Pictorial Essay: Multinodular Disease Raoof Suhail , MD, FCCP, Amchentsev Alexey , MD, Vlahos Ioannis , MD, Goud Ajay , MD, Naidich David P. , MD, FCCP  CHEST  Volume 129, Issue 3, Pages 805-815 (March 2006) DOI: 10.1378/chest.129.3.805 Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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. CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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. CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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. CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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. CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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. CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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). CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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 Figiure 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. CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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. CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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 Figiure 8, in the appropriate clinical stetting this pattern is again consistent with metastatic disease. CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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. CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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. CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions

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. CHEST 2006 129, 805-815DOI: (10.1378/chest.129.3.805) Copyright © 2006 The American College of Chest Physicians Terms and Conditions