupational diseases, perilymphatic nodules are the primary abnormality, typically involving the mid and upper lung fields. While these entities may simulate the appearance of sarcoidosis, they are usually easily diagnosed when correlated with clinical history.15 This includes other rare occupational lung disease, for example, siderosis, that may also simulate the appearance of sarcoidosis.17 While lymphangitic carcinomatosis may result in perilymphatic nodules, in fact, CT scan findings are most often characterized by markedly thickened nodular interlobular septae usually asymmetrically involving the lower lobes and usually associated with adenopathy and effusions.18 Nodules, when present, tend more often to be well-defined and are often associated with discrete feeding vessels, further identifying them as hematogenous in origin. Lymphangitic carcinomatosis rarely mimics findings that are characteristic of sarcoidosis. Step 4
Figure 6. Perilymphatic disease: sarcoidosis. An HRCT scan of a 1-mm section at the level of the carina shows innumerable ill-defined small nodules clustered in the mid-portions of both lungs with relative sparing of the anterior aspects of both upper lobes. Note that these preferentially involve the left major fissure (arrow on left lung) as well as the walls of the peripheral airways (curved arrow on right lung). 808
If nodules prove to be diffuse instead of clustered, they are properly considered to be random in distribution (Table 1). By definition, true random distribution will lead to nodules being identified along pleural and fissural surfaces as well as along the axial Chest Imaging for Clinicians
Figure 7. Perilymphatic disease: sarcoidosis. An HRCT scan of a 1-mm section through the right mid-lung in a different patient than the one in Figure 6 shows evidence of innumerable ill-defined small nodules. Note that these tend to be clustered with relative sparing of the right upper lobe anteriorly and clearly preferentially lie adjacent to the right major fissure (arrow), along pleural surfaces, and along central vascular structures (arrowheads). This distribution of nodules is rarely seen in any other disease.
interstitium. However, in distinction from primarily perilymphatic disease, random nodules may also be identified in even greater numbers when dispersed randomly throughout the lungs. Included in this category most importantly are hematogenous metastases.19 Unlike nodules in patients with sarcoidosis, metastatic nodules tend to be smooth, well-defined lesions (Fig 8, 9).8 However, a wide variety of morphologic appearances has been noted. In a study20 comparing the HRCT scan features of pulmonary metastatic lesions with autopsy findings, while nodules most often proved to have well-defined margins (38% of cases), nodules with well-defined irregular margins, poorly defined smooth margins, and poorly defined irregular margins could be identified in 16%, 16%, and 30% of cases, respectively. While nodules range from a few www.chestjournal.org
millimeters to ⬎ 1 cm, they are frequently similar in size. A basilar predominance is typically noted due to preferential blood flow to the lung bases. Individual nodules may have “feeding vessels” consistent with their hematogenous origin. On HRCT scans, a connection between nodules and the adjacent pulmonary vessels (ie, the mass-vessel sign) may be seen in approximately 75% of cases.21 Nodules may also be either cavitary or surrounded by a “halo” of groundglass attenuation, which is typical of hemorrhagic metastases such as those due to choriocarcinoma.22 Features of lymphangitic cancer may also be present, which again is consistent with a hematogenous origin of disease.19 It should be noted that the reported incidence of malignant disease as a cause of multiple pulmonary nodules has been shown to vary greatly, from as low as 10% to as high as 58% in some surgical series.23 In 133 patients with a known malignancy who underwent video-assisted thoracoscopy for multiple pulmonary nodules, 64% proved to have at least one malignant nodule.24 A number of malignancies can result in a miliary pattern, rendering differential diagnosis more problematic. This includes tumors, such as renal cell carcinoma, head and neck cancers, and testicular tumors, that have their primary venous drainage in the lungs.25 The differential diagnosis includes a number of additional entities that result in random nodules. The most important of these is miliary infection (Fig 10).26,27 In fact, while differentiation between miliary infection and a miliary tumor may be impossible to determine by imaging features alone, in general, close correlation with the clinical history renders these diagnoses relatively straightforward. Miliary metastases are frequently due to metastatic thyroid cancer, renal cancer, and melanoma, among other cancers, while larger less profuse metastases tend to be adenocarcinomas in adults, typically originating from the lung, breast, or the GI tract.19,28 Less commonly, diffuse nodules may be identified in patients with septic emboli, invasive fungal infections, and pulmonary vasculitides.29 These entities frequently result in cavitary nodules, some with a distinct “halo” of ground-glass attenuation,22 and have even been described in patients with organizing pneumonia.30 Despite similarities between these entities and routine metastatic disease, it should be emphasized that the numbers of nodules identified in these cases usually fail to meet the criterion of “too many nodules to count,” with the differential diagnosis again further aided by close clinical correlation. Step 5 Group 2: In distinction with the patterns described in patients in group 1, group 2 includes those CHEST / 129 / 3 / MARCH, 2006
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Figure 8. Random nodules: hematogenous metastases. An HRCT scan of a 1-mm section through the lower lobes shows innumerable sharply defined nodules throughout both lungs. Note that while many of these lie along pleural and fissural surfaces, or less commonly appear related to adjacent vessels (arrows), most are unattached to adjacent structures. When sufficiently well defined and generally uniform in size, this pattern of diffuse nodularity is easily separable from that resulting from perilymphatic disease.
patients in whom no or very few nodules are perifissural or subpleural in distribution. Anatomically, these nodules are grouped together as being centrilobular in distribution.4 By definition, these entities primarily involve centrilobular bronchioles and/or their accompanying pulmonary artery branches. Anatomically, these structures taper peripherally, stopping 5 to 10 mm short of the pleural or interlobular septal surfaces and consequently fail to involve pleural and fissural surfaces (Table 1). As will be discussed, these nodules typically fall into the following two broad categories: those with a “tree-in-bud” configuration; and those that appear as amorphous “ground-glass” nodules. Step 6 Once nodules are characterized as being primarily centrilobular in distribution, further assessment requires determining whether or not these have a tree-in-bud configuration. Tree-in-bud opacities are characterized by the appearance of centrilobular micronodular branching structures that end several millimeters distant from nearby pleural or fissural surfaces (Fig 11).31 Tree-in-bud opacities are nearly always the result 810
of inspissated (ie, frequently aspirated) secretions lodged within centrilobular bronchioles, accounting for a branching configuration when coursing parallel to the CT scan plane.9,32,33 Normal bronchioles, which have a diameter of ⬍ 1 mm and a wall thickness of ⬍ 0.1 mm, are below the limit of HRCT scan spatial resolution.34 The presence of inspissated secretions results in bronchiolar distension and increased density, allowing their direct visualization. Not surprisingly, in many cases there is also evidence of coexisting bronchiectasis. Another frequently encountered finding in patients with bronchiolar disease is so-called mosaic attenuation.33 In these cases, bronchiolar occlusion results in air-trapping, hypoxia of the poorly ventilated lung units with resultant reflex vasoconstriction and air-trapping. This combination of findings causes decreased attenuation of the affected areas of the lung with blood flow redistributed to normal lung. The hypoattenuated diseased lung is therefore surrounded by hyperattenuated, overperfused normal lung, resulting in heterogeneous-appearing mosaic attenuation. While classically described in patients with an endobronchial spread of tuberculosis, in fact, treein-bud opacities can be identified in virtually any Chest Imaging for Clinicians
Figure 9. Random nodules: metastatic thyroid cancer. An HRCT scan of a 1-mm section through the mid-thorax shows innumerable small nodules. Note that, in addition to unattached nodules, many of these lie along both the minor and right major fissures (arrows), as well as along the proximal middle lobe pulmonary artery (arrowheads). Although there are fewer nodules than shown in Figure 8, in the appropriate clinical stetting this pattern is again consistent with metastatic disease.
type of infectious bronchiolitis. This includes Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, bacterial, viral, and fungal infections, and allergic bronchopulmonary mycosis. This pattern is also frequently encountered in patients with AIDS in whom recurrent episodes of bronchial infection are frequent.35 Differential diagnosis also includes follicular bronchiolitis, an entity that is characterized by the presence of hyperplastic lymphoid follicles and germinal centers occurring along the bronchovascular bundles.36 Most often, infectious bronchiolitis results in clusters of tree-in-bud opacities. When they are widespread and diffuse, the differential diagnosis includes “Asiatic panbronchiolitis.”37,38 This entity has a well-established predilection in Japanese, Chinese, and Korean populations, appears to show a genetic predisposition, and is usually seen in association with chronic sinusitis. Diffuse tree-in-bud opacities are also frequently encountered in patients with cystic fibrosis and viral bronchiolitis. It cannot be overemphasized that in the vast majority of cases the finding of tree-in-bud opacities should be taken as being indicative of bronchiolar infection. While tree-in-bud opacities have been described39 as occurring in patients with pulmonary vascular tumor emboli, in our experience this entity www.chestjournal.org
is exceedingly rare. As noted in one retrospective study9 of 141 patients with a variety of airway diseases, including bronchiolitis obliterans, bronchiolitis obliterans-organizing pneumonia, HP, respiratory bronchiolitis (RB), and pneumonia, among others, the finding of tree-in-bud opacities was identified in association only with pneumonia and/or bronchiectasis in 17% and 25% of cases, respectively. Even in patients with panbronchiolitis, while no consistent infectious agent has been associated with this disease, interestingly, most individuals respond, at least initially, to low-dose erythromycin therapy.38,40 Some authors41 have suggested that the therapeutic efficacy of macrolide agents may emanate from their inhibition of proinflammatory cytokines, and from mucus and water secretion from airway epithelial cells. Step 7 Those cases in which centrilobular nodules are present in patients in the absence of tree-in-bud opacities constitute the last part of this CT scan algorithm (Table 1). Included in this category are a variety of diseases or “mixed” entities that have in common localization to the centrilobular portion of the secondary lobule. This includes diseases that CHEST / 129 / 3 / MARCH, 2006
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Figure 10. Random nodules: miliary tuberculosis. A magnified HRCT scan image through the right upper lobe shows innumerable tiny nodules throughout the lungs extensively involving the pleural surfaces (black arrowheads) and along bronchovascular structures (arrows). Numerous unattached nodules are also identifiable. This pattern is typical of a random, miliary distribution. While typically resulting from either metastatic disease or infection, clinical correlation is usually diagnostic. Case courtesy of Nestor Muller, MD, Vancouver, BC, Canada.
primarily affect the centrilobular bronchiole, as well as those that are either primarily peribronchiolar or perivascular in origin.2,4,5 Most often, this group of diseases results in a pattern of diffuse, poorly defined ground-glass nodules, which are typically the result of a primarily peribronchiolar distribution. The classic example of this appearance is subacute HP (Fig 12).42,43 This diagnosis is frequently first suggested on the basis of CT scan findings and is usually established by a combination of exposure history, clinical symptoms of a flu-like illness, the presence of specific serum antibodies when those data are available, increased numbers of lymphocytes and neutrophils in BAL fluid, and, when feasible, clinically significant improvement in symptoms when the patient is removed from the offending environmental agent.44 812
Figure 11. Bronchiolar disease: infectious bronchiolitis. A magnified HRCT scan image through the middle and lower lobes shows numerous nodules associated with linear/branching densities throughout the lungs (arrows). These tree-in-bud opacities are the result of infected mucoid impacted peripheral airways and hence have a distinctly centrilobular pattern of distribution. Note that none of these peripherally is in contact with either pleural or fissural surfaces. Classically the result of the endobronchial spread of tuberculosis, this pattern may be seen in virtually any patient in whom there is infection of the peripheral airways. Not surprisingly, tree-in-bud opacities tend to be clustered rather than truly diffuse and frequently are associated with CT scan evidence of bronchiectasis.
The differential diagnosis encompasses a number of important disease entities, most importantly including RB, lymphocytic interstitial pneumonitis (LIP), and LCH. RB/RB-interstitial lung disease (ILD) are smoking-related disorders that may also result in poorly defined centrilobular nodules.45,46 RB typically results in far fewer ground-glass nodules than the number in patients with subacute HP and generally display a distinctly upper lobe predominance. RB-ILD is associated with widespread ground-glass attenuation and reticular opacities, which are findings that are not seen in patients with subacute HP.45,46 Also included in the differential diagnosis of individuals with diffuse centilobular nodules are diseases related to bronchiolar lymphatics. This includes muChest Imaging for Clinicians
in particular, the presence of randomly distributed thin-walled cysts.47 Poorly defined centrilobular nodules may also be seen early in the course of LCH.49,50 However, these most often are associated with characteristic bizarrely shaped, thick walled cysts, some of which represent cavitary nodules with characteristic sparing of the lung bases.51
Conclusion
Figure 12. Centrilobular disease: subacute HP. A magnified HRCT scan section through the right upper lobe shows innumerable poorly defined, hazy ground-glass nodules throughout the lung (arrows). In addition to a uniform distribution, none of these nodules lies adjacent to the visualized pleural surfaces. Note as well the lack of any tree-in-bud opacities that would suggest the presence of mucoid impacted airways (compare with Fig 11). Few entities besides subacute HP result in this pattern of ill-defined nodules. Differential diagnoses includes RB, typically causing fewer nodules restricted to the upper lobes in known smokers, and LIP, which is usually associated with either Sjogren syndrome or AIDS.
cosa-associated lymphoid tissue lymphoma (maltomas) and, in particular, LIP. LIP is most often seen in patients with underlying immunologic abnormalities, especially Sjo¨gren syndrome and AIDS, and is characterized histologically by diffuse hyperplasia of bronchus-associated lymphatic tissue, resulting in a diffuse, polyclonal lymphoid cell infiltrate surrounding the airways and expanding the lung interstitium.47,48 As reported by Johkoh et al,48 in a study of 22 patients with documented LIP, while subpleural nodules could be identified in 86% of cases, likely reflecting subpleural lymphatic involvement, poorly defined centrilobular nodules could be seen in 100% of cases. Additional imaging features include the presence of thickened bronchovascular bundles and, www.chestjournal.org
The finding of multiple lung nodules is a characteristic that encompasses a number of disparate parenchymal diseases. Although inexact, the use of anatomic and morphologic features to characterize nodules based on HRCT scan findings may help to simplify the differential diagnosis. Most importantly, the use of this imaging algorithm can prove to be an aid in standardizing the clinical approach to differential diagnosis. In a study reported by Gruden et al,4 four experienced chest radiologists independently evaluated HRCT scan images in 58 patients with diffuse nodular disease. In each case, observers were asked to place nodules in one of the following four possible anatomic locations or categories: perilymphatic; random; associated with small airways disease (ie, cases in which the primary abnormality was tree-in-bud opacities); or centrilobular disease. There was agreement among all four observers in 79% of cases, while three of four observers agreed on an additional 17%. Observers were correct (based on subsequent histologic/clinical correlation) in 218 of 232 localizations (94%) in the 58 cases. These data suggest that this algorithm, which has been elaborated on in the present report, represents a reproducible method for categorizing patients with diffuse pulmonary nodules. It should also be noted that, in individual cases, HRCT scan findings may be sufficiently characteristic, especially when coupled with close clinical correlation, to obviate the need to perform a biopsy. Patients with classic HRCT scan findings of sarcoidosis, as well as those with subacute HP for which biopsy confirmation may not be required, should be included in this category. In patients with a known history of smoking, the finding of scattered, tiny, ill-defined centrilobular upper lobe nodules is sufficiently characteristic to warrant a clinical diagnosis of RB, obviating the need for more invasive diagnostic procedures, while the finding of scattered centrilobular opacities associated with bizarrely shaped cysts predominantly involving the upper lobes sparing the lung bases is characteristic of LCH. Similarly, the finding of characteristic tree-in-bud opacities in the appropriate clinical setting may be taken as diagnostic of small airway-bronchiolar infection. In CHEST / 129 / 3 / MARCH, 2006
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distinction, the appearance of diffuse, poorly defined centrilobular nodules in the absence of a clinical history of established antigen exposure, infection, or a history of smoking generally requires open-lung biopsy for definitive evaluation. Given the wide diversity of potential causes for this appearance, the use of an HRCT scan algorithm should be considered an important, if not fundamental, component of clinical assessment in these cases.
References 1 Webb WR, Muller NL, Naidich DP. 3rd ed. Philadelphia, PA: Lippincott, Williams and Wilkins, 2001 2 Colby TV, Swensen SJ. Anatomic distribution and histopathologic patterns in diffuse lung disease: correlation with HRCT. J Thorac Imaging 1996; 11:1–26 3 Bergin C, Roggli V, Coblentz C, et al. Secondary pulmonary lobule: normal and abnormal CT appearance. AJR Am J Roentgenol 1988; 151:21–25 4 Gruden JF, Webb WR, Warnock M. Centrilobular opacities on HRCT: diagnosis and differential diagnosis with pathologic correlation. AJR Am J Roentgenol 1994; 162:569 –574 5 Murata K, Itoh H, Todo G, et al. Centrilobular lesions of the lung: demonstration by high resolution CT and pathologic correlation. Radiology 1986; 161:641– 645 6 Muller NL, Kullnig P, Miller RR. The CT findings of pulmonary sarcoidosis: analysis of 25 patients. AJR Am J Roentgenol 1989; 152:1179 –1182 7 Lee KS, Song KS, Lim TH, et al. Adult onset of pulmonary tuberculosis: findings on chest radiographs and CT scans. AJR Am J Roentgenol 1993; 160:753–758 8 Hirikata K, Nakata H, Haratake J. Appearance of pulmonary metastases on high-resolution CT scans: comparison with histopathologic findings from autopsy specimens. AJR Am J Roentgenol 1993; 161:37– 43 9 Aquino SL, Gamsu G, Webb WR, et al. Tree-in-bud pattern: frequency and significance on thin-section CT. J Comput Assist Tomogr 1996; 20:594 –599 10 Moore AD, Godwin JD, Muller NL, et al. Pulmonary histiocytosis X: comparison of radiographic and CT findings. Radiology 1989; 172:249 –254 11 Revel M-P, Lefort C, Bissery A, et al. Pulmonary nodules: preliminary experience with three-dimensional evaluation. Radiology 2004; 231:459 – 466 12 Weibel ER, Taylor CR. Design and structure of the human lung. In: Weibel ER, Taylor CR, eds. Pulmonary diseases and disorders. New York, NY: McGraw-Hill, 1988; 11– 60 13 Brauner MW, Grenier P, Mompoint D, et al. Pulmonary sarcoidosis: evaluation with high-resolution CT. Radiology 1989; 172:467– 471 14 Nishimura K, Itoh H, Kitaichi M, et al. Pulmonary sarcoidosis: correlation of CT and histopathologic findings. Radiology 1993; 172:467– 471 15 Remy-Jardin M, Remy J, Farre L, et al. Computed tomographic evaluation of silicosis and coal worker’s pneumoconiosis. Radiol Clin North Am 1992; 30:115–1176 16 Ooi GC, Tsang KWT, Cheung TF, et al. Silicosis in 76 men: qualitative and quantitative CT evaluation- clinical-radiologic correlation study. Radiology 2003; 228:816 – 825 17 Kim KI, Kim CW, Lee MK, et al. Imaging of occupational lung disease. Radiographics 2001; 21:1371–1391 18 Johkoh T, Icfhikado Kea J, Tomiyama N, et al. CT findings in lymphangitic carcinomatosis of the lung: correlation with 814
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histologic findings and pulmonary function tests. AJR Am J Roentgenol 1992; 158:1217–1222 Aquino SL. Imaging of metastatic disease to the thorax. Radiol Clin North Am 2005; 43:481– 495 Hirakata K, Nakata H, Haratake J. Appearance of pulmonary metastases on high-resolution CT scans: comparison with histopathologic findings from autopsy specimens. AJR Am J Roentgenol 1993; 161:37– 43 Milne ENC, Zerhouni EA. Blood supply of pulmonary metastases. J Thorac Imaging 1987; 2:15–23 Gaeta M, Blandino A, Scribano E, et al. Computed tomography halo sign of pulmonary nodules: frequency and diagnostic value. J Thorac Imaging 1999; 14:109 –113 Benjamin MS, Drucker EA, McLoud T, et al. Small pulmonary nodules: detection at chest CT and outcome. Radiology 2003; 226:489 – 493 Ginsberg MS, Griff SK, Go BD, et al. Pulmonary nodules resected at video-assisted thorascopic surgery: etiology in 426 patients. Radiology 1999; 213:277–282 Patz EF, Fidler J, Knelson M, et al. Significance of percutaneous needle biopsy in patients with multiple pulmonary nodules and a single known primary malignancy. Chest 1995; 107:601– 604 Muller NL, Fraser RS, Lee KS, et al. Pulmonary infection. In: Diseases of the lung. Philadelphia, PA: Lippincott, Williams and Wilkins, 2003; 17–75 McGuinness G, Naidich DP, Jagardar J, et al. High resolution CT findings in miliary lung disease. J Comput Assist Tomogr 1992; 16:384 –390 Seo JB, Im J-G, Goo JM, et al. Atypical pulmonary metastases: spectrum of radiologic findings. Radiographics 2001; 21:403– 417 Silva CIS, Muller NL, Fujimoto K, et al. Churg-Strauss syndrome: high resolution CT and pathologic findings. J Thorac Imaging 2005; 20:74 – 80 Haro M, Vizcaya M, Texido A, et al. Idiopathic bronchiolitis obliterans organizing pneumonia with multiple cavitary nodules. Eur Respir J 1995; 8:1975–1977 Collins J, Blankenbaker D, Stern EJ. CT patterns of bronchiolar disease: what is “tree-in-bud”? AJR Am J Roentgenol 1998; 171:365–370 Colby TV. Bronchiolitis: pathologic considerations. Am J Clin Pathol 1998; 109:101–109 Hartman TE, Primack SL, Lee KS, et al. CT of bronchial and bronchiolar disease. Radiographics 1994; 14:991–1003 Webb WR, Muller NL, Naidich DP. Normal lung anatomy. In: High-resolution CT of the lung. Philadelphia, PA: Lippincott, Williams and Wilkins, 2001; 49 –70 McGuinness G, Gruden JF, Bhalla M, et al. AIDS-related airways disease. AJR Am J Roentgenol 1997; 168:67–77 Ryu JH, Myers JH, Swensen SJ. Bronchiolar disorders: state of the art. Am J Respir Crit Care Med 2003; 168:1277–1292 Akira M, Kitatani F, Lee YS, et al. Diffuse panbronchiolitis: evaluation with high resolution CT. Radiology 1988; 168:433– 438 Nishimura K, Kitaichi M, Izumi T, et al. Diffuse panbronchiolitis: correlation of high resolution CT and pathologic findings. Radiology 1992; 184:779 –785 Shepard JO, Moore EH, Templeton PA, et al. Pulmonary vascular tumor emboli: dilated and beaded peripheral pulmonary arteries at CT. Radiology 1993; 187:797– 801 Kudoh S. Erythromycin treatment in diffuse panbronchiolitis. Curr Opin Pulm Med 1998; 4:116 –121 Baz MA, Kussin PS, Van Trigt P, et al. Recurrence of diffuse panbronchiolitis after lung transplantation. Am J Respir Crit Care Med 1995; 151:895– 898 Lynch DA, Rose CS, Way D, et al. Hypersensitivity pneumoChest Imaging for Clinicians
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nitis: sensitivity of high resolution CT in a population-based study. AJR Am J Roentgenol 1992; 159:469 – 472 Hansell DM, Wells AU, Padley SP, et al. Hypersensitivity pneumonitis: correlation of individual CT patterns with functional abnormalities. Radiology 1996; 199:123–128 Selman M. Hypersensitivity pneumonitis: a multifaceted deceiving disorder. Clin Chest Med 2004; 25:531–547 Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc 1989; 64:1373–1380 Heyneman LE, Ward S, Lynch DA, et al. Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial pneumonia: different entities or part of the spectrum of the same disease? AJR Am J Roentgenol 1999; 173:1617–1622
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47 Honda O, Johkoh T, Icfhikado K, et al. Differential diagnosis of lymphocytic interstitial pneumonia and malignant lymphoma on high-resolution CT. AJR Am J Roentgenol 1999; 173:71–74 48 Johkoh T, Muller NL, Pickford HA, et al. Lymphocytic interstitial pneumonia: thin section CT findings in 22 patients. Radiology 1999; 212:567–572 49 Brauner MW, Grenier P, Mouelhi MM, et al. Pulmonary histiocytosis X: evaluation with high-resolution CT. Radiology 1989; 172:255–258 50 Kulwiec EL, Lynch DA, Aguayo SM, et al. Imaging of pulmonary histiocytosis X. Radiographics 1992; 12:515–526 51 Howarth DM, Gilchrist GS, Mullan BP, et al. Langerhans cell histiocytosis: natural history, management, and outcome. Cancer 1999; 85:2278 –2290
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Pictorial Essay: Multinodular Disease* A High-Resolution CT Scan Diagnostic Algorithm Suhail Raoof, MD, FCCP; Alexey Amchentsev, MD; Ioannis Vlahos, MD; Ajay Goud, MD; and David P. Naidich, MD, FCCP
The evaluation of patients presenting with multinodular pulmonary disease provides an important clinical challenge for physicians. The differential diagnosis includes an extensive list of benign and malignant processes making the management of these cases frequently problematic. With the introduction of high-resolution CT (HRCT) scanning, the ability to assess various patterns of diffuse multinodular disease has evolved into an essential part of the diagnostic process. The purpose of this article is to develop an approach to the diagnosis of multinodular parenchymal disease using HRCT scan pattern recognition as a point of departure. (CHEST 2006; 129:805– 815) Key words: algorithm; multinodular; multiple nodules Abbreviations: HP ⫽ hypersensitivity pneumonitis; HRCT ⫽ high-resolution CT; ILD ⫽ interstitial lung disease; LCH ⫽ Langerhans cell histiocytosis; LIP ⫽ lymphocytic interstitial pneumonitis; RB ⫽ respiratory bronchiolitis
the purposes of this report, multinodular F ordisease will be defined in a patient in which there are too many nodules to easily count on routine CT scan studies, with most of these nodules measuring ⬍ 1 cm in diameter. While the most common cause of multiple pulmonary nodules is metastatic disease, it is apparent that this definition encompasses a wide range of lung diseases, both benign and malignant. It is our contention that use of a dedicated diagnostic algorithm1 based on characteristic high-resolution CT (HRCT) scan features coupled with clinical findings can provide either a specific *From the Division of Pulmonary and Critical Care Medicine (Drs. Raoof and Amchentsev), New York Methodist Hospital, Brooklyn, NY; the Department of Radiology (Drs. Vlahos and Naidich), Tisch Hospital, New York University Medical Center, New York, NY; and the Department of Radiology (Dr. Goud), Brigham and Women’s Hospital, Boston, MA. No financial or other potential conflicts of interest exist for any of the authors. Manuscript received January 9, 2006; revision accepted January 14, 2006. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Suhail Raoof, MD, FCCP, Chief, Pulmonary and Critical Care Medicine, Medical Director, Respiratory Therapy Department, New York Methodist Hospital, Pulmonary Division, 506 Sixth St, Brooklyn, NY 11215; e-mail: [email protected] www.chestjournal.org
diagnosis or a markedly shortened list of differential diagnoses in a majority of patients presenting with diffuse lung nodules.
Algorithm Overview Due to its ability to evaluate the lung parenchyma in cross-section, eliminating the superimposition of densities, CT scanning offers a unique opportunity to evaluate lung nodules in exquisite detail.2 This includes first the ability to assess lesions by anatomic distribution, and second by morphology.3–5 Anatomic Localization This includes the consideration of the following patterns: diffuse vs focal or clustered; central (peribronchovascular) vs peripheral (subpleural or perifissural); and upper vs lower lung distribution. Most importantly, nodules also need to be characterized by their relation to secondary lobular anatomy allowing a distinction between centrilobular nodules and those that predominantly involve the lobular periphery, including the interlobular septa3–5 (Fig 1). For example, diseases such as sarcoidosis that localize within or adjacent to lymphatics predomiCHEST / 129 / 3 / MARCH, 2006
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Figure 1. Secondary lobular anatomy. A side-by-side diagrammatic representation of two normal secondary pulmonary lobules. Secondary lobules represent fundamental anatomic units of the lung and are defined by centrilobular structures, including pulmonary arteries/arterioles and their accompanying bronchi/ bronchioles, and peripheral structures, including the pulmonary veins and lymphatics within the interlobular septae. As shown, most of these structures are ⬍ 1 mm in size and therefore, with the exception of the centrilobular arteries, lie below the resolution of even HRCT scans. Most importantly, note that centrilobular structures do not extend to the pleural or interlobular septal surfaces. As will be illustrated, knowledge of basic lobular anatomy is the key to differentiating between different etiologies of diffuse pulmonary nodules.
nate in those regions in which lymphatics are most extensive, specifically along the pleural and fissural surfaces, within the interlobular septae, and along the peribronchovascular axial interstitium (Fig 2). Diseases that are primarily hematogenous in origin, such as miliary infections or hematogenous metastases, give rise to nodules that are randomly distributed throughout the secondary lobule, with the greatest profusion in the lung bases (Fig 3). These patterns are clearly separate from nodules that result from inhalational disorders such as occur in patients with endobronchial spread of infection or hypersensitivity pneumonitis (HP), in which nodules are predominantly centrilobular in distribution, sparing the lobular periphery (Fig 4, 5). Morphologic Characterization This includes assessing a number of characteristics including whether nodules are as follows: uniform or variable in size; sharply or poorly marginated6 – 8; solid or subsolid in density (so-called ground-glass opacities) [Fig 5]5; or have a so-called tree-in-bud appearance (Fig 4).9 Additionally, nodules may either be calcified, as occurs in fungal disease, or cavitary, as is seen, for example, in patients with septic emboli, metastatic disease, or Langerhans cell histiocytosis (LCH).10 806
Figure 2. Perilymphatic disease. A diagrammatic representation of the characteristic distribution of lung nodules in patients with perilymphatic disease. Note that nodules are preferentially subpleural, peribronchovascular within the axial interstitium, or along lobular septae. While this appearance is especially characteristic of nodular sarcoidosis, less commonly a similar pattern may also be seen in patients with silicosis or coal-workers pneumoconiosis.
It should be emphasized that many of these characteristics are best evaluated on high-resolution CT scan images. With the introduction of multidetector CT scanners, it is now possible to routinely, prospectively reconstruct both thick and thin sections through the lungs after a single breathhold, provided that the initial data are acquired using appropriately thin collimation. This approach also enables the use of high-definition, multiplanar reconstructions, the use of which may be of value in further characterizing lung nodules.11
Multinodular HRCT Algorithm: A StepWise Approach The use of this algorithm begins by dividing CT scans into two broad arms based on the presence (group 1) or absence (group 2) of pleural or perifissural involvement (Table 1). Step 1 Group 1: Those cases in which a striking proportion of nodules demonstrate pleural or perifissural involvement characterize nodules as predominantly perilymphatic or lymphohematogenous in origin, constituting a separate arm of the algorithm (Table 1). The explanation for this pattern lies in the greater density of lymphatic channels seen in the interlobuChest Imaging for Clinicians
Figure 3. Random nodules. A diagrammatic representation of the characteristic distribution of randomly distributed nodules in patients with lymphohematogenous disease. Note that in distinction with patients having predominantly perilymphatic disease, random nodules may been seen adjacent to all secondary lobular structures. Some nodules may also appear to be attached to pulmonary arterial branches (so-called feeding vessels). Random nodules are most commonly due to metastatic disease, and may vary considerably in size and edge characteristics. The differential diagnosis most importantly includes miliary infection. Lymphangitic carcinomatosis, while hematogenous in origin, is easily distinguished from random metastatic nodules by the presence of characteristically thickened interlobular septae, preferentially involving the lung bases, and usually associated with asymmetric hilar adenopathy and pleural effusions.
Figure 5. Centrilobular disease. A diagrammatic representation of the distribution of diseases that predominantly affect the centrilobular portion of secondary lobules, excluding those diseases that result in predominantly mucoid impaction due to infected secretions. The most common cause of diffuse centrilobular disease is subacute HP. This characteristically results in poorly defined, poorly marginated ground-glass opacities. Similar to tree-in-bud opacities, these rarely involve the pleural or fissural surfaces. While a number of different entities may result in predominantly centrilobular opacities, the differential diagnosis most often includes RB/RB-ILD. In distinction with subacute HP, RB in particular is less extensive, typically upper lobe in distribution, and almost always occurs in smokers.
lar septa and subpleural regions, including along the fissures. Step 2 Once nodules are characterized as predominantly perilymphatic or lymphohematogenous in origin, further assessment requires determining whether or not nodules are distributed diffusely or are patchy or clustered, with particular attention paid to the presence or absence of the extent of axial interstitial involvement. It is recalled that the axial interstitium envelops the main pulmonary vessels and bronchi extending from the hilum outward toward the lung periphery.12 Step 3
Figure 4. Bronchiolar disease. A diagrammatic representation of the typical appearance of bronchiolar inflammation resulting in so-called tree-in-bud opacities. These characteristically result in clusters of ill-defined nodules “attached” to adjacent branching or tubular structures due to extensive bronchiolar mucoid impaction. Most importantly, note that, unlike the situation in patients with either perilymphatic disease or random nodules, mucoid impacted bronchioles do not extend to the pleural, fissural, or septal surface. This pattern is nearly always due to infected secretions resulting from virtually any cause of acute or subacute bronchiolar infection. www.chestjournal.org
If nodules prove to be clustered in a predominantly subpleural/axial distribution, they are deemed to be perilymphatic in distribution (Fig 2). In this category, the main disease to be considered is sarcoidosis (Fig 6, 7).2,13,14 This diagnosis is further suggested by nodules that are typically ill-defined, frequently measuring only a few millimeters in size. Clusters of these nodules often have a “grainy” appearance and when sufficiently profuse may result in an appearance of poorly defined nodules or masses on corresponding chest radiographs (soCHEST / 129 / 3 / MARCH, 2006
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Table 1—HRCT Algorithm for Multinodular Disease*
* CWP ⫽ coal workers pneumoconiosis; MAI ⫽ M avium intracellulare; MTB ⫽ M tuberculosis; PMF ⫽ progressive massive fibrosis.
called alveolar sarcoid). When coalescent, these may simulate progressive massive fibrosis. Ancillary findings include a predominant upper lobe distribution, focal air-trapping due to bronchiolar obstruction, and diffuse adenopathy, often calcified. Calcified nodules may also be present in later stages of the disease.
The most important differential diagnoses for this pattern of disease are silicosis and coal worker pneumoconiosis.15,16 In both of these occupational diseases, perilymphatic nodules are the primary abnormality, typically involving the mid and upper lung fields. While these entities may simulate the appearance of sarcoidosis, they are usually easily diagnosed when correlated with clinical history.15 This includes other rare occupational lung disease, for example, siderosis, that may also simulate the appearance of sarcoidosis.17 While lymphangitic carcinomatosis may result in perilymphatic nodules, in fact, CT scan findings are most often characterized by markedly thickened nodular interlobular septae usually asymmetrically involving the lower lobes and usually associated with adenopathy and effusions.18 Nodules, when present, tend more often to be well-defined and are often associated with discrete feeding vessels, further identifying them as hematogenous in origin. Lymphangitic carcinomatosis rarely mimics findings that are characteristic of sarcoidosis. Step 4
Figure 6. Perilymphatic disease: sarcoidosis. An HRCT scan of a 1-mm section at the level of the carina shows innumerable ill-defined small nodules clustered in the mid-portions of both lungs with relative sparing of the anterior aspects of both upper lobes. Note that these preferentially involve the left major fissure (arrow on left lung) as well as the walls of the peripheral airways (curved arrow on right lung). 808
If nodules prove to be diffuse instead of clustered, they are properly considered to be random in distribution (Table 1). By definition, true random distribution will lead to nodules being identified along pleural and fissural surfaces as well as along the axial Chest Imaging for Clinicians
Figure 7. Perilymphatic disease: sarcoidosis. An HRCT scan of a 1-mm section through the right mid-lung in a different patient than the one in Figure 6 shows evidence of innumerable ill-defined small nodules. Note that these tend to be clustered with relative sparing of the right upper lobe anteriorly and clearly preferentially lie adjacent to the right major fissure (arrow), along pleural surfaces, and along central vascular structures (arrowheads). This distribution of nodules is rarely seen in any other disease.
interstitium. However, in distinction from primarily perilymphatic disease, random nodules may also be identified in even greater numbers when dispersed randomly throughout the lungs. Included in this category most importantly are hematogenous metastases.19 Unlike nodules in patients with sarcoidosis, metastatic nodules tend to be smooth, well-defined lesions (Fig 8, 9).8 However, a wide variety of morphologic appearances has been noted. In a study20 comparing the HRCT scan features of pulmonary metastatic lesions with autopsy findings, while nodules most often proved to have well-defined margins (38% of cases), nodules with well-defined irregular margins, poorly defined smooth margins, and poorly defined irregular margins could be identified in 16%, 16%, and 30% of cases, respectively. While nodules range from a few www.chestjournal.org
millimeters to ⬎ 1 cm, they are frequently similar in size. A basilar predominance is typically noted due to preferential blood flow to the lung bases. Individual nodules may have “feeding vessels” consistent with their hematogenous origin. On HRCT scans, a connection between nodules and the adjacent pulmonary vessels (ie, the mass-vessel sign) may be seen in approximately 75% of cases.21 Nodules may also be either cavitary or surrounded by a “halo” of groundglass attenuation, which is typical of hemorrhagic metastases such as those due to choriocarcinoma.22 Features of lymphangitic cancer may also be present, which again is consistent with a hematogenous origin of disease.19 It should be noted that the reported incidence of malignant disease as a cause of multiple pulmonary nodules has been shown to vary greatly, from as low as 10% to as high as 58% in some surgical series.23 In 133 patients with a known malignancy who underwent video-assisted thoracoscopy for multiple pulmonary nodules, 64% proved to have at least one malignant nodule.24 A number of malignancies can result in a miliary pattern, rendering differential diagnosis more problematic. This includes tumors, such as renal cell carcinoma, head and neck cancers, and testicular tumors, that have their primary venous drainage in the lungs.25 The differential diagnosis includes a number of additional entities that result in random nodules. The most important of these is miliary infection (Fig 10).26,27 In fact, while differentiation between miliary infection and a miliary tumor may be impossible to determine by imaging features alone, in general, close correlation with the clinical history renders these diagnoses relatively straightforward. Miliary metastases are frequently due to metastatic thyroid cancer, renal cancer, and melanoma, among other cancers, while larger less profuse metastases tend to be adenocarcinomas in adults, typically originating from the lung, breast, or the GI tract.19,28 Less commonly, diffuse nodules may be identified in patients with septic emboli, invasive fungal infections, and pulmonary vasculitides.29 These entities frequently result in cavitary nodules, some with a distinct “halo” of ground-glass attenuation,22 and have even been described in patients with organizing pneumonia.30 Despite similarities between these entities and routine metastatic disease, it should be emphasized that the numbers of nodules identified in these cases usually fail to meet the criterion of “too many nodules to count,” with the differential diagnosis again further aided by close clinical correlation. Step 5 Group 2: In distinction with the patterns described in patients in group 1, group 2 includes those CHEST / 129 / 3 / MARCH, 2006
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Figure 8. Random nodules: hematogenous metastases. An HRCT scan of a 1-mm section through the lower lobes shows innumerable sharply defined nodules throughout both lungs. Note that while many of these lie along pleural and fissural surfaces, or less commonly appear related to adjacent vessels (arrows), most are unattached to adjacent structures. When sufficiently well defined and generally uniform in size, this pattern of diffuse nodularity is easily separable from that resulting from perilymphatic disease.
patients in whom no or very few nodules are perifissural or subpleural in distribution. Anatomically, these nodules are grouped together as being centrilobular in distribution.4 By definition, these entities primarily involve centrilobular bronchioles and/or their accompanying pulmonary artery branches. Anatomically, these structures taper peripherally, stopping 5 to 10 mm short of the pleural or interlobular septal surfaces and consequently fail to involve pleural and fissural surfaces (Table 1). As will be discussed, these nodules typically fall into the following two broad categories: those with a “tree-in-bud” configuration; and those that appear as amorphous “ground-glass” nodules. Step 6 Once nodules are characterized as being primarily centrilobular in distribution, further assessment requires determining whether or not these have a tree-in-bud configuration. Tree-in-bud opacities are characterized by the appearance of centrilobular micronodular branching structures that end several millimeters distant from nearby pleural or fissural surfaces (Fig 11).31 Tree-in-bud opacities are nearly always the result 810
of inspissated (ie, frequently aspirated) secretions lodged within centrilobular bronchioles, accounting for a branching configuration when coursing parallel to the CT scan plane.9,32,33 Normal bronchioles, which have a diameter of ⬍ 1 mm and a wall thickness of ⬍ 0.1 mm, are below the limit of HRCT scan spatial resolution.34 The presence of inspissated secretions results in bronchiolar distension and increased density, allowing their direct visualization. Not surprisingly, in many cases there is also evidence of coexisting bronchiectasis. Another frequently encountered finding in patients with bronchiolar disease is so-called mosaic attenuation.33 In these cases, bronchiolar occlusion results in air-trapping, hypoxia of the poorly ventilated lung units with resultant reflex vasoconstriction and air-trapping. This combination of findings causes decreased attenuation of the affected areas of the lung with blood flow redistributed to normal lung. The hypoattenuated diseased lung is therefore surrounded by hyperattenuated, overperfused normal lung, resulting in heterogeneous-appearing mosaic attenuation. While classically described in patients with an endobronchial spread of tuberculosis, in fact, treein-bud opacities can be identified in virtually any Chest Imaging for Clinicians
Figure 9. Random nodules: metastatic thyroid cancer. An HRCT scan of a 1-mm section through the mid-thorax shows innumerable small nodules. Note that, in addition to unattached nodules, many of these lie along both the minor and right major fissures (arrows), as well as along the proximal middle lobe pulmonary artery (arrowheads). Although there are fewer nodules than shown in Figure 8, in the appropriate clinical stetting this pattern is again consistent with metastatic disease.
type of infectious bronchiolitis. This includes Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, bacterial, viral, and fungal infections, and allergic bronchopulmonary mycosis. This pattern is also frequently encountered in patients with AIDS in whom recurrent episodes of bronchial infection are frequent.35 Differential diagnosis also includes follicular bronchiolitis, an entity that is characterized by the presence of hyperplastic lymphoid follicles and germinal centers occurring along the bronchovascular bundles.36 Most often, infectious bronchiolitis results in clusters of tree-in-bud opacities. When they are widespread and diffuse, the differential diagnosis includes “Asiatic panbronchiolitis.”37,38 This entity has a well-established predilection in Japanese, Chinese, and Korean populations, appears to show a genetic predisposition, and is usually seen in association with chronic sinusitis. Diffuse tree-in-bud opacities are also frequently encountered in patients with cystic fibrosis and viral bronchiolitis. It cannot be overemphasized that in the vast majority of cases the finding of tree-in-bud opacities should be taken as being indicative of bronchiolar infection. While tree-in-bud opacities have been described39 as occurring in patients with pulmonary vascular tumor emboli, in our experience this entity www.chestjournal.org
is exceedingly rare. As noted in one retrospective study9 of 141 patients with a variety of airway diseases, including bronchiolitis obliterans, bronchiolitis obliterans-organizing pneumonia, HP, respiratory bronchiolitis (RB), and pneumonia, among others, the finding of tree-in-bud opacities was identified in association only with pneumonia and/or bronchiectasis in 17% and 25% of cases, respectively. Even in patients with panbronchiolitis, while no consistent infectious agent has been associated with this disease, interestingly, most individuals respond, at least initially, to low-dose erythromycin therapy.38,40 Some authors41 have suggested that the therapeutic efficacy of macrolide agents may emanate from their inhibition of proinflammatory cytokines, and from mucus and water secretion from airway epithelial cells. Step 7 Those cases in which centrilobular nodules are present in patients in the absence of tree-in-bud opacities constitute the last part of this CT scan algorithm (Table 1). Included in this category are a variety of diseases or “mixed” entities that have in common localization to the centrilobular portion of the secondary lobule. This includes diseases that CHEST / 129 / 3 / MARCH, 2006
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Figure 10. Random nodules: miliary tuberculosis. A magnified HRCT scan image through the right upper lobe shows innumerable tiny nodules throughout the lungs extensively involving the pleural surfaces (black arrowheads) and along bronchovascular structures (arrows). Numerous unattached nodules are also identifiable. This pattern is typical of a random, miliary distribution. While typically resulting from either metastatic disease or infection, clinical correlation is usually diagnostic. Case courtesy of Nestor Muller, MD, Vancouver, BC, Canada.
primarily affect the centrilobular bronchiole, as well as those that are either primarily peribronchiolar or perivascular in origin.2,4,5 Most often, this group of diseases results in a pattern of diffuse, poorly defined ground-glass nodules, which are typically the result of a primarily peribronchiolar distribution. The classic example of this appearance is subacute HP (Fig 12).42,43 This diagnosis is frequently first suggested on the basis of CT scan findings and is usually established by a combination of exposure history, clinical symptoms of a flu-like illness, the presence of specific serum antibodies when those data are available, increased numbers of lymphocytes and neutrophils in BAL fluid, and, when feasible, clinically significant improvement in symptoms when the patient is removed from the offending environmental agent.44 812
Figure 11. Bronchiolar disease: infectious bronchiolitis. A magnified HRCT scan image through the middle and lower lobes shows numerous nodules associated with linear/branching densities throughout the lungs (arrows). These tree-in-bud opacities are the result of infected mucoid impacted peripheral airways and hence have a distinctly centrilobular pattern of distribution. Note that none of these peripherally is in contact with either pleural or fissural surfaces. Classically the result of the endobronchial spread of tuberculosis, this pattern may be seen in virtually any patient in whom there is infection of the peripheral airways. Not surprisingly, tree-in-bud opacities tend to be clustered rather than truly diffuse and frequently are associated with CT scan evidence of bronchiectasis.
The differential diagnosis encompasses a number of important disease entities, most importantly including RB, lymphocytic interstitial pneumonitis (LIP), and LCH. RB/RB-interstitial lung disease (ILD) are smoking-related disorders that may also result in poorly defined centrilobular nodules.45,46 RB typically results in far fewer ground-glass nodules than the number in patients with subacute HP and generally display a distinctly upper lobe predominance. RB-ILD is associated with widespread ground-glass attenuation and reticular opacities, which are findings that are not seen in patients with subacute HP.45,46 Also included in the differential diagnosis of individuals with diffuse centilobular nodules are diseases related to bronchiolar lymphatics. This includes muChest Imaging for Clinicians
in particular, the presence of randomly distributed thin-walled cysts.47 Poorly defined centrilobular nodules may also be seen early in the course of LCH.49,50 However, these most often are associated with characteristic bizarrely shaped, thick walled cysts, some of which represent cavitary nodules with characteristic sparing of the lung bases.51
Conclusion
Figure 12. Centrilobular disease: subacute HP. A magnified HRCT scan section through the right upper lobe shows innumerable poorly defined, hazy ground-glass nodules throughout the lung (arrows). In addition to a uniform distribution, none of these nodules lies adjacent to the visualized pleural surfaces. Note as well the lack of any tree-in-bud opacities that would suggest the presence of mucoid impacted airways (compare with Fig 11). Few entities besides subacute HP result in this pattern of ill-defined nodules. Differential diagnoses includes RB, typically causing fewer nodules restricted to the upper lobes in known smokers, and LIP, which is usually associated with either Sjogren syndrome or AIDS.
cosa-associated lymphoid tissue lymphoma (maltomas) and, in particular, LIP. LIP is most often seen in patients with underlying immunologic abnormalities, especially Sjo¨gren syndrome and AIDS, and is characterized histologically by diffuse hyperplasia of bronchus-associated lymphatic tissue, resulting in a diffuse, polyclonal lymphoid cell infiltrate surrounding the airways and expanding the lung interstitium.47,48 As reported by Johkoh et al,48 in a study of 22 patients with documented LIP, while subpleural nodules could be identified in 86% of cases, likely reflecting subpleural lymphatic involvement, poorly defined centrilobular nodules could be seen in 100% of cases. Additional imaging features include the presence of thickened bronchovascular bundles and, www.chestjournal.org
The finding of multiple lung nodules is a characteristic that encompasses a number of disparate parenchymal diseases. Although inexact, the use of anatomic and morphologic features to characterize nodules based on HRCT scan findings may help to simplify the differential diagnosis. Most importantly, the use of this imaging algorithm can prove to be an aid in standardizing the clinical approach to differential diagnosis. In a study reported by Gruden et al,4 four experienced chest radiologists independently evaluated HRCT scan images in 58 patients with diffuse nodular disease. In each case, observers were asked to place nodules in one of the following four possible anatomic locations or categories: perilymphatic; random; associated with small airways disease (ie, cases in which the primary abnormality was tree-in-bud opacities); or centrilobular disease. There was agreement among all four observers in 79% of cases, while three of four observers agreed on an additional 17%. Observers were correct (based on subsequent histologic/clinical correlation) in 218 of 232 localizations (94%) in the 58 cases. These data suggest that this algorithm, which has been elaborated on in the present report, represents a reproducible method for categorizing patients with diffuse pulmonary nodules. It should also be noted that, in individual cases, HRCT scan findings may be sufficiently characteristic, especially when coupled with close clinical correlation, to obviate the need to perform a biopsy. Patients with classic HRCT scan findings of sarcoidosis, as well as those with subacute HP for which biopsy confirmation may not be required, should be included in this category. In patients with a known history of smoking, the finding of scattered, tiny, ill-defined centrilobular upper lobe nodules is sufficiently characteristic to warrant a clinical diagnosis of RB, obviating the need for more invasive diagnostic procedures, while the finding of scattered centrilobular opacities associated with bizarrely shaped cysts predominantly involving the upper lobes sparing the lung bases is characteristic of LCH. Similarly, the finding of characteristic tree-in-bud opacities in the appropriate clinical setting may be taken as diagnostic of small airway-bronchiolar infection. In CHEST / 129 / 3 / MARCH, 2006
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distinction, the appearance of diffuse, poorly defined centrilobular nodules in the absence of a clinical history of established antigen exposure, infection, or a history of smoking generally requires open-lung biopsy for definitive evaluation. Given the wide diversity of potential causes for this appearance, the use of an HRCT scan algorithm should be considered an important, if not fundamental, component of clinical assessment in these cases.
References 1 Webb WR, Muller NL, Naidich DP. 3rd ed. Philadelphia, PA: Lippincott, Williams and Wilkins, 2001 2 Colby TV, Swensen SJ. Anatomic distribution and histopathologic patterns in diffuse lung disease: correlation with HRCT. J Thorac Imaging 1996; 11:1–26 3 Bergin C, Roggli V, Coblentz C, et al. Secondary pulmonary lobule: normal and abnormal CT appearance. AJR Am J Roentgenol 1988; 151:21–25 4 Gruden JF, Webb WR, Warnock M. Centrilobular opacities on HRCT: diagnosis and differential diagnosis with pathologic correlation. AJR Am J Roentgenol 1994; 162:569 –574 5 Murata K, Itoh H, Todo G, et al. Centrilobular lesions of the lung: demonstration by high resolution CT and pathologic correlation. Radiology 1986; 161:641– 645 6 Muller NL, Kullnig P, Miller RR. The CT findings of pulmonary sarcoidosis: analysis of 25 patients. AJR Am J Roentgenol 1989; 152:1179 –1182 7 Lee KS, Song KS, Lim TH, et al. Adult onset of pulmonary tuberculosis: findings on chest radiographs and CT scans. AJR Am J Roentgenol 1993; 160:753–758 8 Hirikata K, Nakata H, Haratake J. Appearance of pulmonary metastases on high-resolution CT scans: comparison with histopathologic findings from autopsy specimens. AJR Am J Roentgenol 1993; 161:37– 43 9 Aquino SL, Gamsu G, Webb WR, et al. Tree-in-bud pattern: frequency and significance on thin-section CT. J Comput Assist Tomogr 1996; 20:594 –599 10 Moore AD, Godwin JD, Muller NL, et al. Pulmonary histiocytosis X: comparison of radiographic and CT findings. Radiology 1989; 172:249 –254 11 Revel M-P, Lefort C, Bissery A, et al. Pulmonary nodules: preliminary experience with three-dimensional evaluation. Radiology 2004; 231:459 – 466 12 Weibel ER, Taylor CR. Design and structure of the human lung. In: Weibel ER, Taylor CR, eds. Pulmonary diseases and disorders. New York, NY: McGraw-Hill, 1988; 11– 60 13 Brauner MW, Grenier P, Mompoint D, et al. Pulmonary sarcoidosis: evaluation with high-resolution CT. Radiology 1989; 172:467– 471 14 Nishimura K, Itoh H, Kitaichi M, et al. Pulmonary sarcoidosis: correlation of CT and histopathologic findings. Radiology 1993; 172:467– 471 15 Remy-Jardin M, Remy J, Farre L, et al. Computed tomographic evaluation of silicosis and coal worker’s pneumoconiosis. Radiol Clin North Am 1992; 30:115–1176 16 Ooi GC, Tsang KWT, Cheung TF, et al. Silicosis in 76 men: qualitative and quantitative CT evaluation- clinical-radiologic correlation study. Radiology 2003; 228:816 – 825 17 Kim KI, Kim CW, Lee MK, et al. Imaging of occupational lung disease. Radiographics 2001; 21:1371–1391 18 Johkoh T, Icfhikado Kea J, Tomiyama N, et al. CT findings in lymphangitic carcinomatosis of the lung: correlation with 814
19 20
21 22 23 24 25
26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
histologic findings and pulmonary function tests. AJR Am J Roentgenol 1992; 158:1217–1222 Aquino SL. Imaging of metastatic disease to the thorax. Radiol Clin North Am 2005; 43:481– 495 Hirakata K, Nakata H, Haratake J. Appearance of pulmonary metastases on high-resolution CT scans: comparison with histopathologic findings from autopsy specimens. AJR Am J Roentgenol 1993; 161:37– 43 Milne ENC, Zerhouni EA. Blood supply of pulmonary metastases. J Thorac Imaging 1987; 2:15–23 Gaeta M, Blandino A, Scribano E, et al. Computed tomography halo sign of pulmonary nodules: frequency and diagnostic value. J Thorac Imaging 1999; 14:109 –113 Benjamin MS, Drucker EA, McLoud T, et al. Small pulmonary nodules: detection at chest CT and outcome. Radiology 2003; 226:489 – 493 Ginsberg MS, Griff SK, Go BD, et al. Pulmonary nodules resected at video-assisted thorascopic surgery: etiology in 426 patients. Radiology 1999; 213:277–282 Patz EF, Fidler J, Knelson M, et al. Significance of percutaneous needle biopsy in patients with multiple pulmonary nodules and a single known primary malignancy. Chest 1995; 107:601– 604 Muller NL, Fraser RS, Lee KS, et al. Pulmonary infection. In: Diseases of the lung. Philadelphia, PA: Lippincott, Williams and Wilkins, 2003; 17–75 McGuinness G, Naidich DP, Jagardar J, et al. High resolution CT findings in miliary lung disease. J Comput Assist Tomogr 1992; 16:384 –390 Seo JB, Im J-G, Goo JM, et al. Atypical pulmonary metastases: spectrum of radiologic findings. Radiographics 2001; 21:403– 417 Silva CIS, Muller NL, Fujimoto K, et al. Churg-Strauss syndrome: high resolution CT and pathologic findings. J Thorac Imaging 2005; 20:74 – 80 Haro M, Vizcaya M, Texido A, et al. Idiopathic bronchiolitis obliterans organizing pneumonia with multiple cavitary nodules. Eur Respir J 1995; 8:1975–1977 Collins J, Blankenbaker D, Stern EJ. CT patterns of bronchiolar disease: what is “tree-in-bud”? AJR Am J Roentgenol 1998; 171:365–370 Colby TV. Bronchiolitis: pathologic considerations. Am J Clin Pathol 1998; 109:101–109 Hartman TE, Primack SL, Lee KS, et al. CT of bronchial and bronchiolar disease. Radiographics 1994; 14:991–1003 Webb WR, Muller NL, Naidich DP. Normal lung anatomy. In: High-resolution CT of the lung. Philadelphia, PA: Lippincott, Williams and Wilkins, 2001; 49 –70 McGuinness G, Gruden JF, Bhalla M, et al. AIDS-related airways disease. AJR Am J Roentgenol 1997; 168:67–77 Ryu JH, Myers JH, Swensen SJ. Bronchiolar disorders: state of the art. Am J Respir Crit Care Med 2003; 168:1277–1292 Akira M, Kitatani F, Lee YS, et al. Diffuse panbronchiolitis: evaluation with high resolution CT. Radiology 1988; 168:433– 438 Nishimura K, Kitaichi M, Izumi T, et al. Diffuse panbronchiolitis: correlation of high resolution CT and pathologic findings. Radiology 1992; 184:779 –785 Shepard JO, Moore EH, Templeton PA, et al. Pulmonary vascular tumor emboli: dilated and beaded peripheral pulmonary arteries at CT. Radiology 1993; 187:797– 801 Kudoh S. Erythromycin treatment in diffuse panbronchiolitis. Curr Opin Pulm Med 1998; 4:116 –121 Baz MA, Kussin PS, Van Trigt P, et al. Recurrence of diffuse panbronchiolitis after lung transplantation. Am J Respir Crit Care Med 1995; 151:895– 898 Lynch DA, Rose CS, Way D, et al. Hypersensitivity pneumoChest Imaging for Clinicians
43 44 45
46
nitis: sensitivity of high resolution CT in a population-based study. AJR Am J Roentgenol 1992; 159:469 – 472 Hansell DM, Wells AU, Padley SP, et al. Hypersensitivity pneumonitis: correlation of individual CT patterns with functional abnormalities. Radiology 1996; 199:123–128 Selman M. Hypersensitivity pneumonitis: a multifaceted deceiving disorder. Clin Chest Med 2004; 25:531–547 Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc 1989; 64:1373–1380 Heyneman LE, Ward S, Lynch DA, et al. Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial pneumonia: different entities or part of the spectrum of the same disease? AJR Am J Roentgenol 1999; 173:1617–1622
www.chestjournal.org
47 Honda O, Johkoh T, Icfhikado K, et al. Differential diagnosis of lymphocytic interstitial pneumonia and malignant lymphoma on high-resolution CT. AJR Am J Roentgenol 1999; 173:71–74 48 Johkoh T, Muller NL, Pickford HA, et al. Lymphocytic interstitial pneumonia: thin section CT findings in 22 patients. Radiology 1999; 212:567–572 49 Brauner MW, Grenier P, Mouelhi MM, et al. Pulmonary histiocytosis X: evaluation with high-resolution CT. Radiology 1989; 172:255–258 50 Kulwiec EL, Lynch DA, Aguayo SM, et al. Imaging of pulmonary histiocytosis X. Radiographics 1992; 12:515–526 51 Howarth DM, Gilchrist GS, Mullan BP, et al. Langerhans cell histiocytosis: natural history, management, and outcome. Cancer 1999; 85:2278 –2290
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