High-Resolution CT of the Lung
High-Resolution CT of the
Lung
FIFTH EDITION
W. Richard Webb, MD
Professor Emeritus of Radiology and Biomedical Imaging Emeritus Member,
Haile Debas Academy of Medical Educators University of California San
Francisco San Francisco, California
Nestor L. Müller, MD, PhD
Professor Emeritus of Radiology Department of Radiology, University of British
Columbia Vancouver, British Columbia, Canada
David P. Naidich, MD, FACR, FAACP
Professor of Radiology and Medicine New York University
Langone Medical Center
New York, New York
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Library of Congress Cataloging-in-Publication Data Webb, W. Richard (Wayne Richard), 1945-author.
High-resolution CT of the lung / W. Richard Webb, Nestor L. Müller, David P. Naidich. — Fifth edition.
p. ; cm.
Includes bibliographical references and index.
eISBN 978-1-4698-8765-4
I. Müller, Nestor Luiz, 1948- , author. II. Naidich, David P., author. III. Title.
[DNLM: 1. Lung—radiography. 2. Tomography, X-Ray Computed. 3. Lung Diseases—pathology. WF 600]
RC734.T64
616.2’407572—dc23
2014003388
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DEDICATION
To my father, who encouraged my curiosity and taught me to figure things
out
—WRW
To my wife, Isabela, and my children—Alison, Phillip, and Noah Müller
—NLM
To Jocelyn, whose constant love and support has always been my greatest
inspiration
—DPN
Contributing Authors
Brett M. Elicker, MD
Associate Professor of Clinical Radiology and Biomedical Imaging Chief, Cardiac and Pulmonary Imaging
University of California San Francisco San Francisco, California
Myrna C. B. Godoy, MD, PhD
Assistant Professor of Radiology University of Texas MD Anderson Cancer Center Houston, Texas
C. Isabela S. Müller, MD, PhD
Department of Radiology Delfin Clinic
Salvador, Bahia, Brazil
Preface
During the past 25 years, high-resolution CT (HRCT) has become established as
an indispensable tool in the evaluation of patients with diffuse lung disease.
HRCT is now commonly used in clinical practice to detect and characterize a
variety of lung abnormalities. In the approximately 5 years since our fourth
edition was published, considerable progress has taken place in the
understanding of diffuse lung diseases and the recognition of new entities and
their nature, causes, and characteristics. Without doubt, HRCT has played a
fundamental role in contributing to this progress and has become essential to the
diagnosis of a number of diffuse diseases.
This fifth edition continues what the three of us, independently, in
conjunction, and with each other’s encouragement and support, began some 30
years ago. The photograph of the three of us below was taken by a local resident
at the 1989 Diagnostic Course in Davos, on a walk we took on the promenade
above the Sweitzerhof on the day of our arrival, when as junior faculty, we were
more than a little anxious about teaching along with such important and
impressive chest radiologists as Fraser, Felson, Greenspan, Milne, Flowers,
Heitzman, and many others.
At this meeting, we each spoke about the use of HRCT, which, at the time,
was a little-known technique that was regarded with skepticism by many
radiologists. We learned from each other as we spoke, compared slides in the
speaker-ready room, and gained confidence from our shared opinions. At this
meeting, we began thinking about a collaboration that would combine our
experience and thoughts about this new modality and its potential uses. Our first
edition of this book was published in late 1991, with a grand total of 159 pages.
It was a quarter of an inch thick, and, to our knowledge, referenced every known
paper on HRCT. From our perspective, it was the most important thing we had
ever done.
That is how things start. Maybe that is the best way things should start. It was
certainly fun and rewarding for each of us. And we three have stuck together
over the years, out of our combined respect, admiration, friendship, and good
humor. Each one of us believes that we learned more from our collaboration than
we taught.
In this edition, we have incorporated an update and review of numerous recent
advances in the classification and understanding of diffuse lung diseases and
their HRCT features. Recent technical modifications in obtaining HRCT have
also been reviewed, most notably the use of helical HRCT and dose-reduction
techniques. We hope the reader will find these changes and updates helpful. As
is our wont, we have reorganized our discussions into new sections and chapters,
which we feel best presents the most important topics in HRCT diagnosis for
reference and learning.
A new section has been added at the end of the book to provide a general
review of HRCT, including an illustrated glossary of HRCT terms and a chapter
providing a compilation of the common and typical appearances of the most
common diffuse lung diseases encountered in clinical practice. These sections
are intended to provide an illustrated index to the detailed descriptions of
diseases found elsewhere in the book.
It is with a great deal of pride that we complete our fifth edition of this book,
which has occupied so much of our thoughts, efforts, and time over the years.
This task is accomplished in the hope that this book will encourage future
generations of thoracic imagers to develop mutually productive relationships
with friends and colleagues, in order to explore important questions in our
understanding of the role of imaging in the assessment of thoracic disease.
To this end, we acknowledge the contributions of three esteemed colleagues,
our former fellows, who have authored parts of this book. Their efforts have
greatly inspired our own enthusiasm for the considerable task of bringing this
edition to fruition.
W. RICHARD WEBB NESTOR L. MÜLLER DAVID P. NAIDICH
Acknowledgments
We wish to gratefully acknowledge the many colleagues who have provided us
with insights and inspiration over the years, and allowed us to use their
illustrations for this and prior editions of this book. Although they are too
numerous to mention here, they are recognized throughout the following pages.
Contents
SECTION
I
HIGH-RESOLUTION CT TECHNIQUES AND NORMAL
ANATOMY
1
2
Technical Aspects of High-Resolution CT
Normal Lung Anatomy
SECTION
II
APPROACH TO HRCT DIAGNOSIS AND FINDINGS OF
LUNG DISEASE
3
4
5
6
7
HRCT Findings: Linear and Reticular Opacities
HRCT Findings: Multiple Nodules and Nodular Opacities
HRCT Findings: Parenchymal Opacification
HRCT Findings: Air-Filled Cystic Lesions
HRCT Findings: Decreased Lung Attenuation
SECTION
III
HIGH-RESOLUTION CT DIAGNOSIS OF DIFFUSE LUNG
DISEASE
8
The Idiopathic Interstitial Pneumonias, Part I: Usual Interstitial Pneumonia/Idiopathic
Pulmonary Fibrosis and Nonspecific Interstitial Pneumonia
9
The Idiopathic Interstitial Pneumonias, Part II: Cryptogenic Organizing Pneumonia, Acute
Interstitial Pneumonia, Respiratory Bronchiolitis-Interstitial Lung Disease, Desquamative
Interstitial Pneumonia, Lymphoid Interstitial Pneumonia, and Pleuroparenchymal
Fibroelastosis
10
11
12
13
14
15
16
Collagen-Vascular Diseases
Diffuse Pulmonary Neoplasms and Pulmonary Lymphoproliferative Diseases
Sarcoidosis
Pneumoconiosis, Occupational, and Environmental Lung Disease
Hypersensitivity Pneumonitis and Eosinophilic Lung Diseases
Drug-Induced Lung Diseases and Radiation Pneumonitis
Miscellaneous Infiltrative Lung Diseases
17
18
19
20
21
22
Infections
Pulmonary Edema and Acute Respiratory Distress Syndrome
Cystic Lung Diseases
Emphysema and Chronic Obstructive Pulmonary Disease
Airways Diseases
Pulmonary Hypertension and Pulmonary Vascular Disease
SECTION
IV
HIGH-RESOLUTION CT REVIEW
23 Illustrated Glossary of High-Resolution CT Terms
24 Appearances and Characteristics of Common Diseases
SECTION
I
High-Resolution CT Techniques and Normal Anatomy
1
Technical Aspects of High-Resolution CT
IMPORTANT TOPICS
HIGH-RESOLUTION COMPUTED TOMOGRAPHY: FUNDAMENTAL TECHNIQUES
TECHNIQUES OF SCAN ACQUISITION: SPACED AXIAL SCANNING VERSUS VOLUMETRIC
SCANNING
RADIATION DOSE
EXPIRATORY HIGH-RESOLUTION COMPUTED TOMOGRAPHY
QUANTITATIVE COMPUTED TOMOGRAPHY
ADDITIONAL TECHNICAL MODIFICATIONS
IMAGE DISPLAY
HIGH-RESOLUTION COMPUTED TOMOGRAPHY PROTOCOLS
SPATIAL RESOLUTION OF HIGH-RESOLUTION COMPUTED TOMOGRAPHY
HIGH-RESOLUTION COMPUTED TOMOGRAPHY ARTIFACTS
Abbreviations Used in This Chapter
ASIR
adaptive statistical iterative reconstruction
BOS
bronchiolitis obliterans syndrome
COPD
chronic obstructive pulmonary disease
CTDI
CT dose index
DLP
dose length product
ECG
electrocardiographic
FBP
filtered back projection
FOV
field of view
HU
Hounsfield units
kV
kilovolt
kV(p)
kilovolt peak
MIP
maximum-intensity projection
mA
milliampere
mAs
milliampere seconds
mGy
milligray
mSv
millisievert
MinIP
minimum-intensity projection
MBIR
model-based iterative reconstruction
MDCT
multidetector helical computed tomography
MD-HRCT
multidetector helical HRCT
NSIP
nonspecific interstitial pneumonia
ROI
region of interest
3D
three-dimensional
2D
two-dimensional
High-resolution computed tomography (HRCT) is capable of imaging the lung
with excellent spatial resolution, providing anatomical detail similar to that
available from gross pathologic specimens and paper-mounted lung slices (1–4).
HRCT can readily demonstrate the normal and abnormal lung interstitium and
morphologic characteristics of both localized and diffuse parenchymal
abnormalities; in this regard, HRCT is clearly superior to plain radiographs.
The first use of the term high-resolution computed tomography has been
attributed to Todo et al. (5), who, in 1982, described the potential use of this
technique for assessing lung disease. The first reports of HRCT in English date
to 1985, including landmark descriptions of HRCT findings by Nakata et al.,
Naidich et al., and Zerhouni et al. (6–8). Since then, HRCT has become
established as an important diagnostic tool in pulmonary medicine and has
significantly contributed to our understanding of diffuse lung diseases. Although
many of the HRCT techniques used in these initial studies are still appropriate
today, the recent development of multidetector helical computed tomography
(MDCT) scanners capable of volumetric high-resolution scanning has
significantly changed the manner in which HRCT may be obtained.
In this chapter, we review computed tomography (CT) techniques that are
appropriate for obtaining HRCT in patients with suspected lung disease, scan
protocols recommended in specific clinical settings, the spatial resolution and
radiation dose associated with HRCT, and common HRCT artifacts.
HIGH-RESOLUTION COMPUTED TOMOGRAPHY:
FUNDAMENTAL TECHNIQUES
This section reviews the effect of various technical factors on the appearance of
HRCT and summarizes our recommendations for obtaining appropriate
examinations. Although each author performs HRCT in a different manner, we
generally agree as to what fundamental techniques constitute a “high-resolution”
CT study. Quite simply, these include (a) the use of thin-collimation axial scans
or thin-section reconstruction of volumetric data obtained using MDCT and
narrow detector width (0.5–1.25 mm) and (b) image reconstruction with a high
spatial frequency (sharp or high-resolution) algorithm. Sufficient radiation (in
milliampere seconds [mAs] or effective mAs [mAs/pitch for helical scans]) (9)
must be used to keep image noise at a level low enough to allow accurate image
interpretation, while keeping patient exposure at appropriate levels; keep in mind
that dose reduction techniques can be used while obtaining diagnostic scans
(Table 1-1) (1–4,10–12). Targeted image reconstruction may be used to reduce
pixel size, but is not necessary for clinical diagnosis in most settings (Table 1-1)
(1–4,10–12).
TABLE 1-1 Summary of HRCT Techniques
Recommended
Slice thickness: thinnest available (0.5–1.5 mm)
Reconstruction algorithm: high spatial frequency or “sharp” algorithm
kV(p) 120; 100 or 80 for small or pediatric patients
mA less than 250; mAs (effective) of 100 or less
Scan (rotation) time: as short as possible (e.g., 0.3–0.5 s)
Pitch (MD-HRCT): 1-1.5
Inspiratory level: full inspiration
Position: supine; prone scans routinely in patients with suspected interstitial lung disease; in
patients with minimal or unknown chest film abnormalities, or monitor supine scans for
dependent density
Acquisition: spaced axial imaging or MD-HRCT
Expiratory imaging: postexpiratory scans at three or more levels in patients with obstructive
disease
Reconstruction: transaxial; entire thorax
Windows: at least one consistent lung window setting is necessary. Window mean/width values
of 600–700 HU/1,000–1,500 HU are appropriate. Good combinations are 700/1,000 HU or
600/1,500 HU. Soft-tissue windows of approximately 50/350 HU should also be used for the
mediastinum, hila, and pleura.
Image display: workstation (optimal) or photography of lung windows 12 on 1
Optional
Reduced mAs: low-dose axial HRCT or MD-HRCT best for follow-up studies
Acquisition: ECG gating or segmented reconstruction to reduce motion artifacts
Expiratory imaging: dynamic, volumetric, or spirometrically triggered expiratory scans
Contrast injection: patients with suspected vascular disease
Reconstruction: targeted (15-to 25-cm FOV; 2D or 3D reconstruction; MIP or MinIP
reconstructions)
Windows: windows may need to be customized; a low window mean (800–900 HU) is optimal for
diagnosing emphysema. For viewing the mediastinum, 50/350 HU is recommended. For
viewing pleuroparenchymal disease, 600/2,000 HU is recommended
Slice Thickness
The use of thin sections (0.5–1.5 mm) is essential if spatial resolution and lung
detail are to be optimized (4,6,8,10) (Table 1-1). Generally, 1-mm-thick slices
are adequate for diagnosis; a clear-cut advantage for thinner slices has not been
shown (13). With slices thicker than 1 to 1.5 mm, volume averaging within the
plane of scan significantly reduces the ability of CT to resolve small structures.
The use of 2.5-to 5-mm slice thickness should not be considered adequate for
HRCT.
In an early study, Murata et al. (12) compared the ability of axial HRCT
performed with 1.5-and 3-mm collimation to allow the identification of small
vessels, bronchi, interlobular septa, and some pathologic findings. With 1.5-mm
collimation, greater contrast was evident between vessels and surrounding lung
parenchyma, more branches of small vessels were seen, and small bronchi were
more often recognizable than with 3-mm collimation (12). Also, slight increases
in lung attenuation (as may be seen in early interstitial lung disease), or
decreases in attenuation (as in emphysema), were better resolved with 1.5-mm
collimation. However, the authors concluded that certain pathologic findings,
such as thickened interlobular septa, were similarly visible on images with 1.5and 3-mm collimation (12).
There are several differences in how lung structures are visualized on scans
performed with thin (e.g., 1-mm) and thick (e.g., 5-mm) sections. With thin
slices, it is more difficult to follow the courses of vessels and bronchi than it is
with thick slices. With thick slices, for example, vessels that lie in the plane of
scan look like vessels (i.e., they appear cylindrical or branching) and can be
clearly identified as such. With thin slices, vessels can appear round or oval (i.e.,
nodular) because only short segments may lie in the plane of scan (Fig. 1-1).
With experience, this difficulty is easily avoided.
FIGURE 1-1 Effect of slice thickness on resolution. A: Helical CT with 5-mm slice thickness,
reconstructed with the standard algorithm in a normal subject. A number of branching pulmonary
vessels are visible (arrows). B: Helical CT at the same level with 1.25-mm slice thickness
reconstructed with the same scan data and algorithm. Pulmonary arteries seen as branching or
cylindrical on the thicker scan appear “nodular” on the scan with 1.25-mm slice thickness
(arrows). The resolution is clearly improved with thin slices.
Also, with thin slices, the diameter of a vessel that lies in or near the plane of
scan can appear larger than it does with thicker slices because less volume
averaging occurs between the rounded edge of the vessel and the adjacent airfilled lung; thin scans more accurately reflect vessel diameter in this setting,
analogous to the better estimation of the diameter of a lung nodule that is
possible with thin slices. Furthermore, with thin slices, bronchi that are oriented
obliquely relative to the scan plane are much better defined than they are with
thicker slices, and their wall thicknesses and luminal diameters are more
accurately assessed (14). The diameters of vessels or bronchi that lie
perpendicular to the scan plane appear the same with both thin and thick
collimation.
Reconstruction Algorithm
The inherent or maximum spatial resolution of a CT scanner is determined by
the geometry of the data-collecting system and the frequency at which scan data
are sampled during the scan sequence (10). The spatial resolution of the image
produced is less than the inherent resolution of the scan system, depending on
whether axial or volumetric (helical) imaging is used, the reconstruction
algorithm, the matrix size, and the field of view (FOV), all of which in turn
determine pixel size. In HRCT, these parameters are optimized to increase the
spatial resolution of the image.
With body CT, scan data are usually reconstructed with a relatively low spatial
frequency algorithm (e.g., “standard” or “soft-tissue” algorithms) that smoothes
the image, reduces visible image noise, and improves the contrast resolution to
some degree (11,15). Low spatial frequency simply means that the frequency of
information recorded in the final image is relatively low; it is the same as saying
that the algorithm is low resolution rather than high resolution.
Reconstruction of images using a sharp, high spatial frequency, or highresolution algorithm reduces image smoothing and increases spatial resolution,
making structures appear sharper (Figs. 1-2 to 1-4) (6,10,12,16). Using a highresolution algorithm is a critical element in performing HRCT (Table 1-1)
(11,15). In one study of HRCT techniques (10), the use of a high spatial
frequency algorithm to reconstruct scan data resulted in a quantitative
improvement in spatial resolution when compared to a standard algorithm (Fig.
1-3); in this study, subjective image quality was also rated more highly with the
high spatial frequency algorithm. In another study of HRCT (12), small vessels
and bronchi were better seen when images were reconstructed with a high-
resolution algorithm than when the standard algorithm was used. The use of a
sharp algorithm has also been recommended to improve spatial resolution for
routine chest CT reconstructed with thicker slices (17).
FIGURE 1-2 Effect of reconstruction algorithm on resolution. MD-HRCT obtained with 1.25mm slice thickness in a patient with usual interstitial pneumonia has been reconstructed using a
high-resolution (sharp) algorithm (A) and a smooth (standard) algorithm (B). Lung structures,
reticular opacities, and traction bronchiectasis are much more sharply defined with the highresolution algorithm.
FIGURE 1-3 Effect of reconstruction algorithm on spatial resolution. A: HRCT of a line-pair
phantom obtained with 1.5-mm collimation and reconstructed with the standard algorithm.
Numbers indicate the resolution in line pairs per centimeter. The resolution with this technique is 6
line pairs per centimeter. B: When the same scan is reconstructed using the high-resolution (i.e.,
bone) algorithm, spatial resolution improves. Also, in contrast to the scan reconstructed using the
standard algorithm, 7.5 line pairs are easily resolved (arrow), and edges are considerably sharper.
(From Mayo JR, Webb WR, Gould R, et al. High-resolution CT of the lungs: an optimal approach.
Radiology 1987;163:507, with permission.)
FIGURE 1-4 Effect of reconstruction algorithm on resolution and image noise. A 1.25-mm MDHRCT has been reconstructed with high-resolution (A) and standard (B) algorithms. A: The image
reconstructed with the high-resolution algorithm is sharper and shows more detail, but streak
artifacts due to aliasing and noise are more apparent. B: Resolution is diminished with this
algorithm. The image appears smoother with this algorithm, and noise is less apparent.
Kilovolts (Peak), Milliamperes, and Scan Time
Using a sharp or high-resolution reconstruction algorithm, in addition to
increasing image detail, increases the visibility of noise in the CT image (11,15).
This noise usually appears as a graininess, mottle, or streaks that can be
distracting and may obscure anatomical detail (Fig. 1-4) (10). Because much of
this noise is quantum related, it is inversely proportional to the number of
photons absorbed (precisely, it is inversely proportional to the square root of the
product of mA and scan time) (16). Consequently, it increases with decreasing
mAs or kilovolt peak (kV(p)) and decreases with increased mAs or kV(p) (Fig.
1-5) (10,16). For example, in one study using an early-generation scanner (10), a
measure of image noise was reduced by approximately 30% when kV(p)/mAs
were increased from 120/200 to 140/340 (Fig. 1-5), and the scans with increased
kV(p) and mAs settings were rated as being of better quality in 80% of cases
(Fig. 1-6) (10).
FIGURE 1-5 Effect of algorithm, kV(p), and mA on image noise. Graph of HRCT image noise
(SD of HU measurements) in an anthropomorphic CT phantom as related to the reconstruction
algorithm and scan technique. Noise increases when the bone (high-resolution) algorithm is used
instead of the standard algorithm. With the bone algorithm, noise decreases approximately 30%
with increased kV(p) and mA settings. (From Mayo JR, Webb WR, Gould R, et al. High-resolution
CT of the lungs: an optimal approach. Radiology 1987;163:507, with permission.)
FIGURE 1-6 A and B: Effect of kV(p) and mA on image noise. Axial HRCT obtained with a
tube current of 100 mA (A) and 400 mA (B) in a patient with atypical mycobacterial infection.
There is a relative increase in noise in A, which is evident both in the soft tissues and lung. Note,
however, that the lower-dose scan (A) is still of diagnostic quality.
Although increasing mAs or kV(p) above routine values can reduce image
noise, it is not necessary for obtaining adequate HRCT images, and maintenance
of patient radiation dose at a reasonable level is considered to be more important
(16). With current scanners and reconstruction algorithms, diagnostic scans can
be obtained using mAs and kV(p) techniques considered routine for chest CT.
Scan techniques with a kV(p) of 120 are generally used, although a reduced
kV(p) of 100 or 80 may be used in small or pediatric patients (i.e., less than 80
or 60 kg) (13).
Using mAs (or effective mAs) values of 100 or less has proven satisfactory for
obtaining HRCT in most patients with current-generation scanners (13,18).
Increased patient size and increased chest wall thickness are associated with
increased image noise; this may be reduced with increased mA (Fig. 1-7) (10).
Reducing mA to 40 (i.e., low-dose CT) may be used to reduce image dose, but
this should generally be reserved for small or pediatric patients. Image noise
may be excessive with low mA settings in large patients (Fig. 1-8).
FIGURE 1-7 Relationship of noise to patient size. Graph of image noise measured using an
anthropomorphic chest phantom, with simulated thick and thin chest walls. Noise significantly
increases with the thick chest wall. (From Mayo JR, Webb WR, Gould R, et al. High-resolution CT
of the lungs: an optimal approach. Radiology 1987;163:507, with permission.)
FIGURE 1-8 A–C: Low-dose (40 mA) axial HRCT in a large patient. Images through the
upper (A), mid- (B), and lower (C) lungs are shown from a normal HRCT obtained at 1-cm
intervals in the supine position in inspiration using a fixed tube current (40 mA). Dynamic
expiratory images were also obtained at three selected levels. The estimated effective dose for
this examination was 0.2 mSv. However, image noise is excessive, and subtle abnormalities may
be difficult to detect.
Specific mA, kV(p), pitch (with helical scanning), and gantry rotation times
most appropriate for HRCT vary with different scanners. When obtaining helical
HRCT, the use of dynamic, modulated, or adaptive mA that varies with body
thickness should generally be used to keep radiation dose low, without
sacrificing image quality (19). In large patients, a reasonable maximum mA
should be set when using this technique, to avoid inappropriately high
exposures.
Because of artifacts related to patient motion, breathing, and cardiac pulsation,
it is desirable to minimize scan or gantry rotation time. A scan time or gantry
rotation time of 0.5 s or less is optimal for HRCT and, if available, is
recommended (Table 1-1). Most current scanners have gantry rotation times of
300 to 500 ms.
Field of View and Targeted Reconstruction
Scanning should be performed using the smallest FOV that will encompass the
patient (e.g., 35 cm), as this reduces pixel size. Retrospectively targeting image
reconstruction to a single lung instead of the entire thorax significantly reduces
the FOV and image pixel size, and thus increases spatial resolution (Figs. 1-9
and 1-10) (10,20,21). For example, with a 40-cm reconstruction circle (FOV)
and a 512 × 512 matrix, pixel size measures 0.78 mm. With targeted image
reconstruction using a 25-cm FOV, pixel size is reduced to 0.49 mm, and the
spatial resolution is correspondingly increased (Fig. 1-9). Using a 15-cm FOV
further reduces pixel size to 0.29 mm, but this FOV is usually insufficient to
view an entire lung and is not often used clinically. It should be recognized,
however, that the improvement in resolution obtainable by targeting is limited by
the intrinsic resolution of the detectors used.
FIGURE 1-9 Effect of targeted reconstruction on resolution. A: HRCT image in a patient with
end-stage sarcoidosis obtained with a 38-cm FOV and 1.5-mm collimation, and reconstructed
using a high-resolution algorithm and a 38-cm reconstruction circle. B: The same CT scan has
been reconstructed using a targeted FOV (15 cm), reducing image pixel diameter. Image
sharpness is improved compared to A.
FIGURE 1-10 Effect of targeted reconstruction on spatial resolution. A: HRCT of a line-pair
phantom. The scan was obtained with a 40-cm FOV, and reconstructed using a targeted FOV of
25 cm. The resolution with this technique is 7.5 line pairs (arrow). B: The same scan viewed
without targeting shows the effects of larger pixel size. Only 6 line pairs can be resolved (arrow),
and the margins of the lines appear jagged or wavy. (From Mayo JR, Webb WR, Gould R, et al.
High-resolution CT of the lungs: an optimal approach. Radiology 1987;163:507, with permission.)
The use of targeted reconstruction is often a matter of personal preference. In
clinical practice, the use of image targeting is uncommon because it requires
additional reconstruction time, the raw scan data must be saved until targeting is
performed, and display of the individual lung images is somewhat cumbersome.
With a nontargeted reconstruction, the ability to see both lungs on the same
image allows a quick comparison of one lung to the other; this can be quite
helpful in diagnosis and is preferred to the marginal increase in resolution
achieved with targeting.
Inspiratory Level
Routine HRCT is obtained during suspended full inspiration, which (a)
optimizes contrast between normal structures, various abnormalities, and normal
aerated lung parenchyma; and (b) reduces transient atelectasis, a finding that
may mimic or obscure significant abnormalities. Selected scans obtained during
or after forced expiration may also be valuable in diagnosing patients with
obstructive lung disease or airway abnormalities. The use of expiratory HRCT is
discussed later in this chapter, and in Chapters 2 and 7.
Patient Position and the Use of Prone Scanning
Scans obtained with the patient supine are adequate for diagnosis in most
instances. However, scans obtained with the patient positioned prone are
sometimes necessary for diagnosing subtle lung abnormalities. Atelectasis is
commonly seen in the dependent lung (i.e., posterior lung on supine scans) in
both normal and abnormal subjects, resulting in a so-called dependent density or
subpleural line (Fig. 1-11) (22,23). These normal findings can closely mimic the
appearance of early lung fibrosis, and they can be impossible to distinguish from
true pathology on supine scans alone. However, if scans are obtained in both
supine and prone positions, dependent density can be easily differentiated from
true pathology. Normal dependent density disappears in the prone position (Fig.
1-11); a true abnormality remains visible regardless of whether it is dependent or
nondependent (Figs. 1-12 and 1-13).
FIGURE 1-11 Transient dependent density. A: Supine scan shows ill-defined opacity in the
posterior lungs (arrows). B: On a prone image, the posterior lung appears normal. Note that some
dependent opacity is now visible in the anterior lung.
FIGURE 1-12 Persistent opacity in the posterior lung in a patient with mild pulmonary fibrosis.
A: Supine scan shows ill-defined opacity in the posterior lungs and in a subpleural region
anteriorly. B: On a prone image, the posterior lung is unchanged in appearance, indicative of lung
disease.
FIGURE 1-13 Persistent posterior lung ground opacity on prone scans in a patient with
scleroderma and NSIP. A: Supine scan shows ill-defined opacity in the posterior lungs. B: On a
prone image, the posterior subpleural lung opacity is unchanged in appearance, and the presence
of true lung disease can be diagnosed.
Dependent density results in a diagnostic dilemma only in patients who have
normal lungs or subtle lung abnormalities. In patients with obvious
abnormalities, such as honeycombing, or in patients with diffuse lung disease,
dependent density is not usually a diagnostic problem. Thus, if the patient being
studied has evidence of moderate-to-severe lung disease on plain radiographs,
prone scans are not likely to be needed. However, if the patient is suspected of
having an interstitial abnormality and the plain radiograph is normal or near
normal, or the results of chest radiographs are unknown, prone scans may prove
helpful. In addition, even in patients with obvious lung disease on supine scans,
prone scans may prove useful in identifying specific important diagnostic
findings (i.e., subtle posterior lung honeycombing), not clearly seen on the
supine images.
Volpe et al. (24) assessed the usefulness of prone scans in patients who had
chest radiographs read as normal, possibly abnormal, or definitely abnormal.
Overall, prone scans were considered helpful in 17 of 100 consecutive patients
having HRCT (24). Prone HRCT scans were helpful in confirming or ruling out
posterior lung abnormalities in 10 of 36 (28%) patients who had normal findings
on chest radiographs, 5 of 18 (28%) patients who had possibly abnormal
findings on chest radiographs, and only 2 of 46 (4%) patients who had definitely
abnormal findings on chest radiographs. The proportion of patients who
benefited from prone scans was significantly lower among the patients with
abnormal findings on chest radiographs than among the patients with normal (p
= 0.008) or possibly abnormal (p = 0.02) findings. The two patients who had
abnormal findings on radiographs and in whom CT scans obtained with the
patient prone were helpful had minimal radiographic abnormalities.
Some investigators (21,25) obtain HRCT in the prone position only when
dependent lung collapse is problematic (26); however, this approach requires
that the scans be closely monitored or that the patient be called back for
additional scans. Others use prone scanning in specific clinical settings, for
example, when asbestosis or early lung fibrosis is suspected, whereas still others
obtain prone scans routinely (22,27). In patients who are suspected of having
emphysema, airways disease such as bronchiectasis, or another obstructive lung
disease, dependent atelectasis is not usually a diagnostic problem, and prone
scans are not usually needed.
Spaced axial prone scans, prone scans clustered near the lung bases, or
volumetric helical imaging in the prone position may all be used. Some
protocols call for prone volumetric imaging only (i.e., no supine scans are
obtained) (28); this would be most useful in a patient suspected of having a
disease with a posterior lung predominance, such as asbestosis or idiopathic
pulmonary fibrosis.
TECHNIQUES OF SCAN ACQUISITION: SPACED AXIAL
SCANNING VERSUS VOLUMETRIC SCANNING
Before the introduction of MDCT scanners, HRCT was performed by obtaining
individual scans at spaced intervals. This technique remains in use today.
However, the development of MDCT scanners, capable of rapidly imaging the
thorax using an isotropic technique, has greatly expanded the ways in which a
HRCT study may be obtained (13).
Spaced Axial Scans
HRCT may be performed with individual axial scans being obtained at spaced
intervals, usually 1 to 2 cm, without table motion (Figs. 1-14 and 1-15). In this
manner, HRCT is intended to “sample” lung anatomy, with the assumptions
being that (a) a diffuse lung disease will be visible in at least one of the levels
sampled and (b) the findings seen at the levels scanned will be representative of
what is present throughout the lung. These assumptions have proven valid during
more than 20 years of experience with HRCT (29).
FIGURE 1-14 A and B: Comparison of prone 1.25-mm spaced axial HRCT (A) and 1.25-mm
MD-HRCT (B) in a patient with scleroderma and fibrotic NSIP. Two prone HRCT images at the
same level are shown in a patient with scleroderma-related NSIP. While of similar diagnostic
quality, the axial HRCT (A) has slightly better resolution and the structures and abnormalities
appear sharper than on the helical HRCT (B).
FIGURE 1-15 Comparison of 1.25-mm spaced axial HRCT (A) and 1.25-mm MD-HRCT (B
and C) in a patient with mixed connective tissue disease and NSIP. A: Axial 1.25-mm HRCT
shows irregular reticulation, ground-glass opacity, and traction bronchiectasis with lower-lobe
predominance. Subpleural sparing is present. These findings are typical of NSIP. 2D and 3D
reconstructed images from the MD-HRCT are also shown in Fig. 1-16. B and C: Comparable
levels from the MD-HRCT show identical findings. There is no significant difference in diagnostic
value of the axial and MD-HRCT images, although the MD-HRCT images appear slightly
smoother.
When spaced axial scanning is chosen for HRCT, we consider scans obtained
at 1-cm intervals, from the lung apices to bases, to be the most appropriate
routine scanning protocol, allowing an adequate sampling of the lung and lung
disease regardless of its distribution.
In early reports, HRCT scanning was sometimes performed with scans at 2-,
3-, and even 4-cm intervals (3,26); at three preselected levels (25); or at one or
two levels through the lower lungs (21). Although such wide spacing may be
sufficient for assessing some patients and some lung diseases, in many cases,
these protocols would prove inadequate for initial diagnosis. It should be pointed
out, however, that in patients with a known disease, a limited number of HRCT
images may be sufficient to assess disease extent. For example, in one study
(30), the ability of HRCT obtained at three selected levels (limited HRCT) to
show features of idiopathic pulmonary fibrosis was compared to that of HRCT
obtained at 10-mm increments (complete HRCT). HRCT fibrosis scores strongly
correlated with pathology fibrosis scores for both the complete (r = 0.53, p =
0.0001) and limited (r = 0.50, p = 0.0001) HRCT examinations. HRCT groundglass opacity scores also correlated with the histologic inflammatory scores on
the complete (r = 0.27, p = 0.03) and limited (r = 0.26, p = 0.03) HRCT
examinations. Similarly, in evaluating patients with asbestos exposure, several
investigators have suggested that a limited number of scans should be sufficient
for the diagnosis of asbestosis (22,27,31–34). Obtaining four or five scans near
the lung bases has proved to have good sensitivity in patients with suspected
asbestosis (35). Thick-slice CT, combined with a few HRCT images, has also
been applied to patients with suspected diffuse lung disease and has been shown
to be clinically efficacious (35); HRCT scans obtained at the levels of the aortic
arch, carina, and 2 cm above the right hemidiaphragm allow the assessment of
the lung regions in which lung biopsies are most frequently performed (11).
In patients who are likely to require prone images, prone scans can be added
to the routine supine sequence obtained with 1-cm scan spacing; a reasonable
protocol would include additional prone scans at 2-cm intervals. Although axial
imaging is a low-dose technique, if further radiation dose reduction is a concern,
scans could be obtained at 2-cm intervals from lung apices to bases, in both
supine and prone positions. Because the prone and supine images will be slightly
different, even if an attempt is made to obtain the scans at exactly the same
levels, the number of different levels scanned will be equivalent to a supine
position scan protocol using 1-cm spacing.
Another dose reduction technique used with axial imaging is to customize the
number or location of scans, depending on the patient’s suspected disease,
clinical findings, or the location of plain radiographic abnormalities. For
example, if the lung disease being studied predominates in a certain region of
lung, as determined by chest radiographs, conventional CT (21), or other
imaging studies, it makes sense that more scans should be obtained in the most
abnormal area. In patients with suspected asbestosis, it has been recommended
that more scans be performed near the diaphragm than in the upper lobes
because of the typical basal distribution of this disease, even if the chest
radiograph does not suggest an abnormality in this region (22,27).
Some support for this approach has been lent by a paper (36) describing
theoretical methods useful in selecting the appropriate number of HRCT images
for estimating any quantitative parameter of lung disease. A marked reduction in
the number of images necessary for quantification of a desired parameter can be
achieved by using a stratified sampling technique based on prior knowledge of
the disease distribution.
Spaced axial HRCT scans may be obtained in combination with a volumetric
helical CT study, in which the entire thorax is imaged (11,21,25), although this is
rarely needed in current practice. If both volumetric imaging and HRCT are
needed for diagnosis, it is usually adequate to reconstruct the volumetric scan
with thin slices and a sharp algorithm.
However, Leswick et al. (37) compared the patient radiation dose from a
combination of spaced axial HRCT and volumetric helical MDCT to that from a
volumetric helical HRCT having a noise level similar to that of the axial scans.
The authors found that the volumetric helical HRCT had a radiation dose 32%
higher than that in the combined study (37).
Volumetric High-Resolution Computed Tomography
The use of MDCT scanners capable of rapid scanning and thin-slice acquisition
has revolutionized HRCT technique. Volumetric HRCT using thin detectors
(0.5–0.625 mm) has become the routine in many institutions.
In an early attempt at volumetric imaging (38), four contiguous HRCT scans
were obtained without using helical technique at each of three locations (the
aortic arch, carina, and 2 cm above the right hemidiaphragm) in 50 consecutive
patients with interstitial lung disease or bronchiectasis. At each level, the
diagnostic information obtainable from the set of four scans was compared to
that obtainable from the first scan in the set of four. When the full set of four
scans was considered, more findings of disease were identified. The sensitivity
of the first scan as compared to the set of four was 84% for the detection of
bronchiectasis, 97% for ground-glass opacity, 88% for honeycombing, 88% for
septal thickening, and 86% for nodular opacities (38). However, it is more likely
that the improvement in sensitivity found using the set of four scans reflects the
number of scans viewed rather than the fact that they were obtained in
contiguity.
Although volumetric HRCT images appear slightly smoother than axial
HRCT (Figs. 1-14 and 1-15), the technique has several advantages. It allows (a)
complete imaging of the lungs and thorax, (b) viewing of contiguous slices for
the purpose of better defining lung abnormalities, (c) reconstruction of scan data
in any plane or using maximum-intensity projections (MIPs) or minimumintensity projections (MinIPs), (d) precise level-by-level comparison of studies
obtained at different times for evaluation of disease progression or improvement,
and (e) the diagnosis of additional thoracic abnormalities (Figs. 1-16 to 1-24).
On the other hand, the use of volumetric multidetector helical HRCT (MDHRCT) results in a greater radiation dose than does spaced axial imaging.
FIGURE 1-16 Reconstructed MD-HRCT in a patient with mixed connective tissue disease
and NSIP. This is the same patient as shown in Fig. 1-15. A: 2D coronal reconstruction shows
findings identical to those in Fig. 1-15. The basal distribution of the abnormalities is well shown,
but the same information would be available from review of the transaxial images. B: 2D sagittal
reconstruction clearly shows the posterior and lower-lobe predominance of the abnormalities,
lower-lobe volume loss as evidenced by posterior displacement of the major fissure (white
arrows), and subpleural sparing (black arrows). C: 3D surface-display reconstruction with a
perspective from below the lung bases shows the distribution of basal-predominant lung disease,
but otherwise is of little diagnostic value. D: Transaxial MIP image at the same level as shown in
Fig. 1-15C. MIP imaging in this patient obscures detail and is of little diagnostic value. E and F:
3D MinIP coronal (E) and sagittal (F) reconstructions show the airways and lower-lobe traction
bronchiectasis to best advantage. Ground-glass opacity is less apparent in the lung bases than on
the routine images.
FIGURE 1-17 Reconstructed images in a patient with interstitial pneumonia. This represents
the same patient as shown in Fig. 1-2. A: Transaxial MD-HRCT with 1.25-mm slice thickness
shows reticulation, traction bronchiectasis, and ground-glass opacity with a posterior and
subpleural distribution. The upper lobes were less abnormal. B: Sagittal reconstruction (0.7 mm
thick) shows these abnormalities to predominate in the posterior and basal subpleural lung
(arrows). C: Coronal reconstruction (0.7 mm thick) through the posterior lung shows a similar
distribution.
FIGURE 1-18 Contrast-enhanced MD-HRCT in an AIDS patient with pulmonary
hypertension, obtained with 1.25-mm slice thickness. The differential diagnosis included chronic
pulmonary embolism, vasculitis, and lung disease. Transaxial (A and B) and sagittal
reconstructed (C) HRCTs obtained during a single breath hold show normal findings. D:
Transaxial image shows enlargement of main pulmonary artery consistent with pulmonary
hypertension, but no evidence of pulmonary embolism. The presence of pulmonary hypertension
in the absence of pulmonary embolism or lung disease suggests AIDS-related pulmonary
hypertension with plexogenic arteriopathy.
FIGURE 1-19 Contrast-enhanced MD-HRCT obtained with 1.25-mm slice thickness in a 19year-old woman with hypoxemia. Transaxial (A and B) images show numerous very small
subpleural arteriovenous malformations (arrows). One-centimeter-thick MIP images in the
transaxial (C, D) and coronal (E) planes show the malformations (arrows) and their vascular
supply to better advantage. She was subsequently found to have Osler-Weber-Rendu disease.
FIGURE 1-20 Coronal (A) and sagittal (B) MinIP reconstruction from 1.25-mm MD-HRCT in a
patient with lymphangiomyomatosis. The MinIP images optimize visualization of the lung cysts
and their distribution.
FIGURE 1-21 MIP image in a patient with small lung nodules obtained using a multidetectorrow helical CT scanner with 1.25-mm detector width and a pitch of 6. A: A single HRCT image
shows two small nodules (arrows) that are difficult to distinguish from vessels. B: An MIP image
consisting of eight contiguous HRCT images, including A, allows the two small nodules to be
easily distinguished from surrounding vessels.
FIGURE 1-22 MIP image in a patient with extensive abnormalities due to alveolar proteinosis
obtained using MD-HRCT and 1.25-mm slice thickness. A: A single HRCT image shows a typical
patchy distribution of interlobular septal thickening and ground-glass opacity (i.e., crazy paving)
typical of alveolar proteinosis. B: A MIP image consisting of five contiguous HRCT images,
including A, results in a confusing superimposition of opacities. Septal thickening is more difficult
to diagnose.
FIGURE 1-23 MinIP image in the patient shown in Fig. 1-21A at the same anatomical level.
Normal lung parenchyma appears relatively homogeneous. Pulmonary vessels disappear on
MinIP images.
FIGURE 1-24 MD-HRCT image with contrast enhancement in a patient with bronchiolitis
obliterans and a clinical suspicion of pulmonary embolism. No pulmonary embolism was found. A:
A single HRCT image with 1.25-mm detector width shows bronchiectasis and patchy lung
attenuation with reduced artery size in lucent lung regions due to air trapping and mosaic
perfusion. B: A 10-mm-thick MinIP image at the same level as A accentuates the differences in
attenuation between normal lung and lucent lung, but pulmonary arteries cannot be assessed.
Bronchiectasis is well seen using MinIP imaging. C: MIP at the same level as B shows reduced
vessel size in the lucent lung regions. Inhomogeneous lung attenuation is also visible. The
bronchiectasis is difficult to see on the MIP image.
It is not unusual for only one or two slices from a volumetric HRCT study to
provide the key observations necessary for diagnosis (39–44). For example, in a
patient with suspected idiopathic pulmonary fibrosis, the presence of
honeycombing, which is necessary for a definite diagnosis, may be visible only
on a few images. This finding could be missed on spaced axial images.
MDCT scanners make use of multiple adjacent detector rows that acquire scan
data simultaneously and may be used independently or in combination to
generate images of different thickness (45). Current MDCT scanners are capable
of imaging the entire thorax within a few seconds, with the volumetric
reconstruction of thin, high-resolution slices. For example, using a 64-detector
scanner, data may be simultaneously acquired from sixty-four 0.625-mm-thick
detector arrays, a pitch of 1 to 1.5, and a gantry rotation time of 0.5 s or less. The
volumetric data resulting from this mode of scanning allow isotropic imaging
and HRCT assessment of lung morphology in a continuous fashion from lung
apex to base, the viewing of the scan volume in nontransaxial planes or with
three-dimensional (3D) reconstruction (Figs. 1-16A–C to 1-18), and the
production of MIP and MinIP images at any desired level or in alternate planes
(Figs. 1-16D–F and 1-19 to 1-24). This technique also allows a volumetric CT
examination of the thorax to be easily combined with HRCT.
Even with a rapid scanner, dyspneic patients with diffuse lung disease may not
be able to hold their breath for the duration of a volumetric study. In such
patients, if optimal resolution is desired, the scan protocol may be modified
according to the distribution of the disease suspected. For diseases likely to have
a basal predominance, such as idiopathic pulmonary fibrosis, scanning should
begin near the diaphragm and proceed cephalad. In this manner, the more
important basal lung will be imaged at the beginning of the scan sequence, and if
the patient begins to breathe during scanning, only images through the less
important upper lobes will be degraded by respiratory motion. For the same
reason, in a patient suspected of having a disease with an upper-lobe
predominance (e.g., sarcoidosis), it is appropriate to begin scanning in the lung
apices. Because lung movement with respiration is greatest at the lung bases, an
alternative approach would be to scan from the bases to apices in all patients. If
the patient breathes during the scan, the upper lobes would be less affected.
The helical acquisition of HRCT data results in some broadening of the scan
profile as compared to detector width. Using a low value of pitch (e.g., 1) is
recommended to minimize this effect (29). However, the effective slice thickness
obtained using MD-HRCT is clearly sufficient for HRCT diagnosis when thin
detectors are used (Figs. 1-14 and 1-15). With 0.625-mm detector width and a
pitch of 1, the effective slice thickness is 1 mm or less. Practically speaking, in
most situations, using thin detectors and standard pitch is adequate for diagnosis.
Depending on the technique used and how data from the various detector rows
are combined, images of different thickness may be produced retrospectively
from the same study. Using the protocol described previously, in addition to
viewing images generated from data acquired by the individual detectors, data
from the detector rows may be combined to produce images representing thicker
slices (i.e., 2.5 or 5 mm). Thus, this technique enables HRCT and “routine” or
thick-section chest imaging to be combined as a single examination, blurring the
distinction between these studies.
Combining a volumetric chest CT examination with HRCT by using MDCT
may be of value in patients being studied primarily for diffuse lung disease, for
which HRCT would be the examination of choice, and in patients being
evaluated for a disease or abnormality usually studied using a thicker-slice
helical CT. For example, in patients with hemoptysis, both thin and thick image
reconstruction may be of value in demonstrating both small or large airways
disease and vascular abnormalities (46). Another advantage of MDCT would be
in patients requiring CT for the diagnosis of thoracic disease such a lung
carcinoma. In such patients, scan data may be reconstructed with a thickness
appropriate for the detection of lung nodules and bronchial abnormalities and for
assessment of mediastinal and hilar lymph nodes. At the same time, and without
additional scanning, high-resolution images could be reconstructed for the
purpose of delineating nodule morphology and attenuation, or for the diagnosis
of associated lymphangitic spread of carcinoma.
Similarly, in patients with suspected pulmonary vascular disease, HRCT with
contrast enhancement may be obtained using MDCT, allowing the detailed
assessment of both vasculature and pulmonary parenchyma (Figs. 1-18 and 119) (46,47). In patients having helical CT for the diagnosis of acute or chronic
pulmonary embolism or pulmonary hypertension, scan data can be reconstructed
using different algorithms to look for vascular abnormalities and lung disease
that could be associated with similar symptoms.
Although it is clear that MDCT scanners produce diagnostic helical HRCT
examinations, the results of studies comparing MD-HRCT to spaced axial HRCT
have been mixed, and neither imaging method appears to offer a clear advantage.
For example, Sumikawa et al. (48) found that the quality of MD-HRCT images
was equivalent to that of axial HRCT in 11 autopsy lungs; visualization of
abnormal structures and diagnostic efficacy with MD-HRCT (0.75-mm
collimation, pitch of 1) was equal to that of axial scans with 0.75-mm
collimation. Also, Schoepf et al. (49) compared MD-HRCT using a 1.25-mm
detector and a pitch of 1.5 with spaced axial images (1-mm slices) in two groups
of patients. No significant difference (p = 0.986) was found between multislice
and single-slice axial HRCT sections in an overall score of image quality, spatial
resolution, subjective signal-to-noise ratio, diagnostic value, depiction of bronchi
and parenchyma, and motion and streak artifacts (49). In contrast, Honda et al.
(50) compared the image quality and diagnostic efficacy of MD-HRCT (1.25mm slices) to axial HRCT (1-mm slices) in imaging cadaveric lungs. The image
quality of axial HRCT was considered superior to that of MD-HRCT obtained
with 1.25-mm detectors and a pitch of 0.75 or 1.5, and less image noise was
present with axial HRCT. However, the diagnostic efficacy of MD-HRCT with a
pitch of 0.75 was equal to that of axial HRCT (50).
Kelly et al. (51) found that MD-HRCT may be associated with significantly
greater motion artifact compared with axial HRCT obtained in the same patient.
However, MD-HRCT scans were obtained using 4-or 8-detector scanners, and
scan time was undoubtedly longer than that with current MDCT scanners. On the
other hand, Studler et al. (52) found that motion artifacts were significantly more
common on axial HRCT scans (1-mm collimation) than on MD-HRCT (1.5-mm
detectors, pitch 1.25) images (p < 0.001). However, the authors believed that the
assessment of ground-glass opacity was superior on axial HRCT. The effective
radiation doses were 3.8 millisievert (mSv) for MDCT and 0.9 mSv for axial
HRCT. When considering the relative value of spaced axial HRCT and MDHRCT, the greater radiation dose involved in MD-HRCT should be kept in
mind.
Benaoud et al. (53) compared 1-mm-thick images reconstructed contiguously
through the chest with images spaced at 1-cm intervals in the evaluation of
chronic bronchopulmonary diseases. The spaced reconstructions would have
resulted in a 79% radiation reduction, and there was almost perfect agreement
(kappa = 0.83–1) for both the detection and distribution and findings between
the volumetric and spaced reconstructions (53). In the screening of patients with
scleroderma, Winklehner et al. (54) showed equal sensitivity for interstitial lung
disease comparing volumetric MD-HRCT and spaced 1-mm sections
reconstructed at 1-cm intervals. Certain HRCT findings, however, that have a
heterogenous distribution may be better detected and quantified using volumetric
HRCT. For instance, in the assessment of bronchiolitis obliterans syndrome
(BOS) in lung transplant recipients, Dodd et al. (55) showed that volumetric
MDCT correlated with the stage of BOS, whereas spaced HRCT images did not.
Despite these limitations, volumetric HRCT is becoming standard in many
patients, for many indications, and in many institutions. At least partially, this
reflects recent advances in radiation dose reduction with volumetric CT. Often,
only the supine images will be obtained with volumetric imaging technique.
Reconstruction Techniques with Volumetric HighResolution Computed Tomography
Sagittal and Coronal Reformations
MD-HRCT produces isotropic scans, allowing contiguous 3D visualization of
the lung parenchyma and the capacity to create high-quality two-dimensional
(2D) and 3D reformatted images (Figs. 1-16 to 1-20) (20). Honda et al.
compared the quality of coronal multiplanar reconstructions obtained from an
MDCT data set (0.5-mm collimation, 0.5-mm reconstruction interval) with the
quality of direct coronal MD-HRCT (0.5-mm collimation) scans in 10 normal
autopsy lung specimens. Image quality was considered equal (56). It is clear that
MD-HRCT reconstructions may provide additional information in selected cases
(20), largely in regard to lung disease distribution, but routine transverse images
are adequate for diagnosis in the large majority of cases.
It has been suggested that the use of 2D coronal reconstructions may be useful
for the primary interpretation of thoracic CT, but at present, it would seem most
appropriate to use multiplanar reconstructions as a compliment to axial images.
Kwan et al. (57) compared the accuracy and efficiency of primary interpretation
of thoracic MDCT (5-mm slice thickness) using coronal reformations to that of
routine transverse images. Each image set was assessed for 58 abnormalities of
the lungs, mediastinum, pleura, chest wall, diaphragm, abdomen, and skeleton.
The mean detection sensitivity of all lesions was significantly (p = 0.001) lower
on coronal (44% ± 26% [SD]) than on transverse (51% ± 22%) images, whereas
the mean detection specificity was significantly (p = 0.005) higher (96% ± 5%
vs. 95% ± 6%, respectively). Also, reporting findings for fewer coronal images
took significantly (p = 0.025) longer (mean, 263 ± 56 s vs. 238 ± 45 s,
respectively) (57). Arakawa et al. (58) evaluated the diagnostic utility of coronal
MD-HRCT reformations (1.9-mm thickness) to axial HRCT (2-mm collimation)
in diffuse and focal lung diseases. In 22.1% of cases, coronal MD-HRCT
reformations were regarded as superior to axial HRCT or provided additional
information, whereas in 72.4%, coronal MD-HRCT was regarded as comparable
to axial HRCT, and in 5.5% it was considered inferior to axial images (58).
Remy-Jardin et al. (59) assessed the diagnostic accuracy of coronal
reconstructions as an alternative to transverse MD-HRCT in the diagnosis of
infiltrative lung disease. No significant difference was found between the
transverse and coronal images in the identification of CT features of disease or
their distribution in the central, peripheral, anterior, and/or posterior lung zones.
However, in patients with extensive lung disease, the cephalocaudal distribution
of lung abnormalities was more precisely assessed with coronal reconstructions
(59).
Nishino et al. (60) attempted to determine whether sagittal reformations of
volumetric MD-HRCT provide additional information in evaluating lung
abnormalities, when compared to axial HRCT images. Additional findings of
diagnostic significance were identified on the sagittal reconstructions in 2 or 22
patients, principally related to the relationship of a nodule or mass to the
fissures, pleura, or pericardium (60).
Maximum-and Minimum-Intensity Projections
Several studies have used helical HRCT with thin collimation and MIPs or
MinIPs to acquire and display volumetric HRCT data for a slab of lung
(20,61–63). In a study by Bhalla et al. (61), when compared to conventional
HRCT, volumetric MIP and MinIP images demonstrated additional findings in
13 of 20 (65%) cases. However, the authors found that the conventional HRCT
scans showed fine linear structures, such as the walls of airways and interlobular
septa, more clearly than either MIP or MinIP images.
MIP imaging has been used to best advantage for the diagnosis of nodular
lung disease. MIP images increase the detection of small lung nodules and can
be helpful in demonstrating their anatomical distribution (Fig. 1-21). Coakley et
al. (62) assessed the use of MIP images in the detection of pulmonary nodules by
helical CT. In this study, 40 pulmonary nodules of high density were created by
placement of 2-and 4-mm beads into the peripheral airways of five dogs. MIP
images were generated from overlapped slabs of seven consecutive 3-mm slices,
reconstructed at 2-mm intervals, and acquired at pitch 2. MIP imaging increased
the odds of nodule detection by more than two, when compared to helical
images, and reader confidence for nodule detection was significantly higher with
MIP images.
In a study by Bhalla et al. (61), the use of helical HRCT and MIP images was
compared in patients with nodular lung disease. Because of the markedly
improved visualization of peripheral pulmonary vessels and improved spatial
orientation, MIP images were considered superior to helical scans for identifying
pulmonary nodules and specifying their location as peribronchovascular or
centrilobular, a finding of great value in differential diagnosis.
In another study (63), sliding-thin-slab MIP reconstructions were used in 81
patients with a variety of lung diseases associated with small nodules. In this
study, patients were studied using 1-and 8-mm-thick conventional CT and helical
CT with production of 3-, 5-, and 8-mm-thick MIP reconstructions. When
conventional CT findings were normal, MIPs did not demonstrate additional
abnormalities. When conventional CT findings were inconclusive, MIP enabled
the detection of micronodules (i.e., nodules 7 mm or less in diameter) involving
less than 25% of the lung. When conventional CT scans showed micronodules,
MIP showed the extent and distribution of micronodules and associated
bronchiolar abnormalities to better advantage. The sensitivity of MIP (3-mmthick MIP, 94%; 5-mm-thick MIP, 100%; 8-mm-thick MIP, 92%) was
significantly higher than that of conventional CT (8-mm-thick, 57%; 1-mmthick, 73%) in the detection of micronodules (p < 0.001). The authors (63)
concluded that sliding-thin-slab MIPs may help detect micronodular lung disease
of limited extent and may be considered a valuable tool in the evaluation of
diffuse infiltrative lung disease.
Sakai et al. attempted to determine whether MIP images assisted in the
diagnosis of the distribution of micronodules in a variety of focal and diffuse
infiltrative lung diseases. Ten-millimeter-thick MIP image slabs at 10-mm
intervals were produced from MD-HRCT. Radiology residents interpreting the
images benefited significantly from the use of MIPs, while board-certified
radiologists had equal accuracy with and without the MIPs (64).
Although MIP imaging may be valuable in the detection and diagnosis of lung
nodules or nodular lung disease and in the demonstration of vascular
abnormalities (Fig. 1-19), in patients with other abnormalities, MIP imaging may
result in a confusing superimposition of opacities that tends to obscure
anatomical detail. This is particularly true in patients with extensive groundglass opacity or reticular opacities (Figs. 1-16D and 1-22).
The utility of MinIP images (Figs. 1-20, 1-23, and 1-24) has also been
evaluated. MinIP images are most useful in the demonstration of abnormalities
characterized by low attenuation (Figs. 1-20 and 1-24) (61). In one study (61),
MinIP images were more accurate than routine HRCT scans in identifying (a)
the lumina of central airways (Figs. 1-16E,F and 1-24B), (b) areas of abnormal
low attenuation (e.g., emphysema or air trapping) (Figs. 1-20 and 1-24B), and
(c) ground-glass opacity.
RADIATION DOSE
The radiation dose associated with thoracic CT has received increased attention
in recent years, as have attempts at CT dose reduction (16,19,45,65–70). At the
same time, the development of volumetric MD-HRCT for diagnosing diffuse
lung disease has resulted in an increased patient radiation dose, as compared to
spaced axial HRCT. As pointed out by Aziz et al. (29), our enthusiasm for MDHRCT should be tempered by an understanding of the increased radiation dose
involved. Before the use of spaced axial imaging is abandoned, there should be
evidence that volumetric HRCT is superior (29).
Effective dose is a widely used measure of radiation exposure from medical
imaging (70). Effective dose is calculated by summing the absorbed doses to
individual organs weighted for their radiation sensitivity; the unit of
measurement is the sievert or millisievert. Determining the effective dose
requires the measurement of absorbed dose to each body organ multiplied by
their radiation sensitivity, which is impractical in the clinical setting. However, a
simpler calculation may be made in order to estimate the effective dose, based
on several assumptions (70). Scanner manufacturers use dose data derived from
measurements of radiation dose in phantoms to determine a weighted CT dose
index (CTDI) for each CT scanner model, at all available selections of tube
voltage (kV(p)), tube current (mA), and rotation time. The selected pitch value is
then incorporated to produce a CT dose index called the CTDIVOL, measured in
grays (Gy) or milligrays (mGy). The CTDIVOL allows a comparison of the
amount of radiation associated with different scanners and scan parameters, but
does not take into account the length of the scan or the radiation sensitivity of
affected tissues and organs.
The CTDIVOL is multiplied by the scan length in centimeters to calculate the
dose length product (DLP). The DLP is a measure of the overall radiation dose
delivered to the patient during the scan. An estimated effective dose for a
specified CT scan can be calculated by multiplying the DLP by a normalized
effective dose coefficient for the scanned body part (chest = 0.014 mSv/mGy/cm
or 1.4%) (71). The effective dose coefficient accounts for the radiation
sensitivity of the body region scanned, although specific organs are not
considered, and several assumptions are made; tissue-weighting factors are
averaged over sex and age and patient size, or in other words, this value assumes
an average patient (70). Although it does not provide a precise measurement, it
allows a general comparison of imaging studies. Yearly background radiation is
approximately 2.5 to 3 mSv.
HRCT performed with spaced axial images results in a low-radiation dose as
compared to MD-HRCT obtained with volumetric image acquisition (Fig. 1-25,
Table 1-2) (16,72). For example, Mayo et al. (72) compared the thoracic
radiation dose associated with spaced axial HRCT to that of conventional CT
with contiguous slices. In this study, using an early-generation scanner and scan
technique of 120 kV(p), 200 mA, and 2-s scan time, the mean skin radiation
dose was 4.4 mGy for 1.5-mm HRCT scans at 10-mm intervals, 2.1 mGy for
scans at 20-mm intervals, and 36.3 mGy for conventional 10-mm scans at 10mm intervals. Thus, HRCT scanning at 10-and 20-mm intervals, as done in
clinical imaging, resulted in 12% and 6%, respectively, of the radiation dose
associated with conventional CT. Schoepf et al. (49) compared MD-HRCT to
HRCT obtained with spaced axial images considered to have equal image
quality, spatial resolution, subjective signal-to-noise ratio, diagnostic value,
depiction of bronchi and parenchyma, and motion and streak artifacts. Radiation
dose measured 5.55 mSv for MDCT and 1.25 mSv for the series of 24 axial
HRCT slices obtained (49). Leswick et al. found that if image noise is equalized,
MD-HRCT may result in a higher radiation dose than the combination of a
routine MDCT sufficient for volumetric imaging and spaced axial HRCT images
(37).
FIGURE 1-25 A–C: Axial HRCT with a modulated mA of 100 to 150. Axial HRCT images
were obtained in the supine (A) and prone (B) positions at 1-cm intervals using a modulated tube
current varying between 100 and 150 mA. Dynamic expiratory images (C) were also obtained at
three selected levels using a tube current (mA) of 50. Estimated effective dose for the examination
was 1.5 mSv.
TABLE 1-2 Comparison of Radiation Dose for Chest Imaging
Techniques
Procedure
Effective radiation dose (mSv)
Annual background radiation
2.5
PA chest radiograph
Spaced axial HRCT (10-mm spacing)
Spaced axial HRCT, supine, prone (10-mm
spacing), expiratory
Spaced axial HRCT (20-mm spacing)
Low-dose spaced axial HRCT
MD-HRCT (standard technique)
MD-HRCT (modulated mA of approx. 100)
0.05
0.7
1.5
0.35
0.02
4–7
2–3
Modified from Mayo JR, Aldrich J, Muller NL. Radiation exposure at chest CT: a statement of
the Fleischner Society. Radiology 2003;228:15–21.
Attempts at dose reduction with MD-HRCT using a decrease in mAs may be
achieved by choosing a reduced fixed mA value, body weight-based formulas, or
scanner-based dynamic tube current modulation (19,70,73,74). Tube current
modulation can provide excellent HRCT studies with reduced radiation dose
(Fig. 1-26).
FIGURE 1-26 A–C: Volumetric HRCT with a modulated mA of approximately 100.
Representative images through the upper (A), mid- (B), and lower (C) lungs are shown from a
supine volumetric HRCT acquired with 120 kV(p), a fixed tube current of 100 mA, and
reconstructed at 1.25-mm thickness. Dynamic expiratory images were also obtained at three
selected levels. The estimated effective dose for the examination was 2 mSv. The dose would be
increased by the inclusion of prone images.
However, as pointed out by Mayo et al. (16,75), dose reduction may have an
adverse effect on image quality and reader interpretations. For example, Yi et al.
(76) assessed image noise and subjective image quality with respect to the
radiation dose delivered by MDCT in 20 patients with suspected bronchiectasis.
Images were obtained using 120 kV(p), 2.5-mm collimation, pitch of 1.5, 2.5mm reconstruction intervals, and sharp reconstruction algorithm. The quality of
the images obtained using six mA settings (170, 100, 70, 40, 20, and 10 mA) was
assessed, and it was graded using a 5-point scale (5 = excellent to 1 =
nondiagnostic) at both lung and mediastinal window settings. Also, radiation
doses were measured at each of the six mA settings using a thoracic phantom.
The mean image quality scores at exposures of 170, 100, 70, 40, 20, and 10 mA
were 3.9, 3.7, 3.8, 3.2, 2.5, and 1.6 at lung window settings, and images obtained
at 70 mA were rated significantly better than those obtained at 40 mA or less (p
< 0.01). The average image noise (SD of pixels measured in blood) was 39, 42.7,
53.6, 69.2, 98.5, and 157.2 H, respectively, at 170, 100, 70, 40, 20, and 10 mA,
and the mean radiation doses measured at these mA values were 23.72, 14.39,
10.54, 5.41, 2.74, and 1.50 mGy, respectively (76). The authors point out that the
dose resulting from MDCT obtained with 70 mA (10.54 mGy) is five times that
reported for spaced axial HRCT (2.17 mGy with parameters of 120 kV(p), 170
mA, 1-mm collimation, and 10-mm intervals) for the diagnosis of bronchiectasis
(77).
Das et al. (19) compared the image quality of thoracic MDCT obtained with a
standard protocol (effective mAs = 100) to three methods of dose reduction,
including a dynamic tube current modulation, effective mAs equals body weight
in kilograms, and a combination of these. The mean effective doses for these
protocols, respectively, were 6.83, 5.92, 4.73, and 3.97 mSv. Although there was
a correlation between decreased dose and increased image noise, the image
quality for all techniques was graded as excellent (19).
Tube current modulation allows for dynamic changes of the tube current (mA)
in the craniocaudal (Z plane) and transaxial (X and Y) planes. Tube output varies
depending upon the attenuation profiles of specific anatomical locations. For
example, tube current will be lowered in regions of the body that have less
attenuation, such as levels at which the lungs comprise a large portion of the
cross-sectional area of the chest. Tube current modulation attempts to maintain
fixed image noise at all anatomical levels, reducing radiation exposure without
sacrificing image quality. Using tube current modulation, Kalra et al. (78)
showed a dose reduction of 18% to 26% compared to a fixed mA in patients
undergoing routine chest CT. Angel et al. (79) demonstrated a 16% reduction in
the absorbed dose to the lung with tube current modulation, an effect that was
most pronounced in smaller patients. In larger patients, there was an increase in
the dose of up to 33% (79). When tube current modulation is used, changing
other parameters such as pitch and gantry rotation speed will have limited impact
on radiation dose. For example, increasing the pitch will result in a subsequent
elevation in tube current so that noise image remains constant. The primary
exception is when tube current is already at its maximum level, such as in large
patients.
With tube current modulation, and a state-of-the-art scanner having sensitive
detectors, HRCT (supine volumetric, prone axial at 1-cm intervals, and dynamic
expiratory imaging at three levels) may be performed using 300-ms rotation and
an mA averaging about 100, with an estimated dose of about 2 to 3 mSv, and
excellent image quality. Supine and prone axial imaging (1-cm spacing) and
dynamic expiratory imaging at three levels can be performed with an estimated
dose of about 1 mSv.
Another dose reduction strategy is the use of adaptive statistical iterative
reconstruction (ASIR). ASIR uses a postprocessing algorithm that represents an
adjunct to standard filtered back projection (FBP). In usual clinical practice, a
combination of FBP and ASIR are used to produce the final data set with typical
blends, including 30% to 40% ASIR. Reconstructions using ASIR have reduced
image noise compared to those using only FBP, allowing images to be acquired
with parameters that lower the radiation dose (70). However, the use of ASIR
can affect quantitative CT measurements (80). In one study (81), images were
acquired at various tube current-time products (40–150 mAs) and then
reconstructed using FBP and blended ASIR/FBP. At 40 and 75 mAs, the images
reconstructed with FBP had unacceptable levels of noise, whereas the ASIR/FBP
images had acceptable noise levels (81). In the evaluation of diffuse lung
disease, Prakash et al. (82) showed that images reconstructed with ASIR in a
high-definition mode were superior in quality to FBP in 64% of cases. ASIR’s
primary disadvantages are an increased postprocessing time (30% longer than
FBP), edge definition artifacts, and the production of oversmoothed images.
These disadvantages are limited by the blending of ASIR and FBP in the final
reprocessing. Model-based iterative reconstruction (MBIR) is a more advanced
form of iterative reconstruction that allows for further reduction in radiation dose
at the expense of significantly increased postprocessing time, but is not in
common use at this time.
Radioprotective bismuth shields are another dose reduction technique that
allows for a decrease in the specific target dose to radiosensitive organs such as
the breasts and thyroid. Bismuth shields enable a reduction in the target organ
dose at the expense of increased artifacts. With breast shields, in particular, this
artifact is most pronounced in the anterior lungs (83). In a study by Colombo et
al. (84), bismuth shielding allowed for a 34% reduction in the dose to the breast
during chest CT with only a slight degradation of image quality. The
contemporaneous use of tube current modulation and bismuth shields may result
in an increase in the tube current or image noise depending upon when the shield
is applied, before or after the scout image (85,86). Leswick et al. (86) showed
that z-axis automatic tube current modulation was more effective than shielding
in reducing the radiation exposure to the thyroid. A combination of shielding and
automatic tube current modulation reduced the thyroid dose slightly compared to
tube current modulation alone; however, this was at the expense of increased
artifact (86). The American Association of Physicists in Medicine recommends
using alternative methods of dose reduction, in lieu of shields, because of their
unpredictable effects on image quality and radiation exposure, particularly when
automatic tube current modulation is used (87).
Low-Dose Axial High-Resolution Computed Tomography
Spaced axial HRCT with reduced mAs can allow a diagnosis of diffuse lung
disease with very limited radiation exposure. Obtaining spaced axial HRCT at
20-mm intervals (40 mAs) or at three levels (80 mAs) results in an average skin
dose comparable to that associated with chest radiography (72,88–91). Low-dose
HRCT should not be routinely used for the initial evaluation of patients with
lung disease, although it can be valuable in following patients with a known lung
abnormality or in screening large populations at risk for lung disease. Optimal
low-dose techniques will likely vary with the clinical setting and indication for
the study, and they remain to be established.
The efficacy of low-dose spaced axial HRCT has been assessed in several
studies (88,89,92,93). In a study by Zwirewich et al. (88), scans with 1.5-mm
collimation and 2-s scan time at 120 kV(p) were obtained using both 20 mA
(low-dose HRCT) and 200 mA (conventional-dose HRCT) at selected levels in
the chests of 31 patients. Observers evaluated the visibility of normal structures,
various parenchymal abnormalities, and artifacts using both techniques. Lowand conventional-dose HRCT were equivalent for the demonstration of vessels,
lobular and segmental bronchi, and structures of the secondary pulmonary
lobule, and in characterizing the extent and distribution of reticular
abnormalities, honeycomb cysts, and thickened interlobular septa. However, the
low-dose technique failed to demonstrate ground-glass opacity in 2 of 10 cases,
and emphysema in 1 of 9 cases, although they were evident but subtle on the
usual-dose HRCT. Linear streak artifacts were also more prominent on images
acquired with the low-dose technique, but the two techniques were judged
equally diagnostic in 97% of cases. The authors concluded that HRCT images
acquired at 20 mA yield anatomical information equivalent to that obtained with
200-mA scans in the majority of patients without significant loss of spatial
resolution or image degradation due to streak artifacts.
In a subsequent study (89), the diagnostic accuracies of chest radiographs,
low-dose HRCT (80 mAs, 120 kV(p)), and conventional-dose HRCT (340 mAs,
120 kV(p)) were compared in 50 patients with chronic infiltrative lung disease
and 10 normal controls. For each HRCT technique, only three images were used,
obtained at the levels of the aortic arch, tracheal carina, and 1 cm above the right
hemidiaphragm. A correct first-choice diagnosis was made significantly more
often with either HRCT technique than with radiography; the correct diagnosis
was made in 65% of cases using radiographs, 74% of cases with low-dose
HRCT (p < 0.02), and 80% of conventional HRCT (p < 0.005). A high
confidence level in making a diagnosis was reached in 42% of radiographic
examinations, 61% of the low-dose HRCT examinations (p < 0.01), and 63% of
the conventional-dose HRCT examinations (p < 0.005), and it was correct in
92%, 90%, and 96% of the studies, respectively. Although conventional-dose
HRCT was more accurate than low-dose HRCT, this difference was not
significant, and both techniques provided quite similar anatomical information
(Figs. 1-25 and 1-26) (89).
In a comparison of standard (150 mAs) and low (40 mAs)-dose thin-section
volumetric chest CT, Christie et al. (94) found that there was significantly
increased detection of ground-glass opacities, ground-glass nodules, and
interstitial opacities with the higher-dose scan. The detection of solid nodules,
airspace disease, and airways disease was equivalent using low-and high-dose
images.
Majurin et al. (92) compared a variety of low-dose techniques in 45 patients
with suspected asbestos-related lung disease. Of the 37 patients with CT
evidence of lung fibrosis, HRCT images obtained with mAs as low as 120
clearly showed parenchymal bands, curvilinear opacities, and honeycombing.
However, reliable identification of interstitial lines or areas of ground-glass
opacity required a minimum technique of 160 mAs. Furthermore, these authors
showed that using the lowest possible dosage (60 mAs) HRCT was sufficient
only for detecting marked pleural thickening and areas of gross lung fibrosis.
An additional factor in obtaining low-dose HRCT is a consideration of the
anatomical distribution of suspected disease. Significant dose reduction can be
achieved by limiting scanning to the most appropriate lung regions and the most
appropriate patient positions for obtaining the scans. As an example, in
screening for asbestosis, scanning in the prone position and the posterior lung
bases is most helpful in diagnosis (Fig. 1-27).
FIGURE 1-27 Low-dose HRCT for asbestos screening. HRCT images were obtained at 1-cm
intervals in the prone position using a fixed tube current of 40 mA. No supine or expiratory images
were obtained. Estimated effective dose for the examination was 0.2 mSv.
EXPIRATORY HIGH-RESOLUTION COMPUTED
TOMOGRAPHY
As an adjunct to routine inspiratory images, expiratory HRCT scans have proved
useful in the evaluation of patients with a variety of obstructive lung diseases
(95,96). On expiratory scans, focal or diffuse air trapping may be diagnosed in
patients with large or small airway obstruction or emphysema. It has been shown
that the presence of air trapping on expiratory scans (a) correlates to some
degree with pulmonary function test abnormalities (97,98), (b) can confirm the
presence of obstructive airway disease in patients with subtle or nonspecific
abnormalities visible on inspiratory scans, (c) allows the diagnosis of significant
lung disease in some patients with normal inspiratory scans (99), and (d) can
help distinguish between obstructive disease and infiltrative disease as a cause of
inhomogeneous lung opacity seen on inspiratory scans (100).
In most lung regions of normal subjects, lung parenchyma increases uniformly
in attenuation during expiration (8,101–105), but in the presence of air trapping,
lung parenchyma remains lucent on expiration and shows little change in
volume. Focal, multifocal, or diffuse air trapping is visible as areas of
abnormally low attenuation on expiratory or postexpiratory CT. On expiratory
scans, visible differences in attenuation between normal and obstructed lung
regions are visible using standard lung window settings and can be quantitated
using regions of interest. Differences in attenuation between normal lung regions
and regions that show air trapping often measure more than 100 Hounsfield units
(HU) (106). Air trapping visible using expiratory or postexpiratory HRCT
techniques has been recognized in patients with emphysema (107–110), chronic
airways disease (98), asthma (111–115), cystic fibrosis (116), bronchiolitis
obliterans and BOS (99,108,117–127), the cystic lung diseases associated with
Langerhans histiocytosis and tuberous sclerosis (128), bronchiectasis (108,129),
airways disease related to AIDS (130), and small airways disease associated with
thalassemia (131). Expiratory HRCT has also proved valuable in demonstrating
the presence of bronchiolitis in patients with primarily infiltrative diseases such
as hypersensitivity pneumonitis (132,133), sarcoidosis (134–137), and
pneumonia.
Some investigators obtain expiratory scans routinely in all patients who have
HRCT, whereas others limit their use to patients with inspiratory scan
abnormalities or suspected obstructive lung disease (95). We recommend the
routine use of expiratory scans in a patient’s initial HRCT evaluation because the
functional cause of respiratory disability is not always known before HRCT is
performed. Furthermore, even in patients with a known restrictive abnormality
on pulmonary function tests, or obvious HRCT findings of fibrosis, expiratory
HRCT may show air trapping, a finding of potential value in differential
diagnosis (136). For example, the presence of air trapping in a patient with
HRCT findings of fibrosis and honeycombing excludes the diagnosis of usual
interstitial pneumonia and idiopathic pulmonary fibrosis (138). Limiting
expiratory HRCT to patients with evidence of airway abnormalities on
inspiratory scans will result in some missed diagnoses. Expiratory HRCT may
also show findings of air trapping in the absence of inspiratory scan
abnormalities (99). The use of expiratory scans may be of value in the follow-up
of patients at risk of developing an obstructive abnormality. For example,
expiratory scans are valuable in detecting bronchiolitis obliterans in patients
being followed for lung transplantation (123,125,139–142).
Expiratory HRCT scans may be obtained during suspended respiration after
forced exhalation (postexpiratory CT), during forced exhalation (dynamic
expiratory CT) (95,104,108,143), at a user-selected respiratory level controlled
during exhalation with a spirometer (spirometrically triggered expiratory CT) or
by using other methods (126,144–149). Generally, with these techniques,
expiratory scans are obtained at selected levels. Three scans, five scans, or scans
at 4-cm intervals have been used by different authors. Expiratory imaging may
also be performed using helical technique and 3D volumetric reconstruction
(150,151).
Postexpiratory High-Resolution Computed Tomography
Postexpiratory HRCT scans, obtained during suspended respiration after a forced
exhalation, are easily performed with any scanner and are most suitable for a
routine examination (Fig. 1-28). The primary advantage of this technique is its
simplicity. In obtaining expiratory HRCT, the patient is instructed to forcefully
exhale and then hold his or her breath for the duration of the single scan. This
maneuver is practiced with the patient before the scans are obtained to ensure an
adequate level of expiration. Postexpiratory scans can be performed at several
predetermined levels (e.g., aortic arch, carina, lung bases), at 2-to 4-cm intervals,
or at levels appearing abnormal on the inspiratory images. Scans at two to five
levels have been used by different authors (100,111,112,120,140,152).
Expiratory scans at three selected levels (aortic arch, hila, and lower lobes) are
generally sufficient for showing significant air trapping and may be used
routinely, in addition to the inspiratory scan series, in patients with suspected
airways or obstructive lung diseases. Although targeting postexpiratory scans to
lung regions that appear abnormal on the inspiratory scans would seem
advantageous, using preselected scans allows the same lung regions to be
routinely imaged on follow-up examinations and, in some patients, can show air
trapping when inspiratory scans are normal.
FIGURE 1-28 Postexpiratory air trapping in a patient with idiopathic scoliosis and normal
inspiratory scans. A: An inspiratory scan shows homogeneous lung attenuation without evidence
of airways disease. B: Routine postexpiratory scan shows patchy air trapping (arrows) indicative
of small airways disease.
Each postexpiratory scan is compared to the inspiratory scan that most closely
duplicates its level to detect air trapping. Anatomical landmarks such as
pulmonary vessels, bronchi, and fissures are most useful for localizing
corresponding levels. Because of diaphragmatic motion occurring with
expiration, attempting to localize the same scan levels by using the scout view is
difficult and sometimes misleading.
Dynamic Expiratory High-Resolution Computed
Tomography
Scans obtained dynamically during forced expiration can be obtained using an
electron-beam scanner (Fig. 1-29) or a helical scanner (Figs. 1-30 to 1-33).
There is some evidence to suggest that a greater increase in lung attenuation
occurs with dynamic expiratory imaging than with simple postexpiratory HRCT
and that, consequently, air trapping is more easily diagnosed (Fig. 1-33).
FIGURE 1-29 Dynamic expiratory HRCT in a normal subject obtained using an electronbeam scanner. A: The 10-image dynamic ultrafast HRCT sequence acquired during a single
forced vital capacity maneuver is shown, with the FOV limited to the left upper lobe. These ten
100-ms images were obtained at 600-ms intervals. They are shown in sequence, in a clockwise
fashion, from the left upper corner (1) to the lower left corner (10). Images at full inspiration (insp)
and full expiration (exp) are visible. Note the increase in lung attenuation and decrease in lung
volume that occur as the subject exhales. As in most normal subjects, lung attenuation increase
on expiration is relatively homogeneous. B: A time-attenuation curve is produced by measuring
the mean lung attenuation (HU) for a specific ROI. In this subject, for an ROI in the anterior lung,
attenuation decreases to approximately –870 HU at maximum inspiration (insp) and increases in
attenuation to –670 HU at maximum expiration (exp) for an overall attenuation increase of
approximately 200 HU. Each point on the time-attenuation curve represents one image from the
dynamic sequence. (From Webb WR, Stern EJ, Kanth N, et al. Dynamic pulmonary CT: findings in
normal adult men. Radiology 1993;186:117, with permission.)
FIGURE 1-30 Dynamic expiratory HRCT obtained using a helical scanner in a patient with
bilateral lung transplantation. A: The initial scan from the dynamic HRCT sequence is at full
inspiration and appears normal. No respiratory motion is present. B: An image from the
midportion of the dynamic expiration shows significant motion artifacts, with degradation of image
quality. Note that this image appears to be at a more caudal level than in A because the
diaphragm and lungs have moved cephalad relative to table position (C). The final image from the
dynamic sequence is at expiration, with no respiratory motion visible. Image quality is good, and
marked patchy air trapping is visible as a result of bronchiolitis obliterans.
FIGURE 1-31 Dynamic expiratory HRCT obtained using a helical scanner. A: In a patient with
bilateral lung transplantation, inspiratory HRCT shows stenosis of the bronchus intermedius. The
lungs appear normal. B: An image from the expiratory phase shows marked air trapping in right
middle and lower lobes, with little change in attenuation. Note that the right major fissure (white
arrow) is bowed forward in comparison to the left major fissure and its position on the inspiratory
scan. This also reflects local air trapping. The right upper lobe (black arrow) and left lung increase
normally in attenuation.
FIGURE 1-32 Normal low-dose dynamic expiratory helical HRCT. A: Axial HRCT was
obtained using 120 kV(p) and 200 mA. B–F: Sequential scans from a dynamic expiratory
sequence obtained with 120 kV(p) and 40 mA. Scans show artifacts from respiratory motion and
increased image noise as compared to the axial image shown in A. However, scans are of
sufficient quality for diagnosis and show increased lung attenuation and decreased lung volume
during the sequence. Lung attenuation on scans (B–F), measured using a 2-cm ROI in the left
upper lobe, was –832 HU (B), –789 (C), –770 HU (D), –736 HU (E), and –700 HU (F).
FIGURE 1-33 Postexpiratory and low-dose dynamic expiratory HRCT in a patient with
bronchiolitis obliterans resulting from smoke inhalation. A: Inspiratory axial HRCT shows subtle
lung inhomogeneity due to mosaic perfusion. B: Postexpiratory axial HRCT (240 mA) shows
findings of air trapping with some lung regions remaining lucent. C: Low-dose (40 mA) dynamic
expiratory HRCT shows increased streak artifacts due to aliasing. Several regions of air trapping
are more easily seen on the dynamic scan.
Dynamic scanning with an electron-beam scanner has been termed dynamic
ultrafast HRCT (108,128,153,154). This technique is performed using a scanner
capable of obtaining a series of images with a 100-ms scan time (500-ms
interscan delay, 1.5-to 3-mm collimation, 150 kV(p), 650 mA)
(108,128,153,155). In general, when using this technique, a series of 10 scans
are obtained at a single level during a 6-s period, as the patient first inspires and
then forcefully exhales. Patients are instructed to breathe in deeply and then
breathe out as rapidly as possible (Fig. 1-29). Images are reconstructed using a
high spatial frequency algorithm. Usually, dynamic expiratory CT scan
sequences are obtained at several selected levels through the lungs. In papers
describing this technique, three levels were used (e.g., at the level of the aortic
arch, carina, and lung bases), although the protocol can be varied in individual
cases, with imaging limited to a specific region.
During expiration, the diaphragm ascends, and the lungs move cephalad. Lung
motion is most significant on scans through the lung bases. Although slightly
different regions of the lung are imaged on sequential scans obtained at the same
level, the effect of diaphragmatic motion on the assessment of lung attenuation
has been regarded as inconsequential (104,108,153). Little motion-related image
degradation is visible on dynamic ultrafast HRCT scans because of the very
rapid scan time used (128,155).
Dynamic scans can also be obtained using a helical CT scanner with a gantry
rotation time of 1 s or less. Because of the continuous scanning that is possible
with the helical technique, scans can be reconstructed at any point during the
scan sequence, thus providing a temporal resolution equivalent or superior to
that of dynamic ultrafast HRCT. However, because of the longer time required to
obtain each image, some degradation of anatomical detail can be expected on
individual images. In performing dynamic expiratory CT, although one or more
images obtained during the rapid phases of expiration will show significant
motion-related artifact (Fig. 1-30), images near to and at full expiration show
little artifact and allow optimal assessment of lung attenuation (Figs. 1-30 to 133) (156).
The use of a dynamic helical technique may be combined with a reduced mAs
(e.g., 40 mAs) so that the sequence of images obtained represents a radiation
dose similar to that associated with a single routine expiratory image (Figs. 1-32
and 1-33). Using such a technique, continuous imaging is performed for 6 to 8 s,
as the patient rapidly exhales. Although image quality is reduced using the lowdose technique because of noise, images adequate for the diagnosis of air
trapping are obtained (Figs. 1-32 and 1-33). In a group of lung transplant
recipients studied using both postexpiratory HRCT and low-dose dynamic
expiratory helical HRCT (156), lung attenuation was noted to increase
significantly more with the dynamic technique (204 HU vs. 130 HU, p =
0.0007), and in one patient, air trapping was diagnosed only on the dynamic
images.
Lucidarme et al. (157) also compared the utility of dynamic expiratory scans
(obtained during a 10-s expiratory maneuver) to scans obtained at end expiration
in 49 patients with airways disease. Air trapping was noted in 36 patients using
dynamic expiratory CT and 35 patients at suspended end expiration. The extent
of air trapping and the relative contrast between normal lung and regions of air
trapping were significantly greater when scans were obtained with dynamic
expiration (p = 0.001 and 0.007, respectively) (157).
Regardless of the technique used, the dynamic scan sequence is viewed with
attention to changes in lung attenuation and regional lung volume during the
forced expiration. The images can be evaluated quantitatively or qualitatively,
with measurement of lung attenuation during different phases of the respiratory
maneuver, calculation of time-attenuation curves, or simple viewing of the serial
scans in sequence or in cine mode. Air trapping is considered to be present when
the lung fails to increase normally in attenuation during exhalation
(108,128,153). The image sequence can be analyzed both quantitatively and
qualitatively (Figs. 1-29 and 1-32). The mean HU attenuation for a specific
region of interest (ROI) in the lung can be measured and plotted for each scan,
producing a time-attenuation curve graphically demonstrating the changes in
lung attenuation that have occurred during a single expiration and inspiration
(128). The use of dynamic expiratory HRCT is discussed further in Chapters 2
and 7.
Spirometrically Triggered Expiratory High-Resolution
Computed Tomography
Spirometrically triggered expiratory HRCT is a technique by which expiratory
scanning can be done at specific, reproducible, user-selected lung volumes
(126,144–146,149). With this technique, the patient breathes through a small
handheld spirometer while positioned on the CT table. Before scanning, a
spirometric measurement of the vital capacity is obtained, and trigger level (e.g.,
90% of vital capacity) is chosen. During exhalation, the spirometer and
associated microcomputer measure the volume of gas expired and trigger CT
after a specific volume is reached. When the trigger signal is generated, airflow
is inhibited by closure of a valve attached to the spirometer, and a scanning
starts. Two or three different levels in the chest are typically selected and
evaluated with respect to lung attenuation at specific lung volumes. Using this
method, quantitative assessment of CT images with respect to lung attenuation
can be performed with excellent precision (144,145). This technique may also be
used with a helical scanner or an electron-beam scanner (147). Spirometrically
gated or controlled imaging may be particularly valuable in pediatric patients
(147); with inhibition of respiration, respiratory motion artifacts may be avoided.
Motion-free inspiratory and expiratory imaging can also be obtained in pediatric
patients by using a positive-pressure ventilation device and controlled pauses in
spontaneous respiration (148). As an example of the use of this technique,
Camiciottoli et al. (158) studied the relationship between spirometrically gated
inspiratory and expiratory HRCT and respiratory dysfunction in patients with
chronic obstructive pulmonary disease (COPD). The authors found that both
inspiratory and expiratory measurements were important in patient assessment.
Measurements of lung attenuation at inspiration reflected the extent of
emphysematous tissue loss, while expiratory measurements were related to
airflow limitation and lung hyperinflation (158).
Volumetric Expiratory Computed Tomography
Kauczor et al. (150) first used helical CT (slice thickness, 8 mm; pitch, 2;
increment, 8 mm) with 2D and 3D postprocessing to assess lung volume at deep
inspiration and expiration. Both 2D and 3D reconstructions were found to
correlate with measured lung volumes. In another study, 3D volumetric
reconstructions of total lung volume at inspiration and at expiration, as well as
quantitation of regions of low attenuation (lung attenuation measuring less than
–896 HU on inspiratory CT and –790 HU on expiratory CT), were correlated
with pulmonary function test results (151); in this study, an excellent correlation
was found between the volume of low-attenuation lung and pulmonary function
test findings of obstruction, such as the ratio of forced expiratory volume in 1 s
(FEV1) to the forced vital capacity.
The use of volumetric MD-HRCT following expiration has also been used for
the assessment of volumetric lung-attenuation changes, identification of air
trapping and associated airway abnormalities, and 2D reconstruction of
expiratory scans (60,159–162). This technique is combined with volumetric
MD-HRCT.
The use of this technique has been assessed in several studies (60,159–162).
Nishino et al. reviewed 41 patients with suspected diffuse airway abnormalities.
The volumetric expiratory HRCT was diagnostically acceptable in 83% to 93%
of patients, depending on the level scanned. There was no significant difference
in the detectability of air trapping with volumetric imaging when compared to
six evenly spaced end-expiratory HRCT images, but the airway leading to a
region of air trapping was better identified using volumetric imaging than with
spaced scans (p < 0.0001) (161).
In another study, the use of coronal reformations of expiratory MD-HRCT
was compared to transverse MD-HRCT. Although air trapping was visible on
both transverse and coronal images, and there was no difference in diagnostic
confidence and the size, distribution, and extent of areas of air trapping
identified, the borders of areas of air trapping were better shown in some patients
on the coronal images (162). Sagittal reconstruction of expiratory MD-HRCT
has also been reported (60), but does not appear to offer any significant
advantage in the diagnosis of air trapping. MinIP image reconstruction may be
used with volumetric postexpiratory HRCT to improve the visibility of air
trapping (163).
It should be pointed out that the use of volumetric expiratory imaging results
in a greater radiation dose than spaced axial images. In one study, the total
effective radiation dose for MD-HRCT obtained in both inspiration and
expiration was estimated as 11.61 mSv, even when a reduced mAs was used
(161,162). More recently, Bankier et al. (164) reported that volumetric
expiratory HRCT may be performed with reduced radiation dose, without
impairing the visual quantification of air trapping. In their study, volumetric
expiratory HRCT was performed using MD-HRCT with 140 kV(p) and 80 mAs
(effective) and simulated reduced effective mAs values of 60, 40, and 20. They
found that lower mAs values did not result in a significant change in air trapping
scores, although diagnostic confidence and interobserver agreement both
decreased. The mean effective dose at 140 kV(p) and 80 mAs (effective) was
estimated as 4.7 mSv in women and 3.8 mSv in men; at simulated mAs
(effective) of 20, the estimated dose was 1.2 mSv in women and 1.0 mSv in men
(164).
QUANTITATIVE COMPUTED TOMOGRAPHY
Traditional analysis of HRCT relies primarily on the subjective recognition and
interpretation of findings and patterns. Quantitative computed tomography
(QCT) represents an alternative, by which computerized analysis allows for a
more objective assessment of disease abnormalities or extent. QCT may be used
to detect, characterize, and quantify the severity of HRCT abnormalities. It may
also be used in the longitudinal follow-up of abnormalities over time.
HRCT images may be quantified in a variety of ways, from the application of
density masks to the use of more advanced computer algorithms that attempt to
determine the presence and severity of CT findings that are spatially complex.
These methods are usually applied to a volumetric HRCT data set. The main
indications for quantitative lung imaging are in the evaluation of COPD, airways
diseases, and interstitial lung diseases. A brief discussion of these indications
will be presented here with a more detailed explanation in the pertinent chapters.
The assessment of COPD has been the most rigorously studied use of QCT
(see Chapters 7 and 20) (165–184). COPD is a multifactorial disease that is the
result of several pathologic abnormalities including emphysema, large airways
disease, and small airways disease. QCT has been used in COPD patients to
determine COPD phenotypes (i.e., emphysema-predominant, airwaypredominant, or mixed), the severity and distribution of disease, and longitudinal
changes in abnormalities over time. Emphysema may result in areas of lung with
decreased attenuation on CT and may be quantified by calculating the relative
low-density area or the percentile of the frequency-attenuation distribution. Both
techniques utilize a density mask that measures the attenuation of specific voxels
within an ROI. Low attenuation is measured using the percentage of voxels
below a specific threshold, typically –950 HU. The frequency-attenuation
distribution determines the attenuation value, below which a specific percentage
of the low-attenuation voxel densities are distributed, typically the lowest 15%.
These measurements have been shown to correlate with clinical symptoms
(185), pulmonary function test abnormalities (186), and histologic scoring of
emphysema (187). Given substantial interobserver variability in visual
assessment of emphysema (188), quantitative CT may provide a more objective
and reliable assessment of the severity of COPD. Bankier et al. (189) showed
better agreement between objective quantification of emphysema using density
masks (r = 0.555–0.623) than subjective grading (r = 0.439–0.505), compared to
histology. On the other hand, Kim et al. (190) demonstrated that
semiquantitative visual assessment performed just as well as computerized
quantitative methods. As functional impairment in COPD is multifactorial and
includes pathologic abnormalities other than emphysema, subjective visual
assessment may provide details that density masks do not. While QCT in the
setting of COPD has several potential advantages over visual assessment of CT
images, its exact clinical role in COPD patients is not well defined.
Quantitative CT of the airways may be used independently or as a
complement to emphysema quantification. Direct measurements of the large
airways, including bronchial diameter and wall thickness, may be performed.
Measurements of the small airways are performed indirectly by quantifying air
trapping on expiratory CT. The presence of air trapping is performed by
measuring the percentage of pixels below a threshold of –850 or –856 HU.
Comparison of inspiratory and expiratory images in COPD patients allows the
determination of the predominant pattern of abnormality: emphysema, airway
obstruction, or mixed. These measurements have been shown to correlate with
pulmonary function test abnormalities, and may even show better correlation (r
= –0.077) with FEV1 compared to the quantification of inspiratory images (r = –
0.67) (186). Quantification of both emphysema and airway abnormalities may be
superior than either used in isolation (191). Quantification of airways
abnormalities may also be used in patients with other diseases such as asthma
(192) and bronchiolitis obliterans (193).
Quantification of interstitial lung disease requires more complex, texturebased computer algorithms that are able to differentiate findings on the basis of
their morphology. Because there is variability in the experience and accuracy of
individual radiologists in the assessment of diffuse lung disease, QCT has the
potential to provide objective measurements, independent of radiologists’
experience. Most studies to date have focused upon the feasibility of applying
these algorithms to patients with interstitial lung disease. Early studies have
shown acceptable agreement between quantitative measurements and visual
assessment (194,195) or pulmonary function tests (196).
Inaccuracies in CT quantification may arise from several sources. Differences
in the level of inspiration or expiration may have a significant impact on lung
density and measurements of emphysema (177). Variations in the CT protocol
such as tube current, slice thickness, reconstruction algorithm, and the use of
ASIR may also impact quantification (73,80,197). Additionally, QCT may not
reflect the complex and multifactorial interplay of multiple factors that
contribute to CT abnormalities. For instance, COPD patients who quit smoking
show a rapid increase in the low-attenuation area on longitudinal QCT (198).
This is hypothesized to be due to the decrease in inflammatory factors associated
with active smoke inhalation as opposed to a rapid increase in emphysema. This
example underlies the complexity of diseases that may not be captured by
quantification.
ADDITIONAL TECHNICAL MODIFICATIONS
Reduction of Cardiac Motion Artifacts
HRCT scans obtained in a routine fashion may be degraded by cardiac motion.
Several motion-related artifacts may be seen, particularly in the left paracardiac
region (see High-Resolution Computed Tomography Artifacts section). HRCT
using electrocardiographic (ECG) triggering of scan acquisition, reduced gantry
rotation time, and segmented reconstruction of scan data have all been used in an
attempt to reduce these artifacts (199–203).
Electrocardiographically Triggered High-Resolution Computed
Tomography
Electrocardiographically triggered HRCT may be used to reduce motion-related
artifacts (Fig. 1-34), but has little effect on diagnosis and results in an increased
radiation exposure. In a study using a helical scanner capable of 0.75-s gantry
rotation, 500-ms HRCT scans, representing a 240-degree rotation of the gantry,
were initiated at 50% of the R-R interval (199). Because of the shorter-thanroutine scan time, images were reconstructed using a smoother algorithm than is
usually used for HRCT. In studying 35 patients using this technique, Schoepf et
al. (199) found that ECG triggering significantly reduced artifacts caused by
cardiac motion, such as distortion of pulmonary vessels, double images, or
blurring of the cardiac border, when compared to routine images. Furthermore,
in patients with a heart rate of 75 beats per minute or less, ECG triggering
significantly improved image quality. It should be noted, however, that this
technique was not found to improve diagnostic accuracy.
FIGURE 1-34 ECG-gated MD-HRCT obtained with 0.625-mm slice thickness, a pitch of 1,
and targeted reconstruction. Scans at the level of the upper (A) and lower (B) heart show
excellent spatial resolution without artifacts related to cardiac pulsation. Small lobular vessels in
the lung periphery are clearly seen.
Also, Boehm et al. (201) studied 45 patients referred for HRCT with routine
MD-HRCT and prospectively ECG-triggered HRCT. ECG triggering resulted in
a significant reduction in motion artifacts in the middle lobe, lingula, and left
lower lobe, but no differences in diagnostic outcome were found between
triggered and nontriggered techniques. The authors conclude that ECG-triggered
thin-section CT of the lung is not recommended for routine clinical practice
(201).
Segmented Reconstruction
Partial or segmented reconstruction of scan data can serve to reduce effective
scan time and can result in a significant reduction in motion artifacts without
increasing radiation dose, albeit at the expense of increased image noise. Arac et
al. (202) studied HRCT images obtained using a scanner capable of 1-s rotation
and reconstruction using a full gantry rotation and a 225-degree rotation
segment. Segmented reconstruction reduced cardiac motion artifacts (202). Ha et
al. (203) evaluated the effects of partial (0.3-s) reconstruction to reconstruction
obtained using a full rotation (0.75 s). The use of partial reconstruction resulted
in reduced cardiac motion artifacts on HRCT, but image noise was increased.
For example, image noise in air (38.0 ± 9.2) and lung parenchyma (86.0 ± 23.1)
were greater for 0.3-s images than for 0.75-s images (35.6 ± 9.6 and 76.0 ± 20.3,
respectively; p < 0.01) (203).
Gantry Angulation
When HRCT is obtained using spaced axial images, angling the top of the CT
gantry 20 degrees caudally with the patient supine (i.e., the gantry is angled
toward the feet) improves visibility of the segmental and subsegmental bronchi,
particularly in the middle lobe and lingula, by aligning them parallel to the plane
of scan (Fig. 1-35) (204). This technique may be valuable in assessing patients
with bronchiectasis (205). However, in the majority of patients with
bronchiectasis, spaced HRCT images without gantry angulation are sufficient for
diagnosis, and there would seem to be little use for this technique when
volumetric HRCT is obtained. With MD-HRCT, images could be reconstructed
in any desired plane to demonstrate bronchi to best advantage.
FIGURE 1-35 Gantry angulation in a patient with right middle-lobe bronchiectasis. A: HRCT
image obtained with the gantry vertical shows bronchial wall thickening in the right middle lobe. B:
HRCT image obtained with the gantry angulated 20 degrees allows right middle-lobe bronchi
(arrows) to be imaged along their axes.
Use of Contrast Agents
At present, there is no routine indication for the use of contrast agents with
HRCT, except when studying a focal lung lesion or solitary nodule (206) or in
patients being studied for pulmonary vascular disease (Figs. 1-18 and 1-19).
Because the lung window settings routinely used for HRCT are intended to
accentuate the contrast between air and tissue, vascular opacification is not
visible in patients receiving an injection of intravenous contrast. Using a softtissue window, however, opacification of most segmental and subsegmental
vessels may be seen on both spaced and volumetric HRCT (207).
Use of Dual-Energy kV(p)
Dual-energy CT utilizes two different kV(p) settings, typically 80 to 100 and
140, generated by two separate x-ray tubes or rapid switching of a single x-ray
tube. Attenuation differences at the different energies allow the determination of
the composition of various tissue components (air, iodine, soft tissue) within a
specific voxel (208). Most studies to date have focused on the ability of dualenergy CT to create iodine maps reflecting lung perfusion (209,210). Another
potential clinical use is the ability to map and quantify lung ventilation using
inhaled xenon as a contrast agent (210,211). This has the potential to provide
anatomical and functional information that is complementary to the visual
assessment of CT images.
IMAGE DISPLAY
Use of Workstations
The use of an electronic workstation to view HRCT images is optimal and
recommended. Scans may be viewed at a larger size than generally possible on
film, making small or subtle abnormalities much easier to see. Monitors with a
resolution of 1,000 to 2,000 lines are adequate for viewing.
Workstations used for viewing CT are capable of interpolating or smoothing
the CT data, producing smaller pixels in the resultant image than are present in
the scan itself. Although individual CT pixels are clearly visible on close
inspection of an unprocessed HRCT image, this is not generally the case when
viewing a study on a workstation. In fact, if unprocessed CT images (raw CT
pixels) are viewed, the appearance can be disconcerting, and the images may be
difficult to read. Cameras are capable of photographing CT scans using a range
of settings, from sharp to smooth. If the camera is set on sharp, individual CT
pixels will be visible; on a smooth setting, the data are interpolated, and image
pixel size is reduced (Fig. 1-36). Although it might seem that a sharp setting
would be best for HRCT, this is not the case. Resolution of fine structures is
better with a smooth setting, and image interpretation is easier.
FIGURE 1-36 Image interpolation and pixel size. A: Actual CT pixels are displayed on this
HRCT image in a patient with interlobular septal thickening. The thickening septa have a stair-step
appearance, and centrilobular arteries appear square. B: With interpolation, the appearance of
the image is considerably improved. Note that a small centrilobular bronchiole clearly seen on this
image (arrow) cannot be recognized on the original image (A).
Image compression may be used to reduce the quantity of digital data
involved in the transmission and storage of images. The use of so-called lossy
image compression (JPEG 2000), which is now part of the Digital Imaging and
Communications in Medicine standard, allows the compression ratio to be
adjusted. Ringl et al. (212) assessed the use of different degrees of compression
on the quality of HRCT images. The authors found that images compressed with
a ratio of 3:1 were indistinguishable from uncompressed images, while
compression ratios of 7:1 or more resulted in substantial degradation of image
quality and the potential loss of diagnostic information (212).
Window Settings
The window mean and width used for image display have a significant impact
on the appearance of the lung parenchyma and the dimensions of visualized
structures (Fig. 1-37) (14,213). If the display technique used is not appropriate,
normal structures can be made to look abnormal, or subtle abnormalities may be
overlooked.
FIGURE 1-37 A–L: Effects of window mean and width on the visibility of bronchi and vessels
in a normal subject. Using a narrow window width (500 HU), a high window mean (e.g., –300 HU)
makes bronchi and bronchial walls difficult to see, whereas a low window mean (e.g., –900 HU)
accentuates the apparent thickness of bronchial walls and the diameter of vessels. This effect
decreases with increasing window width (i.e., 1,500 HU) (I–L). A window mean of approximately –
450 HU and width of 1,000 to 1,400 HU have been shown to be best suited to measuring
bronchial wall thickness.
The most important window setting to use in display is the so-called lung
window. It should be emphasized that there is no single correct or ideal window
setting for the demonstration of lung anatomy on HRCT, and several
combinations of window mean and width may be appropriate (214). Within
limits, the precise window width and levels chosen are a matter of personal
preference; the values indicated here should serve only as guidelines. However,
it is important that a single lung window setting be used consistently in all
patients. Unless this is done, it is difficult to compare one case to another,
develop an understanding of what appearances are normal and abnormal, and
compare sequential examinations in the same patient. Although it is not
inappropriate to use some additional window settings in specific cases,
depending on what abnormality is being sought, the effects of the variations in
window settings on the appearance of the resulting images must be kept in mind.
Window level settings ranging from –600 to –700 HU and window widths of
1,000 to 1,500 HU are appropriate for a routine lung window (Fig. 1-37). The
use of an extended window width (i.e., 2,000 HU) reduces contrast between lung
parenchymal structures, such as vessels, bronchi, and the air-containing alveoli,
and may make interstitial structures appear less conspicuous or thinner than they
actually are. In contrast, extended windows may be of some value in detecting
abnormalities of overall lung attenuation (215,216) and are also useful in
evaluating the relationship of peripheral parenchymal abnormalities to the
pleural surfaces. A window width of less than 1,000 HU is not generally
appropriate for viewing lung parenchyma because it unnecessarily increases
contrast and may result in an apparent increase in the size of soft-tissue
structures. For example, the effect of window mean and level on the HRCT
appearance of bronchial walls has been assessed using inflation-fixed lungs
(213). In this study, window widths less than 1,000 HU resulted in a substantial
overestimation of bronchial wall thickness, whereas window widths greater than
1,400 HU resulted in an underestimation of bronchial wall thickness (Fig. 1-37).
Viewing soft-tissue windows is also important in reading HRCT. Window
level/width settings of 40–50/350–450 HU are best for evaluation of the
mediastinum, hila, and pleura. Mediastinal and pleural abnormalities are
sometimes of value in interpreting HRCT of the lung. For example, the presence
of lymph node enlargement, esophageal dilatation, calcification, or pleural
thickening may be helpful in making a correct diagnosis of lung disease. When
performing an HRCT study, images are routinely displayed using both lung and
soft-tissue windows.
As stated, choosing different window levels can be advantageous in individual
cases, despite the fact they may not be optimal for all indications (Fig. 1-37).
Low window settings (–800 to –900 HU) with narrow window widths (500 HU)
can be valuable in contrasting emphysema or air-filled cystic lesions with normal
lung parenchyma. With such a low window mean, normal lung parenchyma
looks gray, whereas areas of emphysema remain black. However, using this
same window to image the lung interstitium would be improper. Such a low
window mean, particularly combined with a narrow window width, would make
the lung interstitium appear much more prominent than it really is and could
make a normal case appear abnormal. This window would also result in
overestimations of the size of vessels and of bronchial wall thickness.
A window width of 2,000 HU is not generally suitable for viewing lung
parenchyma because contrast is significantly reduced. However, window settings
of –500 to –700/2,000 HU may be used and are particularly useful when
pleuroparenchymal abnormalities are being evaluated (3,21).
It is also of diagnostic value, when using a workstation, to vary window
settings or toggle rapidly between different preset window settings (e.g., lung
window, wide lung window, soft-tissue window) at a given scan level. Having
preset windows available is important; in one study assessing the utility of
workstation viewing, interpreting HRCT studies with a fixed window (–
500/2,000 HU) setting proved to be more accurate than viewing them with
operator-varied window settings (215). Having preset windows available also
markedly reduces the time required to interpret the images.
HIGH-RESOLUTION COMPUTED TOMOGRAPHY
PROTOCOLS
HRCT may be obtained in a number of different clinical settings, and to some
extent, the manner in which the examination is obtained is varied according to
the diseases suspected. Either spaced axial scans or MD-HRCT may be used
(13). The following protocols are provided as guides, but these may be varied in
individual cases.
Suspected Emphysema, Airways, or Obstructive Disease
In patients suspected of having emphysema, airways disease such as
bronchiectasis (217), or obstructive disease on the basis of clinical, pulmonary
function, or plain radiographic findings, axial HRCT or MD-HRCT may be
performed (96,143).
Axial scanning should be obtained at full inspiration, at 1-cm intervals from
lung apices to bases, and with the patient supine (Table 1-3); prone scans are not
usually needed. Expiratory scans obtained at three or more levels are also
recommended to detect air trapping.
TABLE 1-3 Scan Protocols: Suspected Emphysema, Airways
Disease, or Obstructive Lung Disease
Full inspiration
Supine position only
Axial scans with 1-cm spacing from lung apices to bases or MD-HRCT
Expiratory scans at three or more levels
Option: dynamic, volumetric, or spirometrically triggered expiratory scans
MD-HRCT, using 0.5-to 1.25-mm detector width, would be ideal for assessing
airways disease and emphysema. Expiratory images may be obtained at selected
levels or by using volumetric postexpiratory MD-HRCT. In patients with
emphysema being evaluated for lung transplantation or volume reduction
surgery, obtaining volumetric MD-HRCT would also be important for the
detection of associated lung carcinoma, which has an incidence of up to 5% in
this patient population (218).
Suspected Fibrotic or Restrictive Disease, or Unknown
Lung Disease
In patients suspected of having a fibrotic or restrictive lung disease on the basis
of clinical, pulmonary function, or plain radiographic findings, or in patients
with an unknown type of respiratory disability, it would be appropriate to obtain
axial HRCT scans at 1-cm intervals with the patient supine. If the chest
radiograph appears normal or subtle lung disease is present, or if chest
radiographs are unavailable for review, additional prone scans should be
obtained, or the scans should be monitored for the presence of problematic
dependent opacity (Table 1-4). If the plain radiograph shows a distinct
abnormality, prone scans will not likely be needed.
TABLE 1-4 Scan Protocols: Suspected Restrictive or Fibrotic Lung
Disease, or Diffuse Lung Disease of Unknown Type
Chest radiograph abnormal
Full inspiration
Supine position
Axial scans with 1-cm spacing from lung apices to bases or MD-HRCT
Expiratory scans at three or more levels (initial examination only)
Chest radiograph normal, minimally abnormal, or unavailable
Full inspiration
Supine position
Axial scans with 1-to 2-cm spacing or MD-HRCT
Prone scans with 2-cm spacing or volumetrically, or monitor scans for dependent density
Expiratory scans at three or more levels (initial evaluation only)
Prone scans at 2-cm intervals, in combination with the supine scans, are
recommended when obtaining prone scans routinely; they obviate the need for
reviewing plain radiographs or monitoring scans. Scans at 2-cm intervals, in
both supine and prone positions, have proven to be a useful protocol for prone
and supine imaging and provide the same number of images to review as
obtained when scanning a patient with obstructive disease (24) (Table 1-4).
In patients having their initial diagnostic evaluation, obtaining expiratory
scans at three or more levels is recommended but not essential. In most patients
with restrictive or fibrotic lung disease, expiratory imaging is of no diagnostic
value. However, in a patient with an unknown lung disease, airway obstruction
may be the cause of the patient’s disability. Furthermore, in a patient with a
restrictive or fibrotic disease, the presence of air trapping visible on expiratory
images may be helpful in differential diagnosis (100,219). Air trapping may be
seen in several fibrotic lung diseases, most notably, hypersensitivity pneumonitis
and sarcoidosis.
MD-HRCT using 0.5-to 1.25-mm detector width obtained in the supine
position may also be used in this clinical setting. Monitoring the study to
determine the need for prone scans would be appropriate, although some
investigators routinely obtain spaced prone scans or volumetric prone scans in
this setting (13). Expiratory imaging, either axial or volumetric, may be used if
needed or desired (13).
In patients with restrictive disease who are having follow-up HRCT
examinations, inspiratory images may be obtained at fewer levels than are
appropriate for the initial diagnostic examination (30), and expiratory scans are
not usually necessary. Follow-up examinations may be obtained using a lowdose technique to reduce radiation exposure.
Hemoptysis
In patients who present with hemoptysis, possibly related to airway
abnormalities or an endobronchial lesion, it is appropriate to obtain volumetric
imaging for the detection of large airway abnormalities. This may be done using
MD-HRCT or volumetric imaging in addition to spaced axial HRCT. In either
instance, HRCT is needed to assess possible airways disease or to detect regions
of hemorrhage appearing as ground-glass opacity or findings of vasculitis (Table
1-5) (220,221). In some situations, the injection of contrast agents may also be
used to identify vascular abnormalities, such as arteriovenous fistula, pulmonary
artery aneurysm, or bronchial artery enlargement (46,47). An ideal examination
would be contrast-enhanced MD-HRCT.
TABLE 1-5 Scan Protocols: Hemoptysis
Full inspiration
MD-HRCT or volumetric CT with spaced axial HRCT at 1-cm intervals
Contrast infusion optional
Expiratory scans at three or more levels (optional for initial evaluation only)
Suspected Pulmonary Vascular Disease
Some patients may have symptoms or signs (e.g., hypoxemia, pulmonary
hypertension) that may result from lung disease (e.g., emphysema), pulmonary
vascular disease (e.g., chronic pulmonary embolism, vasculitis), or a
combination of these (222–226). In such patients, combining HRCT with a
contrast-enhanced helical CT may be necessary for diagnosis. The HRCT study
is used to detect findings of lung disease or small vessel disease, and the
contrast-enhanced helical CT is used to detect large vessel abnormalities and
vascular obstruction.
The use of contrast-enhanced MD-HRCT with 0.5-to 1.25-mm detector width
would be ideal for this indication, allowing the detailed assessment of both large
and small vessel abnormalities and associated lung disease (Figs. 1-18 and 1-19)
(46,47,227–230) (Table 1-6).
TABLE 1-6 Scan Protocols: Suspected Pulmonary Vascular
Disease
Full inspiration
MD-HRCT or volumetric CT with spaced axial HRCT at 1-cm intervals
Contrast infusion
Expiratory scans at three or more levels (optional for initial evaluation only)
SPATIAL RESOLUTION OF HIGH-RESOLUTION
COMPUTED TOMOGRAPHY
A fundamental relationship exists between pixel size and the size of structures
that can be resolved by CT. For optimal matching of image display to the
attainable spatial resolution of the scanner, there should be two pixels for the
smallest structure resolved (11). Using an FOV is sufficient to image the entire
thorax, pixel size is approximately 0.5 mm, and current scanners with thin
detectors are capable of providing a resolution of 10 to 12 line pairs per
centimeter using a high-resolution algorithm, with similar line-pair resolution in
the z-axis (10,199,231,232).
Structures smaller than the pixel size should be difficult to resolve on HRCT;
however, this is sometimes possible. This likely occurs because of the large
differences in attenuation between the soft-tissue structures imaged and the airfilled alveoli surrounding them, and the use of a high spatial frequency algorithm
for reconstruction, which often results in some edge enhancement. The ability of
HRCT to resolve fine lung structures also depends on their orientation relative to
the scan plane (Fig. 1-38). Structures measuring 0.1 to 0.2 mm in thickness can
be seen if they are oriented perpendicular to the scan plane and extend through
the thickness of the scan plane or voxel (e.g., 1 mm) (4,10,233,234). For
example, interlobular septa as thin as 0.1 mm and vessels with a diameter of 0.3
mm are sometimes visible on HRCT using a small FOV, and when oriented
correctly. Similarly sized-structures (i.e., 0.1–0.3 mm) that are oriented
horizontally within the scan plane will not be visible because of volume
averaging with the air-filled lung, which occupies most of the thickness of the
voxel. Bronchi or bronchioles measuring less than 2 to 3 cm in diameter and
having a wall thickness of approximately 0.3 mm are usually invisible in
peripheral lung because they have courses that lie roughly in the plane of scan.
Bronchi or bronchioles of similar sizes are sometimes visible when oriented
perpendicular to the plane of scan.
FIGURE 1-38 Resolution of structures relative to their size, shape, and orientation. The tissue
plane, 0.1 mm thick, and the perpendicular cylinder, 0.2 mm in diameter, are visible on the HRCT
scan because they extend through the thickness of the scan volume or voxel. The horizontal
cylinder cannot be seen.
It should be kept in mind that, although soft-tissue structures can be resolved
when they are thinner or smaller than the pixel size, their apparent size in the
final HRCT image will be determined, at least partially, by the pixel size and the
interpolation algorithm used in the workstation or camera and not by their actual
dimensions. This can make the measurement of such small structures on HRCT
difficult and prone to inaccuracies.
Resolution in the transverse plane using MD-HRCT is similar to that reported
with axial scans. The resolution of lung structures on images reconstructed in the
sagittal or coronal planes depends on the detector width and pitch used. With a
pitch of 1 and the use of thin (0.5–0.625-mm) detectors or collimation, fine lung
structures can be resolved on reconstructed images, and the data set appears to
be nearly isotropic (20). For example, in a study of an anthropomorphic line-pair
phantom, coronal reconstructions obtained using 16-detector MDCT and 0.625mm detector width with a pitch of 1.75 were found to be nearly identical to
transverse images in spatial resolution, up to 9.8 line pairs per centimeter (232);
coronal reconstructions of MDCT using 1.25-mm detectors and a pitch of 1.375
showed a decrease in spatial resolution. In a study of the appearances of
interlobar fissures on sagittal reconstructions from MD-HRCT, it was found that
a collimation of 0.5 mm was necessary for visualization of the minor fissure as a
sharp line (235). It has also been shown that the resolution of anatomical
structures on reconstructed coronal images from MD-HRCT was identical to that
of direct coronal images when 0.5-mm collimation was used for the MD-HRCT
study (56). Resolution with reconstructed MD-HRCT was inferior when 1-mm
collimation was used.
HIGH-RESOLUTION COMPUTED TOMOGRAPHY
ARTIFACTS
Several confusing artifacts can be seen on HRCT. However, familiarity with
their appearances should eliminate potential misdiagnoses (3,10,214,236–238).
Streak Artifacts
Streak artifacts that radiate from the edges of or adjacent to sharply marginated,
high-contrast structures such as bronchial walls, ribs, or vertebral bodies are
common on HRCT. On HRCT, streak artifacts are often visible as fine, linear, or
netlike opacities that can be seen anywhere but are most commonly found
overlying the posterior lung, paralleling the pleural surface and posterior chest
wall (10). Although streak artifacts degrade the image, they do not usually
mimic pathology or cause confusion in image interpretation. Streak artifacts are
thinner and less dense, and have a different appearance than the normal or
abnormal interstitium (interlobular septa) visible in this region. Streak artifacts
can result from several mechanisms: beam hardening, photon starvation, and
aliasing. Streak artifacts are more evident on scans obtained with low mA
(88,214,238).
Photon starvation results in prominent streak artifacts and is most notable in
the paravertebral regions, adjacent to the highly attenuating vertebral bodies. It is
related to insufficient photons reaching the CT detectors (11,238). This type of
artifact is strongly related to radiation dose and can be minimized by increasing
kV(p) and mA. Adaptive or automatic tube current modulation may be used to
reduce this type of streak artifact (238).
Aliasing is a geometric phenomenon that occurs because of undersampling of
spatial information and is related to detector spacing and scan collimation
(11,238). It may appear as fine stripes radiating from the edge of a dense
structure or at a distance from it (238). Because it is independent of radiation
dose, increasing scan technique is of no value in reducing this type of artifact.
The use of MDCT for obtaining HRCT introduces the possibility of a variety
of helical CT artifacts, but most are reduced by using narrow detector width and
low pitch (as in MD-HRCT) (238). Partial volume artifact occurs when a dense
object is located off-center and is incompletely scanned by the x-ray beam when
it is directed in different directions. This can result in the presence of lighter and
darker shading adjacent to the object, but is minimized by using thin collimation
or high pitch. When axial imaging is performed with a helical scanner, some
distortion of the shape of objects may occur because of the helical reconstruction
algorithm. This is greatest when an object rapidly changes shape along the zaxis. Ring artifacts and windmill artifacts may be seen with helical CT and are
familiar to most radiologists (238).
If 2D or 3D reconstructions are performed, additional artifacts may be
introduced. These include stair-step artifacts, which occur when using scan data
obtained with thick detectors or collimation and nonoverlapping reconstructions,
and appear as jagged edges; this artifact is not conspicuous with MD-HRCT
because of the thin detectors used. Zebra artifact results in the presence of
horizontal stripes of varying density in the reconstructed image, corresponding
to the thickness of detectors used, because of noise inhomogeneity in the z-axis.
Motion-Related Artifacts
Pulsation or star artifacts are commonly visible, particularly at the left lung
base, adjacent to the heart (Figs. 1-39 and 1-40). With pulsation artifacts, thin
streaks radiate from the edges of vessels or other visible structures, which
therefore resemble stars, and small areas of apparent lucency may be seen
between these streaks. These lucent areas, if not recognized as artifactual, may
be mistaken for dilated bronchi (237). On MD-HRCT, images reconstructed in
the sagittal or coronal planes may show stair-step artifacts due to cardiac
pulsation.
FIGURE 1-39 “Double fissure” artifact. The left major fissure (arrows) appears to be double.
Fine streak artifacts are visible posteriorly. Pulsation artifacts are also visible adjacent to the left
heart border.
FIGURE 1-40 Bronchiectasis artifact (“pseudobronchiectasis”). Several linear structures
(arrows) appear double, mimicking bronchiectasis.
The major fissure, usually on the left (Figs. 1-39 to 1-41), or other
parenchymal structures such as vessels and bronchi may be seen as double
because of cardiac pulsation or respiration during the scan (214,236). This
appearance of doubling artifacts can mimic bronchiectasis (Fig. 1-41). It results
when a linear structure, such as the fissure or vessel, is in a slightly different
position when scanned by the gantry from opposite directions (180 degrees
apart) (Fig. 1-41). As with image noise, these artifacts are much more
conspicuous when high-resolution techniques are used, simply because they are
more sharply resolved.
FIGURE 1-41 Mechanism of “double fissure” artifact. The major fissure is seen by the
scanner only when the X-ray beam is tangent to it. If the position of the fissure is slightly altered
by cardiac pulsation during the period in which the gantry has rotated 180 degrees (A, B), it
appears to be seen in two different locations on the resulting image (C).
Motion-related artifacts can be reduced by ECG gating of scan acquisition
(199), by using scanners with very rapid scan times (100 ms) (153), or by
spirometrically controlled respiration during scanning (147,148,238).
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2
Normal Lung Anatomy
IMPORTANT TOPICS
THE LUNG INTERSTITIUM
LARGE BRONCHI AND ARTERIES
THE SECONDARY PULMONARY LOBULE AND LUNG ACINUS
ANATOMY OF THE SECONDARY LOBULE AND ITS COMPONENTS
THE CONCEPT OF CORTICAL AND MEDULLARY LUNG
SUBPLEURAL INTERSTITIUM AND PLEURAL SURFACES
NORMAL LUNG ATTENUATION
NORMAL EXPIRATORY HIGH-RESOLUTION COMPUTED TOMOGRAPHY
Abbreviations Used in This Chapter
T/D
bronchial wall thickness/diameter
B/A
bronchoarterial
BI
bronchus intermedius
HU
Hounsfield units
LMB
left main bronchus
MinIP
minimum-intensity projection
RMB
right main bronchus
SD
standard deviation
The accurate interpretation of high-resolution computed tomography (HRCT)
images requires a detailed understanding of normal lung anatomy, normal
variations, normal findings that may mimic an abnormality (1,2) and the
pathologic alterations in normal lung anatomy occurring in the presence of
disease (1–7). In this chapter, those aspects of lung anatomy that are important in
using and interpreting HRCT are reviewed.
THE LUNG INTERSTITIUM
The lung is supported by a network of connective tissue fibers called the lung
interstitium. Although the lung interstitium is not generally visible on HRCT in
normal patients, interstitial thickening is often recognizable. For the purpose of
interpretation of HRCT and identification of abnormal findings, the interstitium
can be thought of as having several components (Fig. 2-1) (8).
FIGURE 2-1 Components of the lung interstitium. Taken together, the peribronchovascular
interstitium and centrilobular interstitium correspond to the “axial fiber system” described by
Weibel (8). The subpleural interstitium and interlobular septa correspond to Weibel’s “peripheral
fiber system.” The intralobular interstitium is roughly equivalent to the “septal fibers” described by
Weibel.
The peribronchovascular interstitium is a system of fibers that invests bronchi
and pulmonary arteries (Fig. 2-1). In the perihilar regions, the
peribronchovascular interstitium forms a strong connective tissue sheath that
surrounds large bronchi and arteries (9). The more peripheral continuum of this
interstitial fiber system, which is associated with small centrilobular bronchioles
and arteries, may be termed the centrilobular interstitium (Fig. 2-1). Taken
together, the peribronchovascular interstitium and centrilobular interstitium
correspond to the “axial fiber system” described by Weibel, which extends
peripherally from the pulmonary hila to the level of the alveolar ducts and sacs
(8).
The subpleural interstitium is located beneath the visceral pleura; it envelops
the lung in a fibrous sac from which connective tissue septa penetrate into the
lung parenchyma (Fig. 2-1). These septa include the interlobular septa, which are
described in detail later in this chapter. The subpleural interstitium and
interlobular septa are parts of the “peripheral fiber system” described by Weibel
(8).
The intralobular interstitium is a network of thin fibers that forms a fine
connective tissue mesh in the walls of alveoli and thus bridges the gap between
the centrilobular interstitium in the center of lobules and the interlobular septa
and subpleural interstitium in the lobular periphery (Fig. 2-1). Together, the
intralobular interstitium, peribronchovascular interstitium, centrilobular
interstitium, subpleural interstitium, and interlobular septa form a continuous
fiber skeleton for the lung (Fig. 2-1). The intralobular interstitium corresponds to
the “septal fibers” described by Weibel (8).
LARGE BRONCHI AND ARTERIES
Within the lung parenchyma, bronchi and pulmonary arteries are closely
associated and branch in parallel. When imaged at an angle to their longitudinal
axis, central pulmonary arteries normally appear as rounded or elliptical
opacities on HRCT, accompanied by uniformly thin-walled bronchi of similar
size and shape (Figs. 2-2 and 2-3). When imaged along their axis, bronchi and
vessels should appear roughly cylindrical or show slight tapering as they branch,
depending on the length of the segment that is visible; tapering of a vessel or
bronchus is most easily seen when a long segment is visible.
FIGURE 2-2 Axial HRCT appearances of large bronchi and arteries in the upper (A) and
lower (B) lobes of a normal subject, imaged with window settings of –700/1,000 HU. The
diameters of vessels and their neighboring bronchi are approximately equal. The outer walls of
bronchi and pulmonary vessels are smooth and sharply defined. Bronchi are usually invisible
within the peripheral 2 cm of lung, despite the fact that vessels are well seen in this region.
FIGURE 2-3 Normal appearances of large bronchi and arteries. In an isolated inflated lung,
the smallest bronchi visible (arrows) measure 2 to 3 mm in diameter. Bronchi and bronchioles are
not visible within the peripheral 1 cm of lung in this preparation, although the artery branches in
the peripheral lung are sharply seen. Note: The “isolated” lungs illustrated in this book are fresh
lungs obtained at autopsy and scanned while inflated with air at a pressure of approximately 30
cm of water. (From Webb WR, Stein MG, Finkbeiner WE, et al. Normal and diseased isolated
lungs: high-resolution CT. Radiology 1988;166(1, pt 1):81–87, with permission.)
The outer walls of pulmonary arteries form a smooth and sharply defined
interface with the surrounding lung, whether they are seen in cross section or
along their length. The walls of large bronchi, outlined by lung on one side and
air in the bronchial lumen on the other, should appear smooth and of uniform
thickness. As indicated in the previous section, bronchi and arteries are encased
by the peribronchovascular interstitium, which extends from the pulmonary hila
into the peripheral lung. Thickening of the peribronchial and perivascular
interstitium can result in irregularity of the interface between arteries and
bronchi and the adjacent lung (6,9,10).
Bronchial Diameter and Bronchoarterial Ratio
In most normal subjects, the bronchi and adjacent pulmonary arteries are similar
in diameter. Their diameters may be compared by using the so-called
bronchoarterial (B/A) ratio, defined as the internal diameter (i.e., luminal
diameter) of the bronchus divided by the diameter of the adjacent pulmonary
artery. To avoid an exaggeration of diameters caused by obliquity of the
bronchus and artery relative to the scan plane, the least diameter of the bronchus
and artery are used for measurement. The B/A ratio in normal subjects generally
averages 0.65 to 0.70 (Figs. 2-4 and 2-5) (11,12). Three-dimensional
reconstruction has also been used to accurately measure bronchial lumen area
and diameter perpendicular to the bronchial axis (13).
FIGURE 2-4 B/A ratio. The B/A ratio is calculated by dividing the internal diameter (i.e.,
luminal diameter) of the bronchus (B) by the diameter of the adjacent pulmonary artery (A). It
averages 0.65 to 0.70 in normal subjects.
FIGURE 2-5 B/A ratio in a normal subject. A detailed view of the right lower lobe (same
subject as shown in Fig. 2-2) shows a bronchus (arrow) having an internal diameter less than the
diameter of the accompanying pulmonary artery. Other visible bronchi show a similar B/A ratio.
A B/A ratio greater than 1 is usually believed to indicate bronchiectasis,
although this may be seen in some normal subjects. For example, in an HRCT
evaluation of 14 normal subjects (12), although the B/A ratio averaged 0.65 ±
0.16, 7% of scan interpretations were believed to show some evidence of
bronchial dilatation.
The presence of a B/A ratio greater than 1 in normal subjects has been
associated with increasing age. In a study by Matsuoka et al. (11), B/A ratios
were measured at the segmental and subsegmental levels in the apical and
posterior basal segments in 85 normal subjects. A significant correlation was
found between the B/A ratio and age (r = 0.768, p < 0.0001). When the subjects
were considered in three age groups, the mean B/A ratios were 0.609 ± 0.05 in
subjects 21 to 40 years old, 0.699 ± 0.067 in subjects 41 to 64 years old, and
0.782 ± 0.078 in subjects 65 years and older (p < 0.0001). At least one bronchus
with a B/A ratio greater than 1 was seen in 41% of patients older than 65 years,
and in this group, 19% of measured bronchi had a B/A ratio greater than 1 (Fig.
2-6). Seven percent of subjects 41 to 64 years of age had at least one bronchus
(5% of measured bronchi) with a B/A ratio greater than 1. None of the subjects
21 to 40 years of age showed this finding. In a study by Copley et al. (2), prone
HRCT scans in 40 subjects over 75 years of age were compared to scans
obtained in a group less than 55 years of age; none had known pulmonary
disease. Bronchial dilatation was seen more frequently (p < 0.001) in the older
group (60%) than in the younger group (6%). This finding was independent of
smoking history.
FIGURE 2-6 Increased B/A ratio in a normal 78-year-old man. The internal diameter of a
bronchus (arrow) in the right lower lobe exceeds the diameter of the adjacent pulmonary artery.
The B/A ratio increases with age and may exceed 1 in normal patients older than 40 years.
An increase in B/A ratio may also be seen in normal subjects living at high
altitude (14–16). It has been suggested that this results from mild hypoxemia
resulting in bronchial dilatation and vasoconstriction. Kim et al. (14) found that
9 of 17 (53%) normal subjects living at an altitude of 1,600 m had evidence of at
least one bronchus equal to or greater in size than the adjacent pulmonary artery;
these authors found that only 2 of 16 (12.5%) individuals living at sea level
showed a similar finding. In this study, the mean B/A ratio was 0.76 at an
altitude of 1,600 m. Similarly, Lynch et al. (16) compared the internal diameters
of lobar, segmental, subsegmental, and smaller bronchi to those of adjacent
pulmonary artery branches in 27 normal subjects living in Denver, Colorado, at
an altitude of about 1 mile. The authors found that 37 of 142 (26%) bronchi
evaluated, and 59% of individuals, had increased B/A ratios.
A convincing relationship has not been shown between the B/A ratio and the
location of the bronchi being evaluated. Evaluation of the distribution bronchi
with a B/A ratio greater than 1 has generally failed to reveal any relationship to
lobe or anteroposterior location within the lungs (14,17).
The B/A ratio may also appear to be greater than 1 if the scan traverses an
undivided bronchus near its branch point and its accompanying artery has
already branched. In this situation, two artery branches may be seen to lie
adjacent to the “dilated” bronchus.
Bronchial Wall Thickness
The thickness of a normal airway wall is related to its diameter. According to
Weibel, 2nd-to 4th-generation (lobar to segmental) bronchi have a wall thickness
of approximately 1.5 mm and a mean diameter between 5 and 8 mm (i.e., the
bronchial wall thickness is about 20%–30% of the bronchial diameter); 6th-to
8th-generation (subsegmental) airways have a wall thickness of approximately
0.3 mm and mean diameters between 1.5 and 3 mm (i.e., the airway wall is
10%–20% of its diameter); and 11th-to 13th-generation airways have diameters
measuring 0.7 to 1 mm with walls of 0.1 to 0.15 mm (i.e., the airway wall is
about 15% of its diameter) (Table 2-1) (18,19).
TABLE 2-1 Relation of Airway Diameter to Wall Thickness
The relationship between bronchial wall thickness and diameter may be
expressed by using the T/D ratio, defined as wall thickness (T) divided by the
total diameter of the bronchus (D) (Fig. 2-7). This ratio may be measured using
HRCT and averages about 20% for segmental and subsegmental bronchi (Fig. 28), quite similar to the anatomical measurements described previously. In one
study (11), HRCT was performed in 85 subjects without cardiopulmonary
disease. The T/D ratio was measured at the segmental and subsegmental levels
of the apical and posterior basal segments. The images were viewed at a window
level of –450 H and a window width of 1,500 H, believed best for accurate
bronchial measurements (20,21). Overall, the T/D ratio measured 0.200 ± 0.015
(range, 0.171–0.227). In another study, the T/D ratio measured 0.23 (± 0.04) in
14 normal subjects (22).
FIGURE 2-7 Measurement of bronchial wall thickness using the T/D ratio. This ratio is defined
as wall thickness (T) divided by the total diameter of the bronchus (D). In normal subjects, it
averages about 0.2 or 20%.
FIGURE 2-8 T/D ratio in a normal subject. A detailed view of the right lower lobe (same
subject as shown in Figs. 2-2 and 2-5). The wall thickness of the bronchus indicated by the arrow
appears to be about one-fifth of its diameter.
In a study by Matsuoka et al. (11), no significant correlation was found
between the T/D ratio and age. However, in a study by Copley et al. (2) of
HRCT findings in normal elderly patients, bronchial wall thickening was seen
more frequently (55%; p < 0.001) in a group of subjects older than 75 years than
in a group of patients less than 55 years of age (6%).
The smallest airways normally visible using HRCT have a diameter of
approximately 2 mm and a wall thickness of 0.2 to 0.3 mm (23). In normal
subjects, airways in the peripheral 2 cm of lung are uncommonly seen because
their walls are too thin (Fig. 2-3) (24). It has also been reported that airways in
the peripheral 1 cm of lung are rarely seen, except adjacent to the mediastinum
(15,25). In a study by Kim et al., airways were visible within 1 cm of the
mediastinal pleura in 40% of normal subjects (25).
It is important to keep in mind that the window settings used for the
interpretation of HRCT may have a significant effect on the apparent thickness
of bronchial walls (see Chapter 1). Furthermore, the bronchial wall as shown on
HRCT represents not only the wall itself, but also the surrounding
peribronchovascular interstitium. Thickening of this interstitium may result in
what appears to be bronchial wall thickening; the term “peribronchial cuffing”
has been used to describe this occurrence on plain radiographs.
THE SECONDARY PULMONARY LOBULE AND LUNG
ACINUS
The lung comprises numerous anatomical units smaller than a lobe or segment.
The secondary pulmonary lobule and lung acinus are widely regarded to be the
most important of these subsegmental lung units (26).
The secondary pulmonary lobule, as defined by Miller, refers to the smallest
unit of lung structure marginated by connective tissue septa (19,27) (Figs. 2-1, 29, and 2-10). Secondary pulmonary lobules are irregularly polyhedral in shape
and vary in size, measuring from 1 to 2.5 cm in diameter in most locations
(8,19,28–30). In one study, the average diameter of pulmonary lobules measured
in several adults ranged from 11 to 17 mm (30).
FIGURE 2-9 Pulmonary lobular anatomy. A and B: Pulmonary lobules that are irregularly
polyhedral or conical in shape are often visible on the surface of the lung, as shown in this
diagram of five lobules visible on the posterior surface of the right lung. B: Lobules are supplied
by small bronchiolar and pulmonary artery branches, which are central in location. They are
variably marginated by connective tissue interlobular septa that contain pulmonary vein and
lymphatic branches. (Specimen photograph courtesy of Martha Warnock, MD.)
FIGURE 2-10 A: Anatomy of the secondary pulmonary lobule, as defined by Miller. Two
adjacent lobules are shown in this diagram. B: Radiographic anatomy of the secondary
pulmonary lobule. Radiograph of a 1-mm lung slice taken from the lower lobe. Two well-defined
secondary pulmonary lobules are visible. Lobules are marginated by thin interlobular septa (S)
containing pulmonary vein (V) branches. Bronchioles (B) and pulmonary arteries (A) are
centrilobular. Bar = 1 cm. (Reprinted from Itoh H, Murata K, Konishi J, et al. Diffuse lung disease:
pathologic basis for the high-resolution computed tomography findings. J Thorac Imaging
1993;8:176, with permission.)
Airways, pulmonary arteries and veins, lymphatics, and the various
components of the pulmonary interstitium are all represented at the level of the
pulmonary lobule (Figs. 2-1, 2-9, and 2-10). Each secondary lobule is supplied
by a small bronchiole and pulmonary artery branch, and is variably marginated
in different lung regions by connective tissue interlobular septa containing
pulmonary veins and lymphatics (31). Secondary lobular anatomy is easily
visible on the surface of the lung because of these interlobular septa (19,28).
The pulmonary acinus is smaller than a secondary lobule. It is defined as the
portion of lung distal to a terminal bronchiole (the last purely conducting
airway) and supplied by a first-order respiratory bronchiole or bronchioles
(32,33). Because respiratory bronchioles are the largest airways that have alveoli
in their walls, an acinus is the largest lung unit in which all airways participate in
gas exchange. Acini are usually described as ranging from 6 to 10 mm in
diameter and average 7 to 8 mm in adults (Figs. 2-10A and 2-11) (30,34).
FIGURE 2-11 Dimensions of secondary lobular structures (A) and their visibility on HRCT (B).
Secondary pulmonary lobules usually comprise a dozen or fewer acini,
although the number varies considerably in different reports (18,35). In a study
by Itoh et al. (36), the number of acini counted in lobules of varying sizes ranged
from 3 to 24.
Historical Considerations
Concepts regarding the importance of the secondary pulmonary lobule, acinus,
and smaller lung units have evolved during the past 300 years in conjunction
with continued progress in understanding lung anatomy, pathology, and
physiology. An excellent perspective on the sequence of events and incremental
discoveries made during this period has been provided by Miller (37).
The earliest detailed description (1676) of the secondary pulmonary lobule
was provided by Thomas Willis, who studied lung structure by the injection of
mercury and other fluids into the bronchi and pulmonary vessels. He found that
“little lobes” (i.e., the lobules) arose from small branches of the trachea and were
separated from each other by a “membrane” (Fig. 2-12). Bronchioles entering
the little lobes were described as dividing into a large number of fine branches,
which led to minute “bladders” or “vesicles.”
FIGURE 2-12 Pulmonary lobules according to Willis (1676). Individual lobules arise from
small bronchial branches.
Georg Rindfleisch (1875) first used the term acinus to indicate a sublobular
lung unit. He described the secondary lobule as supplied by a bronchiole, which
divided into progressively smaller bronchiolar branches, finally giving rise to
arborizing “alveolengänge” (alveolar passages), which collectively formed a
“lung acinus” (Fig. 2-13). The acinus, according to Rindfleisch, was a much
more consistent unit of lung structure than the secondary lobule because of
variation in the size of lobules. However, he regarded the secondary lobule to be
more important than the acinus pathologically, in that disease processes tended
to be limited by the connective tissue septa marginating the lobules.
FIGURE 2-13 A pulmonary lobule and acinus as shown by Rindfleisch (1875). The lobule is
supplied by a bronchiole, which divides into smaller branches. The acinus (arrows) shows
alveolengange (i.e., alveolar ducts).
In 1881, Rudolph Kolliker, using the lung of an executed criminal, provided a
more detailed analysis of the finer divisions of the bronchial tree, and described
respiratory bronchioles as airways having both bronchiolar epithelium and
alveoli in their walls. He distinguished respiratory bronchioles from proximal
airways not having alveoli in their walls (i.e., terminal bronchioles) (Fig. 2-14)
and distal airways with numerous alveoli in their walls (i.e., alveolengange,
subsequently termed alveolar ducts), thus providing the basis for defining the
lung acinus relative to airway anatomy.
FIGURE 2-14 Peripheral airway anatomy described by Kolliker (1881). The airway at the
lower right (indicated as b) represents a terminal bronchiole. More peripheral airways (i.e., br and
br.r) represent respiratory bronchioles. Alveolar ducts (alveolengange) are indicated as ag. The
airways peripheral to the terminal bronchiole are acinar.
In his 1947 book, The Lung, William Snow Miller reviewed lung anatomy in
detail (38). His definitions of the secondary pulmonary lobule and acinus are
still in use today (see previous definitions). However, he also considered the
primary pulmonary lobule to be a fundamental unit of lung structure. He defined
the primary pulmonary lobule as all alveolar ducts, alveolar sacs, and alveoli
distal to the last respiratory bronchiole, along with their associated blood vessels,
nerves, and connective tissues (Figs. 2-15 and 2-16). However, because the term
“primary pulmonary lobule” is not in common use today, “secondary pulmonary
lobule,” “secondary lobule,” and “lobule” are often used interchangeably;
generally, they should be considered as synonymous (26). In this book, each of
these terms is used to refer to Miller’s secondary pulmonary lobule.
FIGURE 2-15 The secondary pulmonary lobule. A: This diagram shows a secondary
pulmonary lobule in the peripheral lung, surrounded by connective tissue septa containing
pulmonary vein branches. Lobular arteries are shown in black, whereas airways are shown in
outline. The lobular bronchiole is traced to alveoli in the lung periphery. The red arrow shows a
terminal bronchiole; the blue arrows show respiratory bronchioles with alveoli arising from their
walls. B: The approximate size of an acinus is shown in blue, whereas a primary pulmonary
lobule is in purple. (Adapted from Miller WS. The lung. Springfield, IL: Charles C Thomas;
1947:204; arrows and shading have been added to the original illustration.)
FIGURE 2-16 The primary pulmonary lobule. Miller defined the primary pulmonary lobule as
all alveolar ducts, atria (A), alveolar sacs (SAL), and alveoli (A) distal to the last respiratory
bronchiole, along with their associated blood vessels, nerves, and connective tissues. (From
Miller WS. The lung. Springfield, IL: Charles C Thomas; 1947:75.)
In 1958, Reid suggested an alternate definition of the pulmonary lobule, based
on the branching pattern of peripheral bronchioles identified bronchographically
rather than by the presence and location of connective tissue septa (31,32,35).
On bronchograms, small bronchioles can be seen to arise at intervals of 5 to 10
mm from larger airways; these small bronchioles show branching at
approximately 2-mm intervals, the so-called millimeter pattern (32). Airways
showing the millimeter pattern were considered by Reid to be intralobular, with
each branch corresponding to a terminal bronchiole (35). She considered lobules
to be the lung units supplied by three to five “millimeter pattern” bronchioles.
Although Reid’s criteria delineate lung units of approximately equal size, about
1 cm in diameter and containing three to five acini, it should be understood that
this definition does not necessarily describe lung units equivalent to the
secondary lobules as defined by Miller and marginated by interlobular septa
(Fig. 2-17) (35,36). Miller’s definition is most applicable to the interpretation of
HRCT, and is widely accepted by both anatomists and pathologists because
interlobular septa are visible on histologic sections (36).
FIGURE 2-17 Relative size and relationships of “Miller’s lobule” and “Reid’s lobule.”
A foundation for our current understanding of secondary lobular anatomy and
its significance in radiographic interpretation was provided by Heitzman et al. in
two papers published in 1969 (28,31) and subsequently detailed in Heitzman’s
book The Lung: Radiologic-Pathologic Correlations (39). He described the plain
radiographic appearances of various lobular abnormalities, carefully correlated
with inflated and fixed lung specimens. In his initial papers, he described the
appearance of septal thickening associated with fibrosis or lymphatic and
pulmonary venous abnormalities, and panlobular consolidation in pulmonary
infarction and bronchopneumonia. In his more detailed descriptions published
later, he further emphasized the radiographic appearances of “lobular core”
structures, and demonstrated the radiographic and pathologic findings of
peribronchiolar nodules and sublobular opacities, which are now generally
referred to using the term “centrilobular.”
ANATOMY OF THE SECONDARY LOBULE AND ITS
COMPONENTS
An understanding of secondary lobular anatomy and the appearances of lobular
structures is key to the interpretation of HRCT (Figs. 2-10, 2-11, and 2-18 to 224). HRCT can show many features of the secondary pulmonary lobule in both
normal and abnormal lungs, and many lung diseases, particularly interstitial
diseases,
produce
characteristic
changes
in
lobular
structures
(5,6,10,23,24,26,40,41). For the purposes of the interpretation of HRCT, the
secondary lobule is most appropriately conceptualized as having three principal
parts or components:
FIGURE 2-18 Interlobular septa in an isolated lung. A: Some thin, normal interlobular septa
(small arrows) are faintly visible in the peripheral lung. Interlobular septa along the mediastinal
pleural surface (large arrows) are slightly thickened by edema fluid and are more easily seen.
Note that a very thin line is visible at the pleural surfaces and in the lung fissure, similar in
appearance and thickness to the normal interlobular septa. This line represents the subpleural
interstitial compartment and visceral pleura. (From Webb WR, Stein MG, Finkbeiner WE, et al.
Normal and diseased isolated lungs: high-resolution CT. Radiology 1988;166:81, with permission.)
B: Paper-mounted lung slice at the same level as A. Lobular lung anatomy in the upper lobe is
well seen because of pigment deposition in relation to interlobular septa. The same pulmonary
lobule (black arrows) as shown in A is visible on the surface of the lung. The branching
centrilobular bronchiole (white arrow) is visible.
FIGURE 2-19 Interlobular septa in continuity in an isolated lung. On HRCT, long interlobular
septa (arrows) can be seen marginating several secondary lobules. The septa in this lung are
slightly thickened by fluid. Septa are well seen peripherally, but note that the septa and, therefore,
secondary lobules are less well defined in the central lung. (From Webb WR, Stein MG,
Finkbeiner WE, et al. Normal and diseased isolated lungs: high-resolution CT. Radiology
1988;166:81, with permission.)
FIGURE 2-20 Normal HRCT lobular anatomy. A: Axial HRCT of the left upper lobe in a
normal subject. Thin interlobular septa (black arrows) are visible in the posterior lung, outlining a
normal pulmonary lobule, but otherwise septa are inconspicuous. The centrilobular artery (white
arrow) is clearly seen. B: In the same patient, a scan through the left lower lobe shows normal
pulmonary vein branches (black arrows) marginating pulmonary lobules. The centrilobular artery
branches (white arrows) are visible as a rounded dot between the veins.
FIGURE 2-21 Normal HRCT lobular anatomy. HRCT of the right upper lobe in a normal
subject. Thin interlobular septa identify a lobule (black arrows) in the lung periphery. A pulmonary
vein branch (large white arrows) is visible in relation to the periphery of the lobule. The
centrilobular artery is also seen as a white dot (small white arrow). Other pulmonary artery
branches are visible 5 to 10 mm from the pleural surface.
FIGURE 2-22 Normal lobular anatomy in the right upper lobe. Interlobular septa are more
evident than in most patients, but likely normal. Centrilobular arteries (red arrows) are visible as
branching or dotlike opacities about 1 cm from the pleural surface. Veins (blue arrows) are seen in
relation to interlobular septa.
FIGURE 2-23 Centrilobular anatomy in an isolated lung. A: On a CT scan obtained with 1-cm
collimation, pulmonary artery branches (arrows) with their accompanying bronchi can be
identified. B: On an HRCT scan at the same level, interlobular septa can be seen marginating one
or more lobules. Pulmonary artery branches (arrows) can be seen extending into the centers of
pulmonary lobules, but intralobular bronchioles are not visible. The last visible branching point of
pulmonary arteries is approximately 1 cm from the pleural surface. Bronchi are invisible within 2 or
3 cm of the pleural surface. (From Webb WR, Stein MG, Finkbeiner WE, et al. Normal and
diseased isolated lungs: high-resolution CT. Radiology 1988;166:81, with permission.)
FIGURE 2-24 HRCT appearance of pulmonary lobules in patients with interlobular septal
thickening. A: Lobular anatomy in a patient with interstitial pulmonary edema. Lobules are easily
identified because of interlobular septal thickening. Centrilobular arteries are visible as branching
of dotlike opacities in the centrilobular region. B: Lobular anatomy on a sagittal reconstruction in a
patient with unilateral pulmonary vein atresia and interlobular septal thickening. Note that lobules
are best delineated in the upper lobes.
1. Interlobular septa and contiguous subpleural interstitium
2. Centrilobular structures
3. Lobular parenchyma and acini
Interlobular Septa
Anatomically, secondary lobules are marginated by connective tissue
interlobular septa, which extend inward from the pleural surface (Figs. 2-10, 211, and 2-18 to 2-24). The interlobular septa are part of the peripheral interstitial
fiber system described by Weibel (Fig. 2-1) (8), and contain pulmonary veins
and lymphatics.
Pulmonary lobules in the lung periphery are relatively large in size, and are
marginated by interlobular septa that are thicker and better defined than in other
parts of the lung (31,42). Peripheral lobules tend to be relatively uniform in
appearance, often appearing cuboidal or pyramidal in shape (31). Pulmonary
lobules in the central lung are smaller and more irregular in shape than in the
peripheral lung, and are marginated by interlobular septa that are thinner and less
well defined. When visible, lobules in the central lung may appear hexagonal or
polygonal in shape. It should be kept in mind, however, that the size, shape, and
appearance of pulmonary lobules as seen on HRCT are significantly affected by
their orientation relative to the scan plane.
Interlobular septa are thickest and most numerous in the apical, anterior, and
lateral aspects of the upper lobes, the anterior and lateral aspects of the middle
lobe and lingula, the anterior and diaphragmatic surfaces of the lower lobes, and
along the mediastinal pleural surfaces (43); thus, secondary lobules are best
defined in these regions (Fig. 2-24B). Septa measure about 100 μm (0.1 mm) in
thickness in a subpleural location (5,8,23,24).
As discussed in Chapter 1, the visibility of normal lobular structures on HRCT
is related to their size and orientation relative to the plane of scan, although size
is most important (Fig. 2-11). Generally, the smallest structures visible on HRCT
range from 0.3 to 0.5 mm in thickness, although thinner structures, measuring
0.1 to 0.2 mm, are occasionally seen. Thus, interlobular septa in the peripheral
lung are at the lower limit of HRCT resolution (23), but nonetheless they are
often visible on HRCT scans performed in vitro (24). With in vitro HRCT,
interlobular septa are often visible as very thin, straight lines of uniform
thickness that are usually 1 to 2.5 cm in length and perpendicular to the pleural
surface (Figs. 2-11 and 2-18). Several septa in continuity can be seen as a linear
opacity measuring up to 4 cm in length (Fig. 2-19) (24).
On clinical scans in normal patients, interlobular septa are less commonly
seen and are seen less well than they are in studies of isolated lungs. A few septa
are often visible in the lung periphery in normal subjects, but they tend to be
inconspicuous (Figs. 2-20 and 2-21); normal septa are seen most often in areas
where they are best developed (i.e., in the apices, anteriorly, and along the
mediastinal pleural surfaces) (6,44). When visible, they are usually seen
extending to the pleural surface. In the central lung, septa are thinner than they
are peripherally and are infrequently seen in normal subjects (Fig. 2-19); often,
interlobular septa that are clearly defined in this region are abnormally thickened
(Fig. 2-22). Occasionally, when interlobular septa are not clearly visible, their
locations can be inferred by locating septal pulmonary vein branches,
approximately 0.5 mm in diameter. Veins can sometimes be seen as linear,
arcuate, or branching structures (Figs. 2-20B and 2-21), or as a row or chain of
dots surrounding centrilobular arteries and approximately 5 to 10 mm from
them. Pulmonary veins may also be identified by their pattern of branching; it is
common for small veins to arise at nearly right angles to a much larger main
branch (Fig. 2-20B).
Interlobular septa are more frequently visible in elderly subjects than in young
patients, in smokers, and tend to increase in visibility over time (1,2,45). In a
study by Copley et al. (2), prone HRCT obtained in 40 subjects over 75 years of
age was compared to HRCT obtained in a younger age group (less than 55 years
of age); none had known pulmonary disease. Interlobular septal thickening was
seen in 18% of the older group and none of the younger patients. The septal
thickening was limited to one lobe in two subjects and was widespread (two or
more lobes) and bilateral in five.
Centrilobular Region and Centrilobular Structures
The central portion of the lobule, referred to as the centrilobular region or
lobular core (31), contains the pulmonary artery and bronchiolar branches that
supply the lobule, lymphatics, and some supporting connective tissue
(5,8,19,23,24,33). It is difficult to precisely define lobules in relation to the
bronchial or arterial trees; lobules do not arise at a specific branching generation
or from a specific type of bronchiole or artery (19).
Branching of the lobular bronchiole and artery is irregularly dichotomous
(36). When they divide, they generally divide into two branches. Most often,
they divide into two branches of different sizes (one branch being nearly the
same size as the one it arose from, and the other being smaller) (Figs. 2-10B and
2-11). Thus, on bronchograms, arteriograms, or HRCT, there often appears to be
a single dominant bronchiole or artery in the center of the lobule, which gives off
smaller branches at intervals along its length.
The HRCT appearances and visibility of centrilobular structures are
determined primarily by their size (Fig. 2-11). Secondary lobules are supplied by
arteries and bronchioles measuring approximately 1 mm in diameter, whereas
intralobular terminal bronchioles and arteries measure approximately 0.7 mm in
diameter, and acinar bronchioles and arteries range from 0.3 to 0.5 mm in
diameter. Arteries of this size can be easily resolved using the HRCT technique
(23,24).
On clinical scans, a linear, branching, or dotlike opacity frequently seen within
the center of a lobule, or within 1 cm of the pleural surface, usually represents
the intralobular artery branch or its divisions (Figs. 2-20 to 2-24) (5,23,24).
Pulmonary artery branches supplying a secondary pulmonary lobule and having
a diameter of about 1 mm contain numerous parallel elastic laminae in their
walls and are termed elastic arteries (46). Arteries smaller than 1 mm and larger
than 0.1 mm in diameter generally contain smooth muscle in their walls, and are
termed muscular arteries. Vessels smaller than 0.1 mm in diameter are termed
pulmonary arterioles (46). The smallest arteries resolved using HRCT extend to
within 3 to 5 mm of the pleural surface or lobular margin and are as small as 0.2
mm in diameter (5,23,24); thus, pulmonary arterioles are not visible on HRCT.
Centrilobular arteries visible on HRCT are not seen to extend to the pleural
surface in the absence of atelectasis (Figs. 2-20 to 2-24).
The visibility of bronchioles in normal subjects depends on their wall
thickness rather than diameter. For a 1-mm bronchiole supplying a secondary
lobule, the thickness of its wall measures approximately 0.15 mm; this is at the
lower limit of HRCT resolution. The wall of a terminal bronchiole measures
only 0.1 mm in thickness, and that of an acinar bronchiole only 0.05 mm, both of
which are below the resolution of HRCT technique for a tubular structure (Fig.
2-11). In one in vitro study, only bronchioles having a diameter of 2 mm or more
or having a wall thickness of more than 100 mm (0.1 mm) were visible using
HRCT (23); and resolution is certainly less than this on clinical scans. It is
important to remember that on clinical HRCT, intralobular bronchioles are not
normally visible, and bronchi or bronchioles are rarely seen within 1 cm of the
pleural surface in most locations (Figs. 2-20 and 2-24) (15,25).
Lobular (Lung) Parenchyma and Lung Acini
The substance of the secondary lobule, surrounding the centrilobular region and
contained within the interlobular septa, consists of functioning lung parenchyma,
namely, alveoli and the associated pulmonary capillary bed, supplied by small
airways and branches of the pulmonary arteries and veins. This parenchyma is
supported by a connective tissue stroma, a fine network of very thin fibers within
the alveolar septa termed the intralobular interstitium (Fig. 2-1) (8,19), which is
normally invisible. On HRCT, the lobular parenchyma should be of greater
opacity than air, but this difference may vary with window settings (see Chapter
1). Some small intralobular vascular branches are often visible.
It should be emphasized that all three interstitial fiber systems described by
Weibel (axial, peripheral, and septal) are represented at the level of the
pulmonary lobule (Fig. 2-1), and abnormalities in any can produce recognizable
lobular abnormalities on HRCT (24). Axial (centrilobular) fibers surround the
artery and bronchiole in the lobular core, peripheral fibers comprising the
interlobular septa marginate the lobule, and septal fibers (the intralobular
interstitium) extend throughout the substance of the lobule in relation to the
alveolar walls.
Pulmonary acini are not themselves recognizable on HRCT. However, artery
branches supplying pulmonary acini measure approximately 0.5 mm and are
large enough to be seen (Fig. 2-11); Murata et al. (23) showed that pulmonary
artery branches as small as 0.2 mm, associated with a respiratory bronchiole and
thus acinar in location, are visible on HRCT and extend to within 3 to 5 mm of
the lobular margins or pleural surface. As with the lobular bronchiole, first-order
respiratory bronchioles supplying an acinus are too small to be seen.
THE CONCEPT OF CORTICAL AND MEDULLARY LUNG
At least partially based on differences in lobular anatomy, it has been suggested
that the lung can be divided into a peripheral cortex and a central medulla
(31,42). Although these terms are not in general use, the concept of cortical and
medullary lung regions is useful in highlighting differences in lung anatomy, as
well as the varying appearances of secondary pulmonary lobules in the
peripheral and central lung regions (47). It also serves to emphasize some
anatomical (and perhaps physiologic) differences between the peripheral and
central lung that are useful in predicting the HRCT distribution of some lung
diseases (48).
Peripheral or Cortical Lung
Cortical lung can be conceived of as consisting of two or three rows or tiers of
well-organized and well-defined secondary pulmonary lobules, which together
form a layer 3 to 4 cm in thickness at the lung periphery and along the lung
surfaces adjacent to the interlobar fissures (Fig. 2-25) (31,42). The pulmonary
lobules in the lung cortex are relatively large in size and are marginated by
interlobular septa that are thicker and better defined than in other parts of the
lung; thus, cortical lobules tend to be better defined than those in the central or
medullary lung. Bronchi and pulmonary vessels in the lung cortex are relatively
small; although cortical arteries and veins are visible on HRCT, bronchi and
bronchioles are uncommonly visible. This contrasts with the anatomy of
medullary lung, in which large vessels and bronchi are visible.
FIGURE 2-25 Corticomedullary differentiation in the lung. The lung cortex is composed of
one or two rows or tiers of well-organized and well-defined secondary pulmonary lobules 3 to 4
cm in thickness. The pulmonary lobules in the lung cortex tend to be well defined and relatively
large, and can be conceived of as being similar to the stones in a Roman arch: all of similar size
and shape. The cortical airways and vessels are small, usually less than 2 to 3 mm in diameter.
Lobules in the lung cortex tend to be relatively uniform in appearance and can
be conceived of as being similar to the stones in a Roman arch: all of similar size
and shape (Fig. 2-25) (42). They can appear cuboidal or be shaped like a
truncated cone or pyramid (31). However, it should be remembered that the size,
shape, and appearance of pulmonary lobules as seen on HRCT are significantly
affected by the orientation of the scan plane relative to the central and
longitudinal axes of the lobules. A single scan typically traverses different parts
of adjacent lobules (Fig. 2-22), resulting in widely varying appearances of the
lobules, despite the fact that they are all of similar size and shape.
Central or Medullary Lung
Pulmonary lobules in the central or medullary lung are smaller and more
irregular in shape than in the cortical lung and are marginated by interlobular
septa that are thinner and less well defined. When visible, medullary lobules may
appear hexagonal or polygonal in shape, but well-defined lobules are
uncommonly seen in normal subjects. In contrast with the peripheral lung,
perihilar vessels and bronchi in the lung medulla are large and easily seen on
HRCT.
SUBPLEURAL INTERSTITIUM AND PLEURAL SURFACES
Diffuse infiltrative lung diseases involving the subpleural interstitium or pleura
can result in abnormalities visible at the pleural surfaces.
Subpleural Interstitium and Visceral Pleura
The visceral pleura consists of a single layer of flattened mesothelial cells that is
subtended by layers of fibroelastic connective tissue; it measures 0.1 to 0.2 mm
in thickness (49,50). The connective tissue component of the visceral pleura is
generally referred to on HRCT as the subpleural interstitium and is part of the
“peripheral” interstitial fiber network described by Weibel (Fig. 2-1) (8). The
subpleural interstitium contains small vessels, which are involved in the
formation of pleural fluid, and lymphatic branches. Interstitial lung diseases that
affect the interlobular septa or result in lung fibrosis often result in abnormalities
of the subpleural interstitium.
Abnormalities of the subpleural interstitium can be recognized over the costal
surfaces of the lung, but are more easily seen in relation to the major fissures; in
this location, two layers of the visceral pleura and subpleural interstitium come
in contact. The major fissures are consistently visualized on HRCT as
continuous, smooth, and very thin linear opacities. Normal fissures are less than
1 mm thick, smooth in contour, uniform in thickness, and sharply defined. The
visceral pleura and subpleural interstitium along the costal surfaces of lung are
not visible on HRCT in normal subjects. A few small dots in relation to the
fissures or at the pleural surface may be seen in normal subjects, reflecting the
presence of subpleural veins or the points of intersection of interlobular septa
with the pleural surface.
Parietal Pleura
The parietal pleura, as with the visceral pleura, consists of a mesothelial cell
membrane in association with a thin layer of connective tissue. The parietal
pleura is somewhat thinner than the visceral pleura, measuring approximately
0.1 mm (49,50). External to the parietal pleura is a thin layer of loose areolar
connective tissue or extrapleural fat, which separates the pleura from the
fibroelastic endothoracic fascia that lines the thoracic cavity (Figs. 2-26 and 227); the endothoracic fascia is approximately 0.25 mm thick (50,51). External to
the endothoracic fascia are the innermost intercostal muscles and ribs. The
innermost intercostal muscles pass between adjacent ribs but do not extend into
the paravertebral regions.
FIGURE 2-26 Anatomy of the pleural surfaces and chest wall.
FIGURE 2-27 Anatomy of the parietal pleura and chest wall in a section of a cadaver. The
parietal pleura and endothoracic fascia are visible as a thin white layer, lining the thoracic cavity.
Little extra thoracic fat is present in this example. The innermost intercostal muscle is visible
external to the parietal pleura, measuring 1 to 2 mm in thickness. External to this is a layer of fat
containing the intercostal vessels and nerve. The intercostal muscles are absent in the
paravertebral regions; only parietal pleura, endothoracic fascia, and paravertebral fat are visible.
As stated in Chapter 1, window-level/width settings of 50/350 HU are best for
evaluating the parietal pleura and adjacent chest wall. Images at a level of –600
HU with an extended window width of 2,000 HU are also useful in evaluating
the relationship of peripheral parenchymal abnormalities to the pleural surfaces
(5,52).
On HRCT in normal patients, the innermost intercostal muscle is often visible
as a 1-to 2-mm-thick stripe of soft-tissue opacity (i.e., the intercostal stripe) at
the lung–chest wall interface, passing between adjacent rib segments in the
anterolateral, lateral, and posterolateral thorax (Fig. 2-28). The parietal pleura is
too thin to see on HRCT along the costal pleural surfaces, even in combination
with the visceral pleura and endothoracic fascia (53). However, in the
paravertebral regions, the innermost intercostal muscle is anatomically absent,
and a very thin line (i.e., the paravertebral line) is sometimes visible at the
interface between the lung and paravertebral fat or rib (Figs. 2-28 and 2-29) (53).
This line probably represents the combined thickness (0.2–0.4 mm) of the
normal pleural layers and endothoracic fascia.
FIGURE 2-28 Normal intercostal stripe and paravertebral line. On HRCT in a normal subject,
the intercostal stripe is visible as a thin white line. Although it represents the combined thickness
of visceral and parietal pleurae, the fluid-filled pleural space, endothoracic fascia, and innermost
intercostal muscle, it primarily represents the innermost intercostal muscle. The intercostal stripe
is seen as separate from the more external layers of the intercostal muscles because of a layer of
intercostal fat. Posteriorly, the intercostal stripe is visible anterior to the lower edge of a rib. Only a
very thin line (i.e., the paravertebral line) is visible in the paravertebral region.
FIGURE 2-29 The paravertebral line. In the paravertebral regions (arrows), the innermost
intercostal muscle is absent, and, at most, a very thin line (the paravertebral line) is present at the
lung–chest wall interface. As in this case, a distinct line may not be seen.
NORMAL LUNG ATTENUATION
Generally speaking, the lung appears homogeneous in attenuation on HRCT
scans obtained at full inspiration. Measurements of lung attenuation in normal
subjects usually range from –700 to –900 HU, corresponding to lung densities of
approximately 0.300 to 0.100 g/mL, respectively (54,55). In most patients,
normal mean lung attenuation ranges from 750 to 860 HU, although it may
measure more or less in individual lung regions. In a study by Lamers et al. (56),
with HRCT obtained using spirometric control of lung volume, the mean lung
attenuation measured in 20 healthy subjects at 90% of vital capacity was –859
HU (standard deviation [SD], 39) in the upper lung zones and –847 (SD, 34) in
the lower lung zones. A study by Chen et al. (57) of 13 patients with normal
pulmonary function tests showed an average lung attenuation of –814 ± 24 HU
on HRCT when the entire cross-section of lung was used for measurement and
an attenuation of –829 ± 21 HU (range, –858 to –770 HU) using three small
regions of interest placed in anterior, middle, and posterior lung regions.
A mean lung density of –866 ± 16 HU was found by Gevenois et al. (58) in a
study of 42 healthy subjects (21 men, 21 women) from 23 to 71 years of age. In
this study, no significant correlation between mean lung density and age was
found, but there was a significant correlation between the total lung capacity,
expressed as absolute values and mean lung density. However, these authors
found a significant correlation between the relative area of pixels less than –950
HU (usually considered emphysema) and age (r = 0.328; p = 0.034). Others (59)
have found a significant correlation between both mean lung density and the
percentage of pixels with lung density less than thresholds of –910 and –950
HU, with age and sex. Although the absolute attenuation differences found in
this study were small, significantly lower mean lung attenuation was found for
nonsmokers older than 75 years (901.7 HU ± 2.5; p = 0.006), compared to those
less than 55 years of age (889.7 HU ± 3.4), and men (905.6 HU ± 2.7; p = 0.003)
as compared to women (894.3 HU ± 2.6) (59). Irion et al. (60) also found that
young (ages 19–41), healthy nonsmokers, with no recognizable lung disease, can
have a small proportion of lung on inspiratory HRCT (mean value 0.19%) with
an attenuation of less than –950 HU. On expiration, this percentage decreased to
0.04%. Mets et al. found this value to be 0.97% in a study of 70 healthy young
men with normal spirometry, most of whom were nonsmokers (61).
An attenuation gradient is normally present, with the most dependent lung
regions being the densest and the least dependent lung regions being the least
dense. This gradient is largely caused by regional differences in blood and gas
volume that, in turn, are determined by gravity, mechanical stresses on the lung,
and intrapleural pressure (52,54). Differences in attenuation between anterior
and posterior lung have been measured in supine patients, and values generally
range from 50 to 100 HU (54,62,63), although gradients of more than 200 HU
have been reported (62). The anteroposterior attenuation gradient was found to
be nearly linear and was present regardless of whether the subject was supine or
prone (62).
Genereux measured anteroposterior attenuation gradients at three levels
(aortic arch, carina, and above the right hemidiaphragm) in normal subjects (63).
An anteroposterior attenuation gradient was found at all levels, although the
gradient was greater at the lung bases than in the upper lung; the anteroposterior
gradient averaged 36 HU at the aortic arch, 65 HU at the carina, and 88 HU at
the lung bases. The attenuation gradient was even larger if only cortical lung was
considered. Within cortical lung, the attenuation differences at the three levels
studied were 45, 81, and 113 HU, respectively.
Vock et al. (54) analyzed CT-measured pulmonary attenuation in children. In
general, lung attenuation in children is greater than in adults (54,62), but
anteroposterior attenuation gradients were similar to those found in adults,
averaging 56 HU at the subcarinal level.
Although most authors have reported that normal anteroposterior lung
attenuation gradients are linear, with attenuation increasing gradually from
anterior to posterior lung, the lingula and superior segments of the lower lobes
can appear relatively lucent in many normal subjects (64); focal lucency in these
segments should be considered a normal finding. Although the reason is unclear,
these slender segments may be less well ventilated than adjacent lung and
therefore less well perfused, or some air trapping may be present.
NORMAL EXPIRATORY HIGH-RESOLUTION COMPUTED
TOMOGRAPHY
Expiratory HRCT is generally performed to detect air trapping in patients with
small airway obstruction or emphysema. On expiratory scans in normal subjects,
HRCT findings include an increase in lung attenuation, decrease in crosssectional lung area (65), and reduction in airway size (66). Air trapping of
limited extent may also be seen in normal subjects.
Lung Attenuation Changes with Expiration
Lung parenchyma normally increases in CT attenuation as lung volume is
reduced during expiration. This change can generally be recognized on HRCT as
an increase in lung opacity (Figs. 2-30 to 2-32; see Figs. 1-27 and 1-30)
(10,54,62,67–70). Robinson and Kreel (68) found a significant inverse
correlation between lung volume determined spirometrically and CT-measured
lung attenuation, for the whole lung (r = –0.680, p > 0.0005) and for anterior,
middle, and posterior lung zones considered individually.
FIGURE 2-30 Normal dynamic expiratory HRCT. Inspiratory (A) and expiratory (B) images
from a sequence of 10 scans obtained during forced expiration in a normal subject. Lung
attenuation increases and cross-sectional lung area decreases on the expiratory scan. C: A
region of interest has been positioned in the posterior lung, and a time-attenuation curve
calculated for this region of interest shows an increase in attenuation from –850 to –625 from
maximal inspiration (I) to maximal expiration (E). Each point on the time-density curve represents
one image from the dynamic sequence.
FIGURE 2-31 Dynamic inspiratory (A) and expiratory (B and C) HRCT in a normal subject,
obtained with low (40) mA. On the inspiratory scan (A), lungs appear homogeneous in
attenuation. Lung attenuation measured –875 HU in the posterior right lung. During rapid
expiration (B), image quality is degraded by respiratory motion. On a scan at maximum expiration
(C), lung decreases in volume and increases in attenuation. Posterior dependent lung increases
in attenuation to a greater degree than anterior nondependent lung, now measuring –750 HU.
Note some anterior bowing of the posterior tracheal membrane, typical of expiratory images.
FIGURE 2-32 Inspiratory (A) and postexpiratory (B) HRCT in a normal subject. On the
expiratory scan, lung increases in attenuation. Posterior dependent lung increases in attenuation
to a greater degree than anterior nondependent lung.
The mean lung attenuation increase between full inspiration and expiration
ranges from 80 to more than 300 HU, with the largest changes being found (a) in
dependent lung regions, (b) at the lung bases, (c) with dynamic scanning during
forced expiration, and (d) when measurements are made using small (e.g., 2–4
cm) regions of interest rather than the entire cross-section of lung
(10,54,56,64,69–73). In a study of young, normal volunteers, an increase in lung
attenuation averaging 200 HU ± 29.7 was found during dynamic forced
expiration, using 2-cm regions of interest, but the increase was variable and
ranged from 84 to 372 HU in different patients and considering dependent and
nondependent lung regions separately (64). In a study of 10 nonsmokers with
normal pulmonary function, using 4-cm regions of interest, the attenuation
increase following expiration ranged from 35 to 139 HU (mean, 90 HU) in the
anterior middle lobe, 64 to 147 HU (mean, 122 HU) in the anterior lingua, and
100 to 363 HU (mean, 237 HU) in the posterior lower lobes (73). In a study by
Chen et al. (57) of patients with normal pulmonary function tests, the average
lung attenuation increase on postexpiratory HRCT was 144 ± 47 HU (range, 85–
235 HU) when three small regions of interest placed in different lung regions
were used for measurement and 149 ± 54 HU when the entire cross-section of
lung was used for measurement. Average lung attenuation on postexpiratory
HRCT was –685 HU ± 51 (range, –763 to –580 HU) using three regions of
interest and –665 ± 80 HU for the entire cross-section of lung (57). Other studies
have shown an increase in average postexpiratory lung attenuation increase of
about 100 to 130 HU in normal subjects or patients with normal pulmonary
function (70,71,74). Millar and Denison (67) calculated the physical density of
lung at full inspiration and expiration, based on the assumption that physical
density had linear relation to radiographic density (physical density = 1 – CT
attenuation in HU/1,000) (75). Using this method, peripheral lung tissue density
was measured as 0.0715 g/cm3 (SD, 0.017) at full inspiration and 0.272 g/cm3
(SD, 0.067) at end expiration. Using dynamic expiratory HRCT, a greater
increase in lung attenuation may be seen than with static imaging.
CT obtained with spirometric control has been used to determine lung
attenuation at specific lung volumes. According to Kalender et al., using
spirometrically triggered CT (76), a 10% change in vital capacity resulted, on
average, in a change of approximately 16 HU, and estimates of lung attenuation
at 0% and 100% of vital capacity were –730 and –895 HU, respectively. In a
study by Lamers et al. (56), with HRCT obtained using spirometric control of
lung volume, the mean lung attenuation in 20 healthy subjects measured in the
upper lung zones at 90% of vital capacity was –859 HU (SD, 39), whereas at
10% of vital capacity, it was –786 HU (SD, 39). In the lower lung zones, lung
attenuation increased from –847 HU (SD, 34) at 90% of vital capacity to –767
HU (SD, 56) at 10% of vital capacity. In a study of spirometrically gated HRCT
(77) at 20%, 50%, and 80% of vital capacity, mean lung attenuation measured –
747, –816, and –855 HU, respectively.
In children, the CT attenuation of lung parenchyma is higher than in adults
and decreases with age (54,62). Attenuation increases seen with expiration are
similar to those found in adults. Ringertz et al. (78), using ultrafast CT, measured
the CT attenuation of children younger than 2.5 years during quiet respiration;
the average CT lung attenuation was –551 HU (SD, 106) on inspiration and –435
HU (SD, 103) on expiration. Vock et al. (54) measured the lung attenuation
changes in children ranging in age from 9 to 18 years. Mean lung attenuation at
full inspiration and full expiration measured –804 and –646 HU, respectively.
The anteroposterior attenuation differences were similar to those seen in adults,
averaging 56 HU at the subcarinal level, and increased with maximal expiration
and increased during expiration (54). Long et al. (79) described normal regional
CT lung attenuation measured using controlled and suspended ventilation at end
inspiration and end expiration in sedated children aged 3 months to 4.5 years.
This study used a positive pressure of 25 cm of water to simulate inspiration,
resulting in approximately 95% of total lung capacity, and a pressure of 0 for
expiration. The average lung attenuation of all children studied averaged –834
HU (± 44 HU) at end inspiration and –633 HU (±102 HU) at end expiration.
Lung density declined linearly in the first few years of life and thereafter
approximated adult values.
Usually, dependent lung regions show a greater increase in lung attenuation
during expiration than do nondependent lung regions irrespective of the patient’s
position (10,62,64,68,69,80). As a result, the anteroposterior attenuation
gradients normally seen on inspiration are significantly greater on expiratory
scans (Fig. 2-32) (54,68,69); the increase in the anterior-to-posterior attenuation
gradient after expiration has been reported to range from 47 to 130 HU in
different studies (10,54,64,69). Furthermore, the expiratory lung attenuation
increase in dependent lung regions is greater in the lower lung zones than in the
middle and upper zones, probably due to greater diaphragmatic movement or
greater basal blood volume (64). In the study by Tanaka et al. of asymptomatic
nonsmokers with normal pulmonary function, the postexpiratory attenuation
increase at the lung bases averaged 131.4 ± 52.1 HU, compared to 102 ± 55.3
and 100 ± 40.2 in the upper and midlungs, respectively (72); similar differences
were also seen in smokers and ex-smokers. The sum of these changes may be
recognizable as increased attenuation or dependent density on supine scans at
low lung volume. Although using measurements of attenuation gradients on
inspiration and expiration has been investigated as a method of diagnosing lung
disease (10,67,81), this technique has yet not assumed a significant clinical role.
Air Trapping on Expiratory High-Resolution Computed
Tomography
Abnormal retention of gas (i.e., air) within a lung or part of a lung, as a result of
airway obstruction or abnormalities in lung compliance, is termed air trapping.
Air trapping is present if lung parenchyma remains lucent on expiratory scans or
shows a less than normal increase in attenuation after expiration.
In as many as 60% of normal subjects, areas of air trapping are visible on
expiratory HRCT scans (Figs. 2-33 and 2-34). This appearance is most common
in the dependent lung, at the lung bases, and in the superior segments of the
lower lobes (82). Air trapping may involve individual pulmonary lobules or
groups of lobules (64,72,83,84). Normal air trapping is generally limited to a
small proportion of lung volume, although the range of reported values varies
from about 5% to about 25% if smokers are included in the analysis
(57,72,73,84).
FIGURE 2-33 Inspiratory (A) and postexpiratory (B) HRCT in a normal subject. On the
expiratory scan, there is relative lucency in the superior segments of the lower lobes, posterior to
the major fissures. This appearance is normal. Also, focal air trapping is present in a single lobule
(arrow) in the posterior right lung. Note the slight anterior bowing of the posterior right BI. This
may be seen in some patients on expiration.
FIGURE 2-34 Dynamic expiratory HRCT in a normal subject showing air trapping in the
anterior lingula (arrows) and relative lucency posterior to the left major fissure. Pulmonary lobules
in the lung medulla are smaller and less well defined than in the periphery. However, vessels and
bronchi in the lung medulla are large and easily seen on HRCT. Note the anterior bowing of the
posterior wall of the right bronchus.
Tanaka et al. (72) found findings of air trapping in 64% of asymptomatic
patients with normal pulmonary function. In a study by Chen et al. (57), focal
areas of air trapping, including the superior segments of the lower lobes, were
visible in 61% of patients with normal pulmonary function tests; air trapping
involved up to 25% of lung when the superior segments were included in
analysis. In a study by Lee et al. (83), air trapping was seen in 52% of 82
asymptomatic subjects with normal pulmonary function tests. Lee et al. (83) also
found that the frequency of air trapping increased with age (p < 0.05), being seen
in 23% of patients aged 21 to 30 years, 41% of those aged 31 to 40 years, 50%
of those aged 41 to 50 years, 65% of those aged 51 to 60 years, and 76% of those
older than 61 years. In a study of 10 young, normal subjects, Webb et al. (64)
found that although air trapping was present in four patients (40%), it was
limited in extent. In another study, discounting the superior segments and air
trapping involving less than two contiguous or five noncontiguous pulmonary
lobules, air trapping was not seen on expiratory scans in 10 healthy nonsmokers,
although it was visible in 40% of patients with suspected chronic airways disease
who had normal pulmonary function tests (85).
Mastora et al. (84) assessed inspiratory and postexpiratory HRCT in 250
volunteers, including 144 smokers, 47 ex-smokers, and 59 nonsmokers. Air
trapping was seen in 62% of the subjects. Lobular air trapping (fewer than three
adjacent lobules) was seen in 47%, without significant differences among
smokers, ex-smokers, and nonsmokers. Segmental (ranging from three adjacent
lobules to a segment) air trapping (seen in 14%) and lobar (larger than a
segment) air trapping (seen in 1%) were more frequent among smokers and exsmokers (p < 0.001). Air trapping was limited to less than 25% of lung area in
72.5% of subjects with air trapping.
Tanaka et al. (72) studied 50 subjects with normal pulmonary function,
including 26 nonsmokers and 24 smokers (14 current and 10 ex-smokers). All 50
subjects who underwent HRCT with images were obtained during deep
inspiration and end expiration at three levels. Air trapping was visually classified
into four degrees (none, lobular, mosaic, or extensive), and the extent of air
trapping was also calculated. The mean increase in lung attenuation in the three
levels at expiration was 111.9 HU ± 46.3. The overall frequency of air trapping
was 64%. Lobular (one or two adjacent lobules), mosaic (three or more regions
of lobular air trapping), and extensive (larger than three adjacent lobules and
subsegmental, segmental, or lobar in distribution) air trapping were seen in 10
(20%), 14 (28%), and 8 (16%) patients, respectively. There was no significant
difference in the visual grade and extent of air trapping among the nonsmokers,
smokers, and ex-smokers (72). The extent of air trapping relative to crosssectional lung area averaged 5.6 ± 6.4% in nonsmokers (range, 0%–20.4%) and
5.9 ± 4.2% and 6.6 ± 4.5% (range, 0%–13.8%) in smokers and ex-smokers,
respectively.
Postexpiratory minimum-intensity projection (MinIP) images may be useful in
detecting air trapping and can increase the conspicuity of this finding (73).
Wittram et al. (73) reviewed inspiratory and postexpiratory HRCT obtained
using helical technique and 1-mm collimation to 10-mm-thick MinIP images in
10 healthy nonsmokers with normal pulmonary function tests. HRCT and
MinIPs demonstrated a smooth anterior-to-posterior attenuation gradient within
the lung parenchyma, which was accentuated by expiration. Expiratory HRCT
and MinIPs demonstrated air trapping in 8 of 10 subjects and in 31 of the 40
regions assessed, although the extent of air trapping was limited, averaging 7.2%
of lung area.
Changes in Cross-Sectional Lung Area
The reduction in cross-sectional lung area that occurs with expiration has been
assessed in several studies and usually ranges from 40% to 50%. In a study of
dynamic expiratory HRCT, Webb et al. (64) determined the percent decrease in
lung cross-sectional area from full inspiration to full expiration in 10 young,
normal volunteers. The area change ranged from 14.8% to 61.3% for all
subjects, subject positions, and lung regions. The greatest percentage decrease in
cross-sectional area during exhalation occurred in the upper lung zones. This
value averaged 51.3% (SD, 6.7) in the supine position and 43.1% (SD, 10.2) in
the prone position. The percentage decrease in lung cross-sectional area was
least at the lung bases, averaging 30.9% (SD, 7.5) in the supine position and
25.2% (SD, 5) in the prone position. The average area changes for the midlung
regions were intermediate between those of upper and lower lung zones,
measuring 38.9% (SD, 7.4) in the supine position and 36.7% (SD, 5.3) in the
prone position. Similarly, in a study by Lucidarme et al. (85), cross-sectional
lung area decreased by an average of 43% (range, 34%–57%) in a group of 10
normal volunteers. Mitchell et al. (65) measured lung area on inspiratory and
end expiratory scans at the level of the carina in 78 normal subjects. The
percentage change in area from inspiration to expiration averaged 55% (SD,
8.7%). Ederle et al. (71) found a decrease in cross-sectional lung area of 24% in
47 patients with normal pulmonary function.
Changes in cross-sectional lung area during expiration can be related to
changes in lung attenuation as shown on HRCT. Simply stated, attenuation
increases at the same time that cross-sectional lung area decreases during
expiration (Fig. 2-30). For example, Robinson and Kreel (68) found a significant
inverse correlation between the expiratory change in cross-sectional lung area
measured on CT and changes in CT-measured lung attenuation (r = –0.793, p >
0.0005). In a study using dynamic expiratory HRCT (64), a correlation between
cross-sectional lung area and lung attenuation was found for each of three lung
regions evaluated (upper lung, r = 0.51, p = 0.03; midlung, r = 0.58, p = 0.01;
lower lung, r = 0.51, p = 0.05). The lower lung zone showed a greater
attenuation increase for a given area change; this phenomenon likely reflects the
much greater effect of diaphragmatic elevation on basal lung attenuation than
occurs in the upper lungs.
In a study by Ederle et al. (71), inspiratory and expiratory HRCT were
compared in 47 patients with normal pulmonary function. Mean lung attenuation
correlated with cross-sectional lung area on both inspiratory (r = –0.66, p <
0.0005) and expiratory scans (r = –0.63, p < 0.0005), and the change in lung area
with expiration correlated with expiratory attenuation change (r = 0.82, p <
0.0005).
Although cross-sectional lung area is most easily assessed on clinical HRCT,
inspiratory-to-expiratory changes in three-dimensional lung volume have been
assessed using helical volumetric CT. Irion et al. (60) found that in young,
healthy nonsmokers, lung volume decreased between 53% and 63% with
expiration. In this study, there was a significant correlation between body surface
area and (a) normal lung volume in inspiration (r = 0.69; p = 0.0001), (b) the
decrease in total lung volume with expiration (r = 0.66; p = 0.0001), and (c) the
percent volume change between inspiration and expiration (r = 0.35; p = 0.05).
Changes in Airway Morphology
The intrathoracic trachea and large bronchi show significant reductions in crosssectional area, anteroposterior diameter, and transverse diameter with expiration
(Figs. 2-31 and 2-35). The trachea and main bronchi are supported by cartilage
along their anterior and lateral walls, but their posterior walls are membranous,
consisting of muscle and fibrous tissue (86). Reduction of anteroposterior
tracheal or bronchial diameter because of anterior bowing of the posterior
membrane is most easily recognized with expiration. Observing the presence and
degree of these changes on expiratory HRCT can be valuable in assessing the
adequacy of the expiratory images. In the absence of significant change in
tracheal or airway diameter on expiratory images, it is unlikely that findings of
air trapping would be visible in patients with a small airway abnormality.
FIGURE 2-35 Normal HRCT appearances of the trachea on inspiratory (A) and expiratory (B)
scans. A: On an inspiratory scan shown at a tissue window setting, the trachea appears elliptic.
B: After forced expiration, there is marked anterior bowing of the posterior tracheal membrane
(arrow), resulting in a decreased anteroposterior diameter. There is little side-to-side narrowing of
the tracheal lumen.
The normal trachea is round or elliptical on inspiration and horseshoe shaped
during and at the end of a full expiration, as the posterior tracheal membrane
bows anteriorly. In a study using ultrafast dynamic CT in 10 healthy men (81),
the mean cross-sectional area of the trachea decreased 35% during a forced vital
capacity maneuver (range, 11%–61%; SD, 18). The anteroposterior diameter
decreased from a mean of 19.6 mm (range, 16.1–23.2 mm; SD, 2.3) to 13.3 mm
(range, 8.3–18.0 mm; SD, 3.5), for a mean decrease of 32%. This change was
largely due to invagination of the posterior tracheal membrane (Fig. 2-35). The
transverse diameter shows less change with expiration; in the same study, it
decreased from a mean of 19.4 mm (range, 15.2–25.3 mm; SD, 2.7) to a mean of
16.9 mm (range, 12.3–20.5 mm; SD, 2.6), for a mean decrease of 13%. The
change of cross-sectional area correlated strongly with the changes in the
anteroposterior and transverse diameters of the trachea (r = 0.88, 0.92; p =
0.0018, 0.0002, respectively). In a study by Ederle et al. (71), a decrease in
tracheal cross-sectional area averaging 17.3% was found on expiratory scans in
patients with normal pulmonary function. Changes in mean lung density and
tracheal area correlated significantly (r = 0.61, p < 0.01).
Boiselle et al. (87) obtained volumetric HRCT at total lung capacity and
during forced exhalation in 51 healthy volunteers (age range, 25–75 years; mean,
50) with normal spirometry. The mean percentage of expiratory reduction in
tracheal lumen cross-sectional area was 54.34% ± 18.6 (SD) in the upper trachea
and 56.14% ± 19.3 in the lower trachea. As found by Stern et al. (81), the
anteroposterior or sagittal tracheal diameter decreased more on expiration than
the transverse or coronal diameter. In Boiselle’s study, the mean percentage of
reduction in sagittal diameter was 45.48% ± 19.0 in the upper and 47.95% ± 15.3
in the lower trachea. The mean percentage of reduction in coronal diameter was
29.93% ± 13.9 in the upper and 28.0% ± 19.3 in the lower trachea.
The cross-sectional area of main and lobar bronchi also decreases with
expiration, and invagination of the posterior wall of the right main bronchus
(RMB) or bronchus intermedius (BI) commonly occurs during forced expiration
(Figs. 2-33 and 2-34). Because slightly different levels are usually imaged on the
inspiratory and expiratory scans, comparing individual bronchi or specific
bronchial levels is often difficult, unless expiratory images are obtained in a
volumetric fashion. In the study by Ederle et al. of postexpiratory scans (71), the
diameters of the right and left main bronchi decreased by an average of 9% and
13%, respectively, in patients with normal pulmonary function.
Litmanovich et al. (88) reviewed the same cohort of 51 patients that was
reported by Boiselle et al. (87) in order to assess changes in bronchial diameter
with expiration. Cross-sectional area measurements of the RMB, left main
bronchus (LMB), and BI were obtained on end-inspiratory and forced-expiratory
CT images. The mean percentage of expiratory lumen collapse was 66.9% ±
19.0 (SD) for the RMB and 61.4% ± 16.7 for the LMB. Among 37 subjects in
whom the BI was also imaged, the mean percentage of expiratory collapse was
61.8% ± 22.8.
The decrease in cross-sectional area of each of these bronchi was principally
due to a decrease in their sagittal diameter with invagination of the posterior
bronchial wall similar to that which occurs in the trachea. For the RMB, the
mean sagittal diameter was 12.6 mm ± 1.9 at end inspiration and 5.0 mm ± 2.7
following forced expiration; the mean coronal diameter was 16.3 mm ± 2.2 at
end inspiration and 12.0 mm ± 2.6 after forced expiration. For the LMB, the
mean sagittal diameter at inspiration and forced expiration were 11.6 mm ± 1.8
and 5.7 mm ± 2.0, respectively, while corresponding measurements of the
coronal diameter were 13.5 mm ± 1.6 and 9.8 mm ± 2.3. Thus, the mean forcedexpiratory reduction in sagittal diameter was 60.3% ± 19.2 for the RMB and
50.9% ± 18.0 for the LMB. The mean forced-expiratory reduction in coronal
diameter was significantly less, measuring 26.4% ± 14.2 for the RMB and 27.4%
± 14.8 for the LMB. Similar area and diameter changes were found for the BI; in
four subjects complete expiratory collapse of the BI was noted (88).
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SECTION
II
Approach to HRCT Diagnosis and Findings of Lung
Disease
The high-resolution computed tomography (HRCT) detection and diagnosis of
diffuse lung disease is primarily based on the recognition of (a) a limited number
of specific abnormal findings, (b) specific combinations or patterns of these
abnormalities, (c) one or more specific distributions of abnormal findings, and
(d) the use of basic history and clinical information.
HRCT FINDINGS OF LUNG DISEASE
Abnormal HRCT findings, which have been enumerated over the last 25 years,
and their differential diagnosis are reviewed in the subsequent five chapters.
These findings can be classified in general terms as:
1. linear and reticular opacities;
2. multiple nodules and nodular opacities;
3. parenchymal opacification, including consolidation and ground-glass
opacity;
4. air-filled cystic lesions, including lung cysts, cystic lung disease,
emphysema, and dilated bronchi (bronchiectasis); and
5. decreased lung attenuation, including mosaic perfusion, mosaic attenuation,
and air trapping on expiratory scans.
COMBINATIONS AND PATTERNS OF HRCT
ABNORMALITIES
The diagnosis or differential diagnosis of diffuse lung disease is often based on
the recognition of specific combinations of HRCT abnormalities, representing
specific patterns of disease. For example, in a patient with honeycombing visible
on HRCT, idiopathic pulmonary fibrosis may be a likely diagnosis, but if
honeycombing is associated with mosaic perfusion or air trapping,
hypersensitivity pneumonitis should be suggested instead. On the other hand,
mosaic perfusion or air trapping associated with bronchiectasis suggests airways
disease. Furthermore, in some patients, ancillary abnormalities such as lymph
node enlargement, mediastinal and cardiac abnormalities, or abnormalities in the
upper abdomen may be helpful.
DISTRIBUTION OF HRCT ABNORMALITIES
When attempting to reach a diagnosis or differential diagnosis of lung disease
using HRCT, the predominant distribution of abnormalities must be considered
along with their appearance and morphology, and the combination or pattern or
abnormal findings present. Although abnormalities in patients with a diffuse
lung disease may involve the entire lung to an equal degree, a specific
predominance in one or more regions is often discernable. Many lung diseases
show specific regional distributions, or a predominance in relation to specific
lung structures, a fact that is related to their underlying histology, pathogenesis,
and pathophysiology.
In different diseases, abnormalities may predominate in relation to:
1. one lung. Many lung diseases are diffuse, and involve both lungs to an
equal or nearly equal degree. On the other hand, some diseases may be
asymmetrical, predominating in one lung, or may show this finding in some
cases. A few lung diseases can be unilateral.
2. the lung in cross section, as displayed on transaxial HRCT images. In
different diseases, abnormalities may predominate in (a) the peripheral or
subpleural lung, (b) the lung periphery, but with relative sparing of the
immediate subpleural regions, or (c) central or peribronchovascular regions,
sparing the supleural lung, or maybe (d) diffuse, equally involving the
entire cross section of lung.
3. the upper-, mid-, or lower lungs. This predominance may be ascertained by
comparing the severity of abnormal findings on transaxial scans through the
upper-, mid-, and lower lung regions, or by using two-dimensional
reconstructions from volumetric imaging.
4. the anterior or posterior lung as seen on transaxial images or sagittal
reconstructions.
5. the secondary pulmonary lobule or lobular structures, being centrilobular,
bronchiolar, perilobular, involving the interlobular septa, or lobular.
6. specific lung structures, such as the pleura (visceral or parietal), bronchi, or
vascular structures, or a combination of specific lung structures. For
example, some patients with nodular lung disease may show a
preponderance of nodules in relation to bronchi and peribronchovascular
regions, the subpleural lung, and interlobular septa; this combination is
termed a lymphatic or perilymphatic distribution. It is typical of sarcoidosis
and a few other diseases.
It is important to keep in mind that predominance in more than one of the
regions described above may be identified in any given case; as when identifying
specific HRCT abnormalities, a specific combination of these may be suggestive
of a particular diagnosis or differential diagnosis. For example, in a patient with
sarcoidosis, a perilymphatic distribution of nodules on HRCT is usually
associated with upper-lobe predominance, and the abnormalities may be
symmetrical or asymmetrical.
Also, significant variations in classical patterns of lung involvement can be
seen in individual patients. A specific diagnosis that otherwise seems likely
should not be excluded because of an atypical distribution of abnormalities.
CLINICAL FINDINGS
Although history and other clinical findings can be of great value in suspecting
or diagnosing a specific disease, in clinical practice, many HRCT studies are
performed and interpreted with little or no clinical information available.
Patients may be referred for HRCT without having seen a local physician or
pulmonologist, or prior to their first appointment. However, even in such cases,
some basic clinical information useful in diagnosis is often available. Such basic
history as whether the patient’s symptoms are acute or chronic, or whether a
fever is present, can be helpful. These will be stressed in the subsequent
chapters, as specific findings and patterns are reviewed.
For example, in a patient with HRCT showing ground-glass opacity as the
predominant HRCT abnormality, knowing whether symptoms are acute or
chronic can limit an otherwise lengthy and nonspecific differential diagnosis. In
a patient with ground-glass opacity and acute symptoms, the most likely
diagnoses include pulmonary edema or hemorrhage, atypical pneumonia,
aspiration, or diffuse alveolar damage; in a similar patient with progressive or
chronic symptoms, the differential diagnosis is long, and includes such diseases
as hypersensitivity pneumonitis, nonspecific interstitial pneumonia (NSIP),
desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-interstitial
lung disease (RB-ILD), lymphoid interstitial pneumonia (LIP), organizing
pneumonia (OP), eosinophilic lung disease, alveolar proteinosis, lipoid
pneumonia, and invasive pulmonary mucinous adenocarcinoma.
3
HRCT Findings: Linear and Reticular Opacities
IMPORTANT TOPICS
INTERLOBULAR SEPTAL THICKENING
HONEYCOMBING
INTRALOBULAR INTERSTITIAL THICKENING (INTRALOBULAR LINES)
NONSPECIFIC RETICULATION
THE INTERFACE SIGN
TRACTION BRONCHIECTASIS AND TRACTION BRONCHIOLECTASIS
PERIBRONCHOVASCULAR INTERSTITIAL THICKENING
PARENCHYMAL BANDS
SUBPLEURAL INTERSTITIAL THICKENING
SUBPLEURAL CURVILINEAR LINE
NORMAL RETICULAR OPACITIES IN THE ELDERLY
DISTRIBUTION OF RETICULAR OPACITIES IN THE DIAGNOSIS OF LUNG DISEASE
Abbreviations Used in This Chapter
AIP
acute interstitial pneumonia
ARDS
acute respiratory distress syndrome
COPD
chronic obstructive pulmonary disease
CWP
coal worker’s pneumoconiosis
DAD
diffuse alveolar damage
DIP
desquamative interstitial pneumonia
HP
hypersensitivity pneumonitis
IP
interstitial pneumonia
IPF
idiopathic pulmonary fibrosis
LIP
lymphoid interstitial pneumonia
NSIP
nonspecific interstitial pneumonia
OP
organizing pneumonia
RB-ILD
respiratory bronchiolitis-interstitial lung disease
UIP
usual interstitial pneumonia
Thickening of the lung interstitium by fluid, fibrous tissue, or because of cellular
infiltration usually results in an increase in reticular or linear opacities on highresolution computed tomography (HRCT). Reticular abnormalities identifiable
on HRCT are generally characterized as belonging to one of three recognizable
patterns, which can sometimes be seen together. These are (a) interlobular septal
thickening, (b) honeycombing, and (c) intralobular interstitial thickening, also
described as intralobular lines by its HRCT appearance (Fig. 3-1). The first two
of these are most easily recognized and have a limited differential diagnosis. The
last is less specific.
FIGURE 3-1 Linear and reticular opacities visible on HRCT.
Additional findings that may be seen in isolation or associated with one or
more of these reticular patterns include traction bronchiectasis, the interface
sign, peribronchovascular interstitial thickening, parenchymal bands, subpleural
interstitial thickening, and subpleural lines (Fig. 3-1).
INTERLOBULAR SEPTAL THICKENING
On HRCT, numerous clearly visible interlobular septa almost always indicate the
presence of an interstitial abnormality; only a few septa should be visible in
normal patients (see Chapter 2). Septal thickening can be seen in the presence of
interstitial fluid, cellular infiltration, infiltration by other materials such as
amyloid, lymphatic dilatation or proliferation, or fibrosis.
Interlobular septal thickening can be diagnosed if visible linear opacities can
be seen to outline what can be recognized as pulmonary lobules because of their
characteristic size and shape. Within the peripheral lung, thickened septa 1 to 2
cm in length may outline part of or an entire lobule and are usually seen
extending to the pleural surface, being roughly perpendicular to the pleura (Figs.
3-1 to 3-14) (1–8). Lobules at the pleural surface may have a variety of
appearances, but they are often longer than they are wide, resembling a cone or
truncated cone. Within the central lung, thickened septa usually outline lobules
that are 1 to 2.5 cm in diameter and appear polygonal, or sometimes hexagonal,
in shape (Fig. 3-2). Lobules delineated by thickened septa commonly contain a
visible dotlike or branching centrilobular pulmonary artery. The characteristic
relationship of the interlobular septa and centrilobular artery is often of value in
identifying each of these structures.
FIGURE 3-2 Smooth interlobular septal thickening in two patients with pulmonary edema. A:
The reticular pattern can be recognized as interlobular septal thickening because the lines outline
recognizable pulmonary lobules. A lobule in the anterior lung outlined by interlobular septa (yellow
arrows) shows dotlike pulmonary artery branches in its center (red arrows). Small nodular
opacities (blue arrows) seen in relation to some septa represent pulmonary vein branches seen in
cross section. B: Smooth thickening of numerous interlobular septa is visible in the upper lobe.
Smooth peribronchovascular interstitial thickening (appearing as peribronchial cuffing or bronchial
wall thickening) is also present. This finding is commonly associated with interlobular septal
thickening.
FIGURE 3-3 Smooth interlobular septal thickening in a patient with pulmonary edema. A
coronal reconstruction shows smoothly thickened interlobular septa (arrows), which are most
evident in the peripheral lung. Thickening of the peribronchovascular interstitium and subpleural
interstitial thickening are present.
FIGURE 3-4 Smooth interlobular septal thickening in a patient with lymphangitic carcinoma.
This appearance is indistinguishable from pulmonary edema.
FIGURE 3-5 A–C: Interlobular septal thickening in a patient with lymphangitic spread of
breast carcinoma. Diffuse, smooth interlobular septal thickening outlines numerous pulmonary
lobules, primarily in the right lung. In addition to septal thickening, there is increased prominence
of the peribronchovascular interstitium, mostly easily recognized as bronchial wall thickening (B,
arrow). A small pneumothorax is visible on the right because of a recent thoracentisis.
FIGURE 3-6 Smooth interlobular septal thickening in a child with lymphangiomatosis.
Mediastinal widening is also present.
FIGURE 3-7 Smooth interlobular septal thickening in Erdheim–Chester disease, a nonLangerhans cell histiocytosis that can result in lung infiltration along lymphatics. A: Thickening of
numerous interlobular septa is visible on HRCT. B: Sagittal lung slice after lung removal for
transplantation. Thickened interlobular septa are most evident in the upper lobes. Histology
showed a combination of fibrosis and histiocytic infiltration. (Courtesy of Kevin O. Leslie MD,
Mayo Clinic, Scottsdale.)
FIGURE 3-8 Interlobular septal thickening in alveolar proteinosis. Thickened septa are
associated with ground-glass opacity. The combination of interlobular septal thickening and
ground-glass opacity in the same lung region is typical of alveolar proteinosis and is termed crazy
paving.
FIGURE 3-9 “Beaded” or nodular septal thickening in two patients with sarcoidosis. A:
Interlobular septa in the upper lobe are nodular in appearance (arrows); this has been termed the
beaded septum sign. B: Numerous nodules are visible within interlobular septa (arrows). The
nodules are too numerous to represent normal pulmonary veins.
FIGURE 3-10 Nodular interlobular septal thickening in lymphangitic spread of carcinoma. A–
C: Nodular interlobular septal thickening in a patient with metastatic colon carcinoma. Nodules are
clearly visible within the septa outlining a lobule in the lung apex (arrows, A). D: Nodular septal
thickening (arrows) shown in a lung specimen of a patient with lymphangitic spread of carcinoma.
FIGURE 3-11 Irregular interlobular septal thickening in patients with fibrotic HP. A and B:
Irregular interlobular septal thickening is visible (arrows) in less-abnormal regions, but in areas
with severe fibrosis, septa are more difficult to recognize. C: In a different patient with chronic HP
with fibrosis, well-defined septa are visible in less-abnormal regions at the lung bases (red
arrows), but are more difficult to recognize and more irregular in contour in more severely involved
regions (yellow arrows).
FIGURE 3-12 Irregular interlobular septal thickening in patients with fibrotic sarcoidosis.
Numerous irregularly thickened interlobular septa (arrows) are associated with lung fibrosis and
distortion of lung architecture. Some nodules remain visible.
FIGURE 3-13 Irregular septal thickening in UIP. A: Irregular reticular opacities (arrows) are
visible in the peripheral lung in a patient with pulmonary fibrosis related to treatment with
methotrexate. These may represent irregularly thickened septa or perilobular fibrosis. B: Irregular
interlobular septal thickening or perilobular fibrosis (arrows) in a patient with IPF. C: Histologic
section in a patient with IPF. Irregular bands of fibrosis (arrows) are visible within the periphery of
lobules, involving the interlobular septa.
FIGURE 3-14 A perilobular pattern in OP. A and B: Thickened interlobular septa and thicker
arcades are visible (arrows) in a patient with OP related to dematomyositis. Areas of consolidation
are also present.
The terms septal lines or septal thickening (Figs. 3-1 to 3-14) may also be
used to describe interlobular septal thickening (9,10), and these terms are
preferred to earlier descriptions such as peripheral lines, short lines, and
interlobular lines (4,8,11). Similarly, although thickened septa outlining one or
more pulmonary lobules have been described as producing a “large reticular
pattern” (1,12) or “polygons” (13), and, if they can be seen contacting the pleural
surface, as “peripheral arcades” or “polygonal arcades” (4), the terms
interlobular septal thickening, septal thickening, and septal lines are considered
more specific in describing these appearances (9,14).
Thickening of the interlobular septa is commonly seen in patients with
interstitial lung diseases (15,16), but may also be seen in normal elderly patients
(17) and otherwise normal smokers. The presence of septal thickening is of little
diagnostic value when other HRCT abnormalities are also visible (15). However,
when visible as an isolated or predominant abnormality, this finding has a
limited differential diagnosis (Table 3-1). Septal thickening can be smooth,
nodular, or irregular in contour in different pathologic processes (2,18–21). A
simple algorithm (Fig. 3-15) based on the recognition of these findings may be
useful for diagnosis.
TABLE 3-1 Differential Diagnosis of Interlobular Septal Thickening
Diagnosis
Comments
Lymphangitic carcinomatosis,
lymphoma, leukemia
Lymphoproliferative disease
Common; predominant finding in most; usually smooth;
sometimes nodular
Smooth or nodular; other abnormalities (i.e., nodules) typically
(e.g., LIP)
Lymphangiomatosis
Congenital pulmonary
lymphangiectasia
Pulmonary edema
Pulmonary hemorrhage
Erdheim-Chester disease
Pneumonia (e.g., viral,
Pneumocystis carinii)
Sarcoidosis
IPF or other cause of UIP
NSIP
Silicosis/CWP; talcosis
Asbestosis
HP (chronic)
Amyloidosis
OP
Elderly patients
present
Rare, smooth
Rare, smooth
Common; predominant finding in most; smooth; ground-glass
opacity can be present
Smooth; associated with ground-glass opacity
Rare, smooth
Smooth; associated with ground-glass opacity
Common; usually nodular or irregular; conglomerate masses
of fibrous tissue with traction bronchiectasis typical in end
stage
Sometimes visible but not common; appears irregular;
intralobular thickening and honeycombing usually
predominates
With findings of ground-glass opacity and reticulation
Occasionally visible; usually nodular; irregular in end-stage
disease
Sometimes visible; irregular
Uncommon; irregular reticular opacities and honeycombing
usually predominate
Smooth or nodular
Perilobular pattern; thick, ill-defined “septal thickening”
Some septal thickening normal
FIGURE 3-15 Algorithmic approach to the diagnosis of interlobular septal thickening.
Regardless of the cause or appearance of septal thickening, this finding is
often associated with peribronchial interstitial thickening and subpleural
interstitial thickening, which are described later.
Smooth Septal Thickening
Smooth septal thickening is usually seen in patients with venous, lymphatic, or
infiltrative diseases (19). Specifically, it may be seen in the presence of
pulmonary edema or hemorrhage (Figs. 3-2 and 3-3) (22–25), pulmonary
venoocclusive disease (22,24,26,27), lymphangitic spread of carcinoma (Figs. 34 and 3-5) (4,7,28), lymphoma, leukemia, and lymphoproliferative diseases;
lymphangiomatosis (Fig. 3-6) (29,30); congenital pulmonary lymphangiectasia
(31,32), interstitial infiltration associated with amyloid (33), Erdheim-Chester
disease (Fig. 3-7) (34), some pneumonias (35), and in a small percentage of
patients with pulmonary fibrosis. Smooth interlobular septal thickening,
regardless of its cause, is often associated with smooth peribronchovascular and
subpleural interstitial thickening, which is most easily recognized as thickening
of fissures. As discussed below, perilobular abnormalities in patients with
organizing pneumonia (OP) can mimic smooth interlobular septal thickening
(Fig. 3-14) (36).
In many diseases associated with smooth septal thickening, the thickening is
diffuse. The primary exception is lymphangitic spread of neoplasm, in which the
abnormality may be unilateral or bilateral, asymmetrical, patchy, and upper-or
lower lobe predominant. Also, in patients with diffuse septal thickening, or
conditions such as pulmonary edema, in which a basal predominance may be
seen, often thickened septa are best defined in the apices and upper lobes, as
interlobular septa are best developed in this region.
Smooth septal thickening may also be seen in association with ground-glass
opacity, a pattern termed crazy paving (see Chapter 5). This pattern is typical of
alveolar proteinosis (Fig. 3-8) but has a long differential diagnosis, which is
reviewed in Chapter 5 (37–42).
Nodular Septal Thickening
Nodular or “beaded” septal thickening occurs in lymphatic or infiltrative
diseases, including lymphangitic spread of carcinoma and lymphoma (4,7,28),
lymphoproliferative disease such as lymphoid interstitial pneumonia (LIP)
(43–45), sarcoidosis (46–49), silicosis or coal worker’s pneumoconiosis (CWP)
(50), and amyloidosis or light-chain deposition disease (33,51) (Figs. 3-9 and 310).
Nodular septal thickening is most appropriately considered along with other
nodular patterns of diffuse lung disease. Septal nodules are often associated with
a so-called “perilymphatic” or “lymphatic” distribution of nodules, in which
abnormalities occur primarily in relation to pulmonary lymphatics (9,14,30,47).
In addition to septal nodules, a perilymphatic pattern is associated with
interstitial thickening or nodules involving (a) the subpleural regions, (b) the
peribronchovascular interstitium in a perihilar location, and (c) the centrilobular
peribronchovascular interstitium. This pattern is most typical of patients with
sarcoidosis, silicosis, lymphangitic spread of carcinoma or other neoplasms, and
lymphoproliferative disease. Nodular patterns of diffuse lung disease are
discussed in detail in the next chapter.
Nodular septal thickening in sarcoidosis, silicosis, and CWP is usually best
seen in the upper lobes and parahilar regions, because of the tendency of these
diseases to predominate in the upper lobes, but this is not always the case.
Lymphoproliferative disease is often diffuse in distribution or basal predominant.
Lymphangitic spread of neoplasm has a variable distribution, and may be diffuse
or localized.
Irregular Septal Thickening
In patients who have interstitial fibrosis, septal thickening visible on HRCT is
often irregular in appearance and associated with distortion of lung architecture
(Figs. 3-11 to 3-13) (52–56). Although interlobular septal thickening can be seen
on HRCT in association with fibrosis and honeycombing (11), it is not usually a
predominant feature (5,57,58). Generally speaking, in the presence of significant
fibrosis and honeycombing, distortion of lung architecture makes the recognition
of thickened septa difficult, except in less-involved lung regions (Fig. 3-11).
Among patients with pulmonary fibrosis and “end-stage” lung disease, the
presence of interlobular septal thickening on HRCT is most frequent in patients
with sarcoidosis (Fig. 3-12) (56% of patients) and is less common in those with
usual interstitial pneumonia (UIP) of various causes (Fig. 3-13), asbestosis, and
hypersensitivity pneumonitis (HP) (Fig. 3-11) (58). The frequency of septal
thickening and fibrosis in patients with sarcoidosis reflects the tendency of
active sarcoid granulomas to involve the interlobular septa.
In patients with idiopathic pulmonary fibrosis (IPF) or UIP of other cause,
irregular reticular opacities are often visible on HRCT, which appear to represent
thickened interlobular septa. However, this finding usually correlates with the
presence of fibrosis predominantly affecting the periphery of acini and the
secondary lobule rather than the septa themselves (30,57). Nonetheless, the
HRCT appearance is similar to that of irregular septal thickening (Fig. 3-13).
In patients with irregular interlobular septal thickening resulting from fibrosis,
other findings such as honeycombing, traction bronchiectasis, and the
distribution of abnormalities are usually most valuable in differential diagnosis.
The Perilobular Pattern
Pulmonary disease occurring predominantly in relation to interlobular septa and
the periphery of lobules has been termed perilobular (10,19,36,59,60). Johkoh et
al. (41,60) emphasized that a perilobular distribution of disease may reflect
abnormalities of the peripheral alveoli and subpleural interstitium in addition to
thickening of interlobular septa (Fig. 3-13). Peripheral lobular fibrosis may result
in irregular reticular opacities, which mimic the appearance of interlobular septal
thickening.
A peripheral lobular or “perilobular” distribution of abnormalities has been
reported in as many as half of patients with OP (36). These abnormalities result
in an appearance (on HRCT) of arcuate or polygonal opacities, which are less
well defined, and may be thicker, than thickened interlobular septa, and may be
associated with areas of ground-glass opacity or consolidation (Fig. 3-14).
Although the histologic correlates of this pattern are unclear, it is likely related to
OP involving distal airspaces.
HONEYCOMBING
Extensive interstitial fibrosis that results in alveolar disruption and
bronchiolectasis produces the classic and characteristic appearance of
honeycombing or honeycomb lung (61). Pathologically, honeycombing is defined
by the presence of small air-containing cystic spaces, generally lined by
bronchiolar epithelium and having thickened walls composed of dense fibrous
tissue. Honeycombing indicates the presence of end-stage lung and can be seen
in a number of diseases leading to end-stage pulmonary fibrosis (58,62).
Honeycombing produces a characteristic cystic appearance on HRCT, and
when present, allows a confident diagnosis of lung fibrosis (Table 3-2) (5,52,61).
On HRCT, the cystic spaces of honeycombing usually range from 3 mm to 1 cm
in diameter, although they can be as large as several centimeters in diameter;
they are characterized by clearly definable walls 1 to 3 mm in thickness (5,52)
(Figs. 3-1 and 3-16 to 3-19). The cysts are air-filled and appear lucent in
comparison to normal lung parenchyma. Although there is some overlap
between the appearances of fine honeycombing and intralobular interstitial
thickening, if the spaces between the lines (i.e., the holes) appear to be air-filled
(i.e., black), rather than having the density of lung parenchyma, honeycombing
is likely present. Honeycombing has been described by Zerhouni et al. as
producing an “intermediate reticular pattern” to distinguish it from the larger
pattern seen with interlobular septal thickening and the smaller pattern visible
with intralobular interstitial thickening (12).
TABLE 3-2 HRCT Characteristics of Honeycomb Cysts
Thick, easily seen walls
Air-filled (i.e., black)
Usually 3–10 mm in diameter
Immediately subpleural in location
They occur in clusters or layers and share walls (multiple layers are seen in late disease)
Nonbranching
Associated with other findings of fibrosis (traction bronchiectasis, irregular reticulation, volume
loss, lung distortion)
FIGURE 3-16 A — C: Honeycombing in IPF. A: HRCT shows honeycomb cysts in the
peripheral and subpleural regions. They are air-filled and have a thick and easily recognizable
wall. Note that the cysts occur in several layers and are generally less than 1 cm in diameter. B:
Resected left lung at a similar level in a different patient with IPF shows honeycomb cysts, which
are most extensive in the posterior and peripheral lung. C: Sagittal lung slice in a patient with IPF
shows honeycombing (arrows) in the posterior subpleural lung. (Courtesy of Martha Warnock,
MD.)
FIGURE 3-17 A and B: Honeycombing in a patient with IPF (prone HCRT). Honeycombing
results in cysts of various sizes, which have a peripheral predominance. The cysts have thick and
clearly defined walls. In areas of honeycombing, lobular anatomy cannot be resolved because of
architectural distortion.
FIGURE 3-18 A–C: Honeycombing in rheumatoid lung disease. HRCT shows honeycomb
cysts with a distinct subpleural predominance. The cysts are generally smaller than 1 cm in
diameter and share walls. Other findings of fibrosis include irregular thickening of the left major
fissure (B, arrow) and traction bronchiectasis (C, arrow).
FIGURE 3-19 Honeycombing in association with paraseptal emphysema in a patient with IPF.
A: Some cysts in the lung periphery, particularly in the left lung, likely reflect paraseptal
emphysema, rather than lung fibrosis. The cysts are larger than 1 cm. B and C: More typical
honeycombing is visible in the posterior right lung base. Emphysema and honeycombing may
occur in combination in some patients, and their distinction on any one slice may be difficult.
Emphysema, however, predominates in the upper lobes and honeycombing predominates in the
lower lobes. In the presence of emphysema, honeycomb cysts may be larger than is typical.
Honeycomb cysts often predominate in the peripheral and subpleural lung
regions regardless of their cause, and perihilar lung can appear normal despite
the presence of extensive peripheral abnormalities (Fig. 3-16). It must be
emphasized that unless cysts are visible in the immediate subpleural lung,
honeycombing cannot be diagnosed with certainty. Air-filled cysts that are not
subpleural may represent traction bronchiectasis, emphysema, pneumatoceles, or
a cystic lung disease such as lymphangiomyomatosis or Langerhans cell
histiocytosis. Also, a basal predominance is usually present, a finding that is
helpful in distinguishing honeycombing from paraseptal emphysema, in which
subpleural cysts are visible.
In early honeycombing, only a few isolated subpleural cysts may be seen, but
it is best to reserve a diagnosis of honeycombing for scans showing clusters,
groups, or rows of clearly defined subpleural cysts with easily recognized walls
(Figs. 3-16 to 3-18). It is generally a good idea to be conservative when
describing this finding as it means that pulmonary fibrosis is present, and it is an
essential criterion in the diagnosis of UIP and IPF (10,63). A reasonable, but
admittedly arbitrary, rule of thumb would be that honeycombing can be
diagnosed if at least three air-filled (black) cysts, 3 to 10 mm in diameter, with
thick, recognizable walls, are seen in a row or cluster in a subpleural location
(Fig. 3-17).
Extensive subpleural honeycomb cysts share walls and often occur in several
contiguous layers (Figs. 3-16 to 3-18). This latter finding can allow
honeycombing to be distinguished from subpleural emphysema (paraseptal
emphysema); in paraseptal emphysema, subpleural cysts usually occur in a
single layer (Table 3-3). But also keep in mind that paraseptal emphysema and
honeycombing may coexist; in such patients, the cystic spaces of honeycombing
may appear larger than usual, and it may be difficult to determine where
emphysema stops and honeycombing begins (Fig. 3-19). The differentiation of
honeycombing and paraseptal emphysema is further discussed in Chapter 6.
Lung consolidation or infiltration in a patient with emphysema or cystic lung
disease can mimic the appearance of honeycombing.
TABLE 3-3 Comparison of HRCT Features of Paraseptal
Emphysema and Honeycombing
Honeycombing is usually associated with other findings of lung fibrosis, such
as volume loss, architectural distortion, intralobular lines, traction
bronchiectasis, traction bronchiolectasis, and irregular subpleural interstitial
thickening. Subpleural cysts seen in the absence of other findings of fibrosis
likely represent another abnormality such as emphysema. Significant
interlobular septal thickening is not commonly visible in association with
honeycombing, except in patients with sarcoidosis (58). In patients with HRCT
findings of septal thickening, the presence of honeycombing distinguishes
fibrosis from other causes of reticulation, such as pulmonary edema or
lymphangitic spread of carcinoma.
Significance of Honeycombing
The presence of honeycombing on HRCT is indicative of significant lung
fibrosis and, in many cases, will lead to a diagnosis of UIP and a consideration
of its most common causes, including IPF (Figs. 3-16, 3-17, and 3-20)
(15,64,65); collagen-vascular diseases (66), most notably rheumatoid arthritis
(Fig. 3-18) (67) and scleroderma (68); drug-related fibrosis; asbestosis and other
pneumoconioses (69,70); chronic HP; diffuse alveolar damage (DAD) resulting
from acute respiratory distress syndrome (ARDS) or radiotherapy; fibrosis in
some smokers (71,72); and in association with interstitial pneumonias (IPs) other
than UIP (Table 3-4).
FIGURE 3-20 Algorithmic approach to the differential diagnosis of honeycombing.
TABLE 3-4 Differential Diagnosis of Honeycombing
Diagnosis
Comments
IPF
Collagen-vascular
disease
Drug-related fibrosis
Asbestosis
HP (chronic)
Common (70%); peripheral, basal, and subpleural predominance
Common; any collagen-vascular disease but most common in
rheumatoid arthritis and scleroderma
Many drugs possible; may be indistinguishable from other causes
Common in advanced disease; peripheral, basal, and subpleural
predominance
Common in advanced disease; may be peripheral, patchy, or diffuse;
midlung predominance common
DAD in the ARDS
Pleuroparenchymal
fibroelastosis
Radiotherapy
Sarcoidosis
NSIP (fibrotic)
Other idiopathic IPs
(i.e., DIP, RB-ILD,
OP, AIP, LIP)
Silicosis/CWP, other
pneumoconioses
Honeycombing in some; may be anterior
Upper-lobe, peripheral predominance; pleural thickening
Localized to the radiation port
A few percent of cases; may be peripheral or patchy; upper-lobe
predominance common; associated with peribronchovascular fibrosis
Uncommon and minimal extent; other findings usually predominate
Uncommon and minimal extent; other findings usually predominate
Uncommon
For example, in a study of HRCT appearances of 129 proven cases of
idiopathic IP, admittedly including atypical cases requiring biopsy for diagnosis,
honeycombing was visible in 71% of patients with UIP, 39% of patients with
desquamative interstitial pneumonia (DIP), 30% of patients with acute interstitial
pneumonia (AIP), 26% of patients with nonspecific interstitial pneumonia
(NSIP), and 13% of patients with OP (73). Honeycombing with a basal
predominance was found in 59% of patients with UIP, 26% of patients with DIP,
22% of patients with NSIP, and 4% of patients with OP (73). However,
honeycombing is significantly less extensive in patients with IPs other than UIP
(15). In a study by Sumikawa et al. (15), the extent of honeycombing averaged
4.4% of lung parenchyma in UIP; 0.3% and 0.6% in patients with cellular and
fibrotic NSIP, respectively; 0.7% in DIP or respiratory bronchiolitis-interstitial
lung disease (RB-ILD); and 0.2% in LIP.
In a survey of patients with end-stage lung (58), subpleural honeycombing
was present in 96% of patients with UIP associated with IPF or rheumatoid
arthritis, in 100% of asbestosis patients, in 44% of those with sarcoidosis, and in
75% of those with chronic HP (58,74). Honeycombing is relatively uncommon
and limited in extent in patients with NSIP (75–77), but may be seen in a few
percent of patients with fibrotic NSIP (65).
The distribution of honeycombing is of value in differential diagnosis (Fig. 320). Honeycombing in patients with IPF and asbestosis is usually most severe in
the subpleural lung regions and at the lung bases (63). The honeycombing in
chronic HP may be most marked in the subpleural lung regions, but is more
often patchy in distribution, and tends to be most severe in the midlung zones
with relative sparing of the lung bases (58,74). Honeycombing in sarcoidosis
often has an upper-lobe predominance. In patients who have pulmonary fibrosis
resulting from ARDS (78), findings of fibrosis and honeycombing on follow-up
HRCT had a striking anterior distribution. This distribution of reticular opacities
and lung fibrosis is unusual in other diseases. Lung fibrosis limited to anterior
lung regions probably reflects the fact that patients with ARDS typically develop
posterior lung atelectasis and consolidation during the acute phase of their
disease; it is believed that consolidation protects the posterior lung regions from
the effects of mechanical ventilation, including high ventilatory pressures and
high oxygen tension (78).
Honeycombing in the Diagnosis of UIP and IPF
In patients who present with clinical features of UIP and lack a history of
collagen-vascular disease or exposure to dusts, organic antigens, or drugs, the
presence of a predominantly subpleural and basal distribution of fibrosis and
honeycombing on HRCT can be sufficiently characteristic of IPF to obviate
biopsy (63,79–81). HRCT findings, including the presence of honeycombing
with a subpleural and basal predominance, have been shown to be highly
accurate in making this diagnosis (58,63,82–90). In a study by Hunninghake et
al. (89) of 91 patients with idiopathic IP, clinical, physiologic, chest
radiographic, and CT features were prospectively recorded; 54 patients (59%)
received a pathologic diagnosis of UIP/IPF. On multivariate analysis, lower-lung
honeycombing (odds ratio, 5.36) and upper-lung irregular lines (odds ratio, 6.28)
were the only independent predictors of UIP/IPF. Using only these two factors, a
diagnosis of UIP/IPF could be established with a sensitivity of 74%, a specificity
of 81%, and a positive predictive value of 85%.
A recent paper (63) presented the cooperative statement of the American
Thoracic Society, European Respiratory Society, Japanese Respiratory Society,
and Latin American Thoracic Association regarding the diagnosis of UIP and
IPF. The numerous authors concluded that, in the absence of a lung biopsy, a
clinical diagnosis of IPF can be solely based on the presence of a UIP pattern on
HRCT and the absence of a history of diseases or exposures usually associated
with this pattern (i.e., collagen disease, drugs, dusts, or organic antigens). Keep
in mind that the differential diagnosis of a UIP pattern is shorter than the
differential diagnosis of honeycombing, and typically includes IPF, collagenvascular diseases, asbestosis, drug reactions, and sometimes HP.
The authors, in turn, specify that the HRCT diagnosis of a UIP pattern should
be based on four criteria, all of which must be present (Table 3-5, Fig. 3-21)
(63). These are:
FIGURE 3-21 A UIP pattern in a patient with IPF. A–C: Fibrosis is characterized by reticular
opacities, traction bronchiectasis, and areas of honeycombing (arrows). The honeycomb cysts are
seen in rows and clusters. Findings of fibrosis predominate in the bases and subpleural regions.
No atypical findings are present.
1. the presence of a basal and subpleural predominance of abnormalities,
2. reticular opacities with or without traction bronchiectasis,
3. honeycombing, and
4. the absence of findings inconsistent with the diagnosis.
TABLE 3-5 HRCT Findings Predicting a UIP Pattern (All are
Necessary)
Basal and subpleural-predominant distribution
Reticular opacities, traction bronchiectasis (i.e., findings supportive of fibrosis)
Honeycombing
Absence of inconsistent findings (see Table 3-6)
This combination of four findings predicts a pathologic diagnosis of UIP in
95% to 100% of cases. However, that not all cases of UIP will meet these
criteria. These criteria are specific, but likely not sensitive. A HRCT diagnosis of
a “possible UIP pattern” is based on the same criteria, but with honeycombing
being absent.
The same authors describe HRCT findings that are considered inconsistent
with a UIP pattern (63). Each of these findings is typical of an IP other than UIP
or a different lung disease (Table 3-6). Any one of these findings is sufficient for
determining that HRCT is inconsistent with a UIP pattern. These findings
include:
1. an upper-or midlung predominance of abnormalities (Fig. 3-11C),
2. a peribronchovascular predominance of abnormalities (Fig. 3-12),
3. extensive ground-glass opacity, exceeding reticulation in extent,
4. profuse micronodules, bilateral and upper lobe,
5. discrete cysts, not representing honeycombing,
6. mosaic perfusion or air trapping, bilateral and in three or more lobes (Fig.
3-22), and
7. segmental or lobar consolidation.
FIGURE 3-22 HRCT inconsistent with UIP and IPF in a patient with chronic HP and
honeycombing. A and B: Inspiratory images show reticulation, traction bronchiectasis, and
honeycombing (arrows) in the subpleural lung. C and D: Dynamic expiratory images at the same
levels show air trapping in multiple lobules (arrows) in three lobes, a finding inconsistent with UIP.
TABLE 3-6 Features Inconsistent with a UIP Pattern
HRCT feature
Likely alternative diagnoses
Ground-glass opacity outside areas of fibrosis,
exceeding reticulation
Mosaic perfusion/air trapping
Centrilobular nodules
Perilymphatic nodules
Peripheral fibrosis with only minimal
honeycombing, subpleural sparing
Upper-lobe distribution of abnormalities
Parahilar, peribronchovascular predominance
Lower-lobe distribution of findings, not
subpleural-predominant
NSIP, HP, other IPs
HP
HP
Sarcoidosis, pneumoconioses
NSIP
Sarcoidosis, pneumoconioses, HP
NSIP, HP, sarcoidosis, pneumoconioses
HP, NSIP
The presence, extent, and progression of honeycombing are important in
determining the prognosis of patients with IPF and other interstitial lung diseases
(91,92). A recent study (92) assessed the prognostic implications of CT and
physiologic variables at baseline and on sequential evaluation in patients with
fibrosing IP, both idiopathic and associated with collagen vascular disease. The
only independent predictors of mortality were the baseline extent of
honeycombing and progression of honeycombing on follow-up studies (p =
0.001 and 0.002, respectively). Neither baseline nor serial change in physiologic
variables, nor the presence of collagen vascular disease, was predictive of rate of
survival.
Variability in the Diagnosis of Honeycombing
Although it may seem that honeycombing should be easily diagnosed, with good
interobserver agreement, this is not always the case. Subtle or early
honeycombing may be difficult to distinguish from pure reticulation or traction
bronchiectasis, and other abnormalities such as paraseptal emphysema and cystic
lung diseases may be confused with this finding (93). In a recent study (93)
assessing interobserver variability in the diagnosis of honeycombing, five
experts scored 80 HRCT images for the presence of honeycombing using a 5point scale (5 = definitely present to 1 = definitely absent) to establish a
reference standard. Forty-three observers, a number of whom were expert
thoracic radiologists, subsequently scored the HRCT using the same scoring
system. Their agreement with the reference standard was only moderate
(weighted k values: 0.40–0.58); of note, agreement among the five study experts
as to the presence of honeycombing was only slightly better (k value = 0.45–
0.67). On a case-by-case basis, observers agreed that honeycombing was present
in 21 of the 80 (26%) cases and agreed that honeycombing was absent in 18
(22%). They disagreed as to the presence of honeycombing in 23 images (29%);
these cases included honeycombing mixed with traction bronchiectasis, large
cysts, and fibrosis with superimposed emphysema. The remaining 18 images
(22%) did not fulfill the criteria of the previous three categories.
INTRALOBULAR INTERSTITIAL THICKENING
(INTRALOBULAR LINES)
Intralobular interstitial thickening results in a fine reticular pattern on HRCT,
with the visible lines separated by a few millimeters (Fig. 3-1) (52). Lung
regions showing this finding characteristically show a fine lace-or netlike
appearance (Figs. 3-1 and 3-23 to 3-28).
FIGURE 3-23 Intralobular interstitial thickening and traction bronchiolectasis in a patient with
IPF. A: Prone HCRT shows a fine network of lines in the lung periphery. Intralobular bronchioles
(arrows) are visible throughout the peripheral lung as a result of fibrosis and traction
bronchiolectasis. B: Histologic specimen in a patient with IPF shows fibrosis, intralobular
interstitial thickening, and bronchiolecstasis (br.) (Courtesy of Martha Warnock, MD.)
FIGURE 3-24 Intralobular interstitial thickening in a patient with early IPF. On a supine scan,
fine reticular opacities are visible posteriorly. This abnormality reflects intralobular interstitial
thickening.
FIGURE 3-25 Prone scans in a patient with fibrotic NSIP. A and B: Abnormal reticulation
represents intralobular interstitial thickening. Traction bronchiectasis (arrows) is easily seen.
FIGURE 3-26 Prone scans in a patient with IPF. A: Abnormal reticulation representing
intralobular interstitial thickening predominates in the subpleural lung. B: At a lower level, fibrosis
is more extensive. Traction bronchiectasis and bronchiolectasis are predominant features. Also,
note the irregular thickening of the major fissure (large arrow) and irregular interlobular septal
thickening. C: Typically, traction bronchiectasis and bronchiolectasis are characterized by
irregular, varicose, or cockscrew appearance (arrows).
FIGURE 3-27 Cellular NSIP with intralobular interstitial thickening and ground-glass opacity.
Ground-glass opacity predominates in the posterior lung, with subpleural sparing typical of NSIP.
Fine reticular opacities in association with the ground-glass represent intralobular lines.
FIGURE 3-28 Pulmonary hemorrhage with intralobular interstitial thickening and ground-glass
opacity. Patchy ground-glass opacity and intralobular lines represent focal pulmonary
hemorrhage.
Intralobular interstitial thickening is a nonspecific finding; it may be
associated with interstitial fibrosis (Figs. 3-23 to 3-26) or interstitial infiltration
or inflammation in the absence of fibrosis (Figs. 3-27 and 3-28). The presence of
intralobular interstitial thickening is described using the term intralobular lines
(10,52). This finding is responsible for the “small reticular pattern” originally
described by Zerhouni et al. (12). Intralobular lines may be seen in isolated or
associated with interlobular septal thickening or honeycombing.
In patients with intralobular interstitial thickening resulting from fibrosis,
intralobular bronchioles may be visible in the peripheral lung (Figs. 3-1 and 323). This is not a normal finding, and it results from a combination of
bronchiolar dilatation (i.e., traction bronchiolectasis) and thickening of the
peribronchiolar interstitium that surrounds them (52,57). Traction
bronchiectasis, dilatation of large bronchi occurring because of fibrosis, may
also be seen (Figs. 3-25 and 3-26). Traction bronchiectasis and traction
bronchiolectasis are described in more detail below.
Intralobular interstitial thickening as perceived on HRCT reflects thickening
of the distal peribronchovascular interstitial tissues and the intralobular
interstitium. As an isolated finding, it is most commonly seen in patients with
pulmonary fibrosis (Figs. 3-23 to 3-27). In patients who have IPF or other causes
of UIP, such as rheumatoid arthritis, scleroderma, or other collagen-vascular
diseases, fibrosis tends to predominantly involve alveoli in the periphery of
acini, resulting in a “peripheral acinar distribution” of interstitial fibrosis (30,57);
this histologic finding correlates with the presence of intralobular lines on
HRCT.
Intralobular lines, resulting in a fine reticular pattern, can also be seen in
patients with NSIP or other IPs (Table 3-7) (Figs. 3-25, 3-27, and 3-29)
(15,73,75-77,94). In NSIP, the presence of intralobular lines or irregular linear
opacities correlated with the presence of interstitial fibrosis and was often
associated with bronchial or bronchiolar dilatation (traction bronchiectasis or
bronchiolectasis) (75,95). In a study of HRCT appearances of various idiopathic
IPs, intralobular lines were visible in 97% of patients with UIP, 93% of patients
with NSIP, 78% of patients with DIP, 71% of patients with OP, and 70% of
patients with AIP (73). Intralobular lines are also common in asbestosis (96).
TABLE 3-7 Differential Diagnosis of Intralobular Interstitial
Thickening
Diagnosis
Comments
IPF or other cause of UIP
HP (chronic)
Asbestosis
NSIP
Other idiopathic IPs (i.e., DIP,
OP, AIP)
Lymphangitic carcinomatosis,
Common (97%); often associated with honeycombing
Common; associated with other findings of fibrosis
Common; associated with other findings of fibrosis
Common (93%); ground-glass opacity (cellular NSIP) or
traction bronchiolectasis (fibrotic NSIP) commonly visible
Common (70%); other findings (i.e., traction bronchiolectasis,
ground-glass opacity, consolidation also present)
Smooth or nodular; associated with septal thickening
lymphoma, leukemia
Pulmonary edema
Pulmonary hemorrhage
Pneumonia (e.g., viral,
Pneumocystis carinii)
Alveolar proteinosis
Other causes of septal
thickening, lung fibrosis, or
lung infiltration
Smooth; associated with septal thickening and ground-glass
opacity
Smooth; associated with septal thickening and ground-glass
opacity
Smooth; associated with septal thickening and ground-glass
opacity
Smooth; associated with septal thickening and ground-glass
opacity
See interlobular septal thickening, honeycombing, crazy
paving differential diagnoses
FIGURE 3-29 Algorithmic approach to the differential diagnosis of intralobular lines.
Intralobular interstitial thickening can be seen in the absence of significant
fibrosis in patients with a variety of infiltrative or inflammatory lung diseases
(Table 3-7) (Figs. 3-27 to 3-29) (97). When this is the case, traction
bronchiectasis and other manifestations of fibrosis are less evident or absent, and
ground-glass opacity may be visible instead. Intralobular interstitial thickening
may be seen in association with interlobular septal thickening in patients with
diseases such as pulmonary edema, pulmonary hemorrhage, atypical pneumonia,
lymphangitic spread of carcinoma, and other infiltrative processes such as
cellular NSIP (7). In the absence of traction bronchiectasis or bronchiolectasis,
the differential diagnosis of this finding is identical to that of interlobular septal
thickening.
Intralobular lines may also be seen in patients with ground-glass opacity or the
pattern of crazy paving, in association with diseases such as pulmonary edema or
hemorrhage (25), some pneumonias (e.g., Pneumocystis jiroveci,
cytomegalovirus), IPs such as NSIP and OP, HP, invasive mucinous
adenocarcinoma, and alveolar proteinosis (Figs. 3-8 and 3-29).
NONSPECIFIC RETICULATION
Generally speaking, if a reticular pattern visible on HRCT cannot be
characterized as representing interlobular septal thickening, honeycombing, or
intralobular interstitial thickening (intralobular lines), the nonspecific terms
“reticulation,” “reticular pattern,” or “reticular opacities” can be used to describe
the abnormality present (10).
Reticular opacities 1 to 3 mm thick, that cannot be characterized as
representing one of these patterns, are often visible in patients with interstitial
disease, representing bands of fibrosis or other causes of interstitial infiltration
(9). Such opacities may represent poorly characterized irregular interlobular
septal thickening, poorly characterized areas of honeycombing, bands of fibrous
tissue in the periphery of pulmonary lobules or bridging the lobule from the
centrilobular region to the lobular periphery, or thickening of the intralobular
interstitium by fibrous tissue or because of inflammation or infiltration.
This finding is nonspecific and may be seen in a variety of diseases, including
those associated with inflammation or fibrosis, including UIP and NSIP (73,75–
77), and in a percentage of cigarette smokers (71,72). In patients who have UIP,
irregular reticulation may be seen instead of honeycombing, particularly in early
cases or in less abnormal regions (i.e., in the upper lobes of patients with IPF); in
patients with NSIP, reticulation is more common than honeycombing.
THE INTERFACE SIGN
The presence of irregular interfaces between the aerated lung parenchyma and
bronchi, vessels, or visceral pleural surfaces has been termed the interface sign
by Zerhouni et al. (1,12) (Figs. 3-1 and 3-30). The interface sign is nonspecific
and is commonly seen in patients with an interstitial abnormality, regardless of
its cause. In the original description of the interface sign, this finding was visible
in 89% of patients with interstitial lung disease (12).
FIGURE 3-30 The interface sign in fibrotic sarcoidosis. The irregular appearance of the
fissure and the edges of vessels reflects the presence of increased lung reticulation, whether due
to intralobular lines, septal thickening, or honeycombing.
The interface sign is generally associated with an increase in lung reticulation;
the presence of thin linear opacities contacting the bronchi, vessels, or pleural
surfaces is responsible for their having an irregular or spiculated appearance on
HRCT (Fig. 3-30). The linear opacities producing the interface sign may
represent thickened interlobular septa, intralobular lines, or irregular scars (Fig.
3-1). The interface sign is most frequently visible in patients with fibrotic lung
disease, but it may also be seen in patients with infiltrative diseases,
inflammatory disease, and pulmonary edema. Nishimura et al. (57) reported the
presence of irregular pleural surfaces and irregular vessel margins in 94% and
98%, respectively, of patients with IPF. In virtually all cases showing the
interface sign, other, more specific, abnormal findings will also be visible on
HRCT.
TRACTION BRONCHIECTASIS AND TRACTION
BRONCHIOLECTASIS
In patients with lung fibrosis and a reticular pattern visible on HRCT, bronchial
dilatation is commonly present, resulting from traction by fibrous tissue on the
bronchi walls. This is termed traction bronchiectasis (Figs. 3-1 and 3-31); it
typically results in irregular bronchial dilatation with the abnormal bronchus
appearing varicose or “corkscrew” (52,98). Traction bronchiectasis usually
involves the segmental and subsegmental bronchi and is most commonly visible
in the perihilar regions in patients with significant lung fibrosis (Figs. 3-25 and
3-26) (49,99). It can also affect small peripheral bronchi or bronchioles (Fig. 323), an occurrence termed traction bronchiolectasis. The branching or irregular
tubular appearance of traction bronchiectasis or bronchiolectasis should be
distinguished from honeycombing whenever possible. As reviewed above, the
diagnosis of honeycombing should be limited to cases showing rows, layers, or
clusters of thick-walled air cysts in the immediate subpleural lung. In a patient
with fibrosis, thick-walled, air-filled cysts separated from the pleural surface
often represent traction bronchiectasis or traction bronchiolectasis.
FIGURE 3-31 Traction bronchiectasis and traction bronchiolectasis in pulmonary fibrosis. A
thin lung slice from a patient with IPF shows honeycombing in the posterior lung. Irregular
dilatation of bronchi (traction bronchiectasis) having a varicose or corkscrew appearance (red
arrows) reflects the presence of lung fibrosis. Dilatation of bronchioles (traction bronchiolectasis,
blue arrows) in less-abnormal lung regions also reflects surrounding lung fibrosis.
The presence of traction bronchiectasis usually indicates that lung fibrosis is
present, and the differential diagnosis includes a large number of fibrotic lung
diseases. Common lung diseases associated with fibrosis and traction
bronchiectasis, but without visible honeycombing, include fibrotic NSIP, end-
stage sarcoidosis, and chronic HP, but keep in mind that UIP may also result in
lung fibrosis without honeycombing. When honeycombing is also present, UIP
is most likely.
Some patients with cellular NSIP and other inflammatory lung diseases can
show bronchial dilatation resembling traction bronchiectasis that resolves with
the resolution of the lung disease. Often, bronchial dilatation in these patients is
cylindrical rather than irregular and varicose, and findings of inflammation such
as ground-glass opacity or consolidation predominate in the abnormal regions.
Likely, a decrease in lung compliance associated with interstitial infiltration
results in bronchial dilatation in these cases.
In patients with lung fibrosis and intralobular interstitial thickening,
intralobular bronchioles may be visible because of their dilatation (traction
bronchiolectasis) and surrounding fibrous tissue (Fig. 3-23). The differential
diagnosis of this finding is that of lung fibrosis. Akira et al. (69) found traction
bronchiolectasis to be more common in patients with IPF (78%) than in those
with asbestosis (20%). In some cases, the HRCT pattern of intralobular lines can
reflect the presence of very small honeycomb cysts or dilated bronchioles
associated with surrounding lung fibrosis. Nishimura et al. (57) reviewed 46
cases of IPF with UIP, correlating findings on CT with appearances of lung
histology from open biopsy specimens or autopsy. Visibility of centrilobular
bronchioles in association with a fine reticulation or increased lung attenuation
was found in 96% of cases, indicating the presence of bronchiolar dilatation,
fibrosis, and “microscopic” honeycombing, with dilated bronchioles or small
cysts measuring approximately 1 mm in diameter (57).
PERIBRONCHOVASCULAR INTERSTITIAL THICKENING
Central bronchi and pulmonary arteries are surrounded and enveloped by a
strong connective tissue sheath, termed the peribronchovascular interstitium,
extending from the level of the pulmonary hila into the peripheral lung. In the
lung periphery, the peribronchovascular interstitium surrounds centrilobular
arteries and respiratory bronchioles (Fig. 2-1) (100). The peribronchovascular
interstitium has been termed the axial interstitium by Weibel (101).
Thickening of the perihilar peribronchovascular interstitium occurs in many
diseases that cause a generalized interstitial abnormality (Table 3-8) (2,4,7,102).
Peribronchovascular interstitial thickening is common in patients with
lymphangitic spread of carcinoma (4,7,103); lymphoma (104); leukemia (105);
lymphoproliferative disease such as LIP (43–45); interstitial pulmonary edema
(23,106); diseases that result in a perilymphatic distribution of nodules (e.g.,
sarcoidosis) (49); and in many diseases that result in pulmonary fibrosis,
particularly sarcoidosis, which has a propensity to involve the
peribronchovascular interstitium (48,107). Peribronchovascular interstitial
thickening has also been reported in as many as 65% of patients with NSIP (75)
and 19% of patients with chronic HP (74).
TABLE 3-8 Differential Diagnosis of Peribronchovascular
Interstitial Thickening
Diagnosis
Comments
Lymphangitic carcinomatosis,
lymphoma, leukemia
Lymphoproliferative disease
(e.g., LIP)
Pulmonary edema
Sarcoidosis
IPF or other cause of UIP
NSIP
Silicosis/CWP, talcosis
HP (chronic)
Common; smooth or nodular; may be the only abnormality
Smooth or nodular; other abnormalities typically present
Common; smooth
Common; usually nodular or irregular; conglomerate masses
of fibrous tissue with traction bronchiectasis typical in end
stage
Common; often irregular; associated with traction
bronchiectasis; other findings of fibrosis predominate
With findings of ground-glass opacity and reticulation
Conglomerate masses
Sometimes visible; often irregular; associated with traction
bronchiectasis
Because the thickened peribronchovascular interstitium cannot be
distinguished from the underlying opacity of the bronchial wall or pulmonary
artery, this abnormality is usually perceived on HRCT as an increase in bronchial
wall thickness or an increase in diameter of pulmonary artery branches (Fig. 332) (7). Apparent bronchial wall thickening is the easier of these two findings to
recognize. This finding is exactly equivalent to “peribronchial cuffing” seen on
plain chest radiographs in patients with an interstitial abnormality. In patients
with pulmonary interstitial emphysema, air is commonly seen within the
peribronchovascular interstitium, outlining vessels and bronchi (Fig. 3-32D)
(108–110).
FIGURE 3-32 Differentiation of peribronchovascular interstitial thickening and bronchiectasis.
A: In a normal subject, bronchi are uniformly thin-walled and appear approximately equal in
diameter to adjacent pulmonary arteries. B: In the presence of peribronchovascular interstitial
thickening, there appears to be an increase in bronchial wall thickness and a corresponding
increase in the diameter of pulmonary artery branches. The contours of the bronchi and vessels
can appear smooth, nodular, or irregular in different diseases. C: In bronchiectasis, bronchi are
usually thick walled and appear larger than adjacent pulmonary arteries. This results in the socalled signet ring sign. D: CT with 3-mm collimation in a patient with pulmonary interstitial
emphysema. Air is visible within the peribronchovascular interstitial sheath, outlining pulmonary
arteries (large black arrows) and bronchi (small black arrow). Air also surrounds pulmonary veins.
Peribronchovascular interstitial thickening is commonly present in patients
with interlobular septal thickening, and as with septal thickening, it can appear
smooth, nodular, or irregular in different diseases (Figs. 3-2 to 3-5) (100).
Smooth peribronchovascular interstitial thickening is most typical of patients
with lymphangitic spread of carcinoma or lymphoma (Fig. 3-33) and interstitial
pulmonary edema (23,106), but can be seen in patients with fibrotic lung disease
as well. Nodular thickening of the peribronchovascular interstitium is
particularly common in sarcoidosis (Fig. 3-34) and lymphangitic spread of
carcinoma. The presence of irregular peribronchovascular interstitial thickening,
as an example of the interface sign, is most frequently seen in patients with
adjacent lung fibrosis. Extensive peribronchovascular fibrosis can also result in
the presence of large conglomerate masses of fibrous tissue (Fig. 3-35). This can
occur in patients with sarcoidosis, silicosis, tuberculosis, and talcosis,
(49,107,111) and is discussed in greater detail in Chapter 4.
FIGURE 3-33 Peribronchovascular interstitial thickening. In a patient with unilateral
lymphangitic spread of carcinoma including the left lung, there is smooth thickening of the
peribronchovascular interstitium manifested as peribronchial cuffing (arrows); this appearance is
easily contrasted with that of normal bronchi in the right lung. Note that the left-sided pulmonary
artery branches appear similar in diameter to the cuffed bronchi because the thickened
interstitium surrounds them as well. Small intrapulmonary vessels on the left also appear more
prominent than those on the normal side because of perivascular interstitial thickening.
Interlobular septal thickening and subpleural nodules are also visible on the left.
FIGURE 3-34 Nodular peribronchovascular interstitial thickening in a patient with sarcoidosis.
Numerous small nodules surround the central bronchi and vessels.
FIGURE 3-35 Peribronchovascular interstitial thickening in end-stage sarcoidosis, with
conglomerate masses of fibrous tissue surrounding the central vessels and bronchi. Bronchi
appear dilated and thick walled because of surrounding fibrosis and traction bronchiectasis. Note
that the vessels and bronchi appear to be of similar diameter.
Peribronchovascular interstitial thickening is easy to diagnose if it is marked;
in this instance, bronchial walls appear several millimeters thick, and
bronchovascular structures may show evidence of the interface sign or nodules.
However, the diagnosis of minimal peribronchovascular thickening can be
difficult and is quite subjective, particularly if the abnormality is diffuse and
symmetric. Although the thickness of the wall of a normal bronchus should
measure from one-sixth to one-tenth of its diameter (see Chapter 2) (112), and in
several HRCT studies, averaged about 0.2 of the bronchial diameter (113,114),
there are no reliable criteria as to what represents the upper limit of normal for
the combined thickness of bronchial wall and the surrounding interstitium (115).
Furthermore, these measurements vary, depending on the lung window chosen,
and too low a window mean can make normal bronchi or vessels appear
abnormal. However, in many patients with peribronchovascular interstitial
thickening, and particularly in patients with lymphangitic spread of carcinoma
and sarcoidosis, this abnormality is unilateral or patchy, sparing some areas of
lung. In such patients, normal and abnormal lung regions can easily be
contrasted (Fig. 3-33). As a rule, bronchial walls in corresponding regions of one
or both lungs should be similar in thickness.
Bronchial wall thickening occurring in patients with true bronchiectasis or
chronic obstructive pulmonary disease (COPD) produces an abnormality that
closely mimics the HRCT appearance of peribronchovascular interstitial
thickening. However, airway diseases and interstitial diseases can usually be
distinguished on the basis of symptoms or pulmonary function abnormalities,
and confusion between these two is not often a problem in clinical practice. In
addition, several HRCT findings allow these two entities to be differentiated
(Fig. 3-32). First, peribronchovascular interstitial thickening is often associated
with other findings of interstitial disease, such as septal thickening, irregular
reticulation, intralobular lines, honeycombing, or the interface sign, whereas
bronchiectasis usually is not. Second, in patients with bronchiectasis, the
abnormal thick-walled and dilated bronchi often appear much larger than the
adjacent pulmonary artery branches, with a bronchoarterial ratio exceeding 1
(see Chapter 2) (Fig. 3-36). This results in the appearance of large ring shadows,
each associated with a small, rounded opacity, a finding that has been termed the
signet ring sign, and is considered to be diagnostic of bronchiectasis (116–120).
In patients with peribronchovascular interstitial thickening, however, the size
relationship between the bronchus and artery is maintained, and they appear to
be of approximately equal size. The diagnosis and appearances of bronchiectasis
and bronchial wall thickening is discussed in greater detail in Chapter 6.
FIGURE 3-36 Bronchiectasis with the signet ring sign. A: Thick-walled and dilated bronchi
(large arrows) appear larger than the adjacent pulmonary artery branches (small arrows). This
appearance is termed the signet ring sign and is typical of bronchiectasis. B: In another patient,
upper-lobe bronchiectasis is present, with several good examples of the signet ring sign (arrows).
The signet ring sign indicates that the bronchoarterial ratio is abnormally increased.
Diseases that cause peribronchovascular interstitial thickening often result in
prominence of the centrilobular artery, which normally appears as a dot, Yshaped, or X-shaped branching opacity. This finding reflects thickening of the
intralobular component of the peribronchovascular interstitium, also termed the
centrilobular interstitium (Fig. 2-1) (2,4,8,12). On HRCT, linear, branching, or
dotlike centrilobular opacity may be seen (Fig. 3-1).
Thickening of the centrilobular interstitium is often associated with
interlobular septal thickening or intralobular interstitial thickening (Fig. 3-1) but
sometimes occurs as an isolated abnormality. Centrilobular interstitial thickening
is common in patients with lymphangitic spread of carcinoma or lymphoma (4,7)
and interstitial pulmonary edema (23,121). In patients with lung fibrosis,
centrilobular interstitial thickening is common but almost always associated with
honeycombing, traction bronchiolectasis, or intralobular lines. However, it is
significantly more extensive in patients with NSIP than UIP (15).
PARENCHYMAL BANDS
The term parenchymal band has been used to describe a nontapering, reticular
opacity, usually 1 to 3 mm in thickness and up to 5 cm in length, seen in patients
with atelectasis, pulmonary fibrosis, or other causes of interstitial thickening,
and often associated with pleural thickening (Figs. 3-1, 3-36, and 3-37)
(8–10,122). A parenchymal band is often peripheral and generally contacts the
visceral pleural surface, which may be thickened and retracted inward.
FIGURE 3-37 Parenchymal bands in a patient with asbestos. A prone scan shows both thick
and thin bands. These may be seen in relation to visceral pleural thickening, representing scars or
atelecstasis.
In some patients, these bands represent contiguous thickened interlobular
septa and have the same significance and differential diagnosis as septal
thickening (11). When parenchymal bands can be identified as thickened septa,
the use of a separate term to describe this finding is unjustified; the term septal
thickening should suffice.
However, parenchymal bands visible on HRCT can also represent areas of
peribronchovascular fibrosis, coarse scars, or atelectasis associated with lung
infiltration or pleural fibrosis (Figs. 3-37 and 3-38) (11,123). These nonseptal
bands are often several millimeters thick and irregular in contour and are
associated with significant distortion of adjacent lung parenchyma and
bronchovascular structures (124).
FIGURE 3-38 Parenchymal band in a patient with otherwise normal lungs. This likely
represents an isolated scar.
Parenchymal bands may be seen in various diseases, and have been reported
as most common in patients with asbestos-related lung and pleural disease (Fig.
3-37), sarcoidosis with interstitial fibrosis (49), silicosis associated with
progressive massive fibrosis and conglomerate masses, tuberculosis, and lung
disease associated with ankylosing spondylitis (53,125–127) (Table 3-9). In
patients with asbestos exposure, multiple parenchymal bands are common; in
one study (8), multiple parenchymal bands were seen in 66% of asbestosexposed patients. In patients with asbestos-related disease, parenchymal bands
can reflect thickened interlobular septa, indicating pulmonary fibrosis, or, more
often, areas of atelectasis and focal scarring occurring in association with
visceral pleural thickening or pleural plaques. In asbestos-exposed patients,
parenchymal bands are frequently associated with areas of thickened pleura and
have a basal predominance (8,123). They may precede the development of
rounded atelectasis.
TABLE 3-9 Differential Diagnosis of Parenchymal Bands
Diagnosis
Comments
Multiple parenchymal bands common; smooth; associated with
thickened pleura
Sarcoidosis
Common; associated with septal thickening
Silicosis/CWP
In association with progressive massive fibrosis and emphysema
Tuberculosis
Associated with scarring
IPF or other cause of
Common; often irregular; associated with traction bronchiectasis; other
UIP
findings of fibrosis predominate
NSIP
With findings of ground-glass opacity and reticulation
Silicosis/CWP, talcosis Conglomerate masses
Sometimes visible; often irregular; associated with traction
HP (chronic)
bronchiectasis
Ankylosing spondylitis Apical
Asbestosis
SUBPLEURAL INTERSTITIAL THICKENING
Usually, thickening of the interlobular septa within the peripheral lung is
associated with thickening of the subpleural interstitium (1,2); both the septa and
the subpleural interstitium are part of the peripheral interstitial fiber system
described by Weibel (Fig. 2-1) (101). Subpleural interstitial thickening can be
difficult to recognize in locations where the lung contacts the chest wall or
mediastinum but is easy to see adjacent to the major fissures (Figs. 3-1 to 3-3).
Because two layers of the subpleural interstitium are seen adjacent to each other
in this location, any subpleural abnormality appears twice as abnormal as it does
elsewhere. Thus, thickening of the fissure visible on HRCT often represents
subpleural interstitial thickening. If the thickening is smooth, it may be difficult
to distinguish from fissural fluid. If the interface sign is present and the
thickening is irregular in appearance (1,12), or if the thickening is nodular, an
interstitial abnormality is more easily diagnosed.
In general, the differential diagnosis of subpleural interstitial thickening is the
same as that of interlobular septal thickening, although subpleural interstitial
thickening is more common than septal thickening in patients with IPF or UIP of
any cause. The presence of subpleural interstitial fibrosis with irregular or
“rugged” pleural surfaces has been reported by Nishimura et al. (57) as a
common finding in IPF, correlating with the presence of fibrosis predominantly
affecting the lobular periphery; this finding was present in 94% of the cases of
IPF that he studied. A subpleural predominance of fibrosis can also be seen in
patients with collagen-vascular diseases and drug-related fibrosis (30).
Nodular thickening of the subpleural interstitium can also be seen, and it has
the same differential diagnosis as nodular septal thickening (47). Remy-Jardin et
al. (47) reported the appearance of subpleural micronodules, defined as 7 mm or
less in diameter, on HRCT in patients with sarcoidosis, CWP, lymphangitic
spread of carcinoma, and LIP, and in a small percentage of normal subjects.
Subpleural nodules are described further in the next chapter.
SUBPLEURAL CURVILINEAR LINE
A curvilinear opacity a few millimeters or less in thickness, less than 1 cm from
the pleural surface and paralleling the pleura, is termed a subpleural line or
subpleural curvilinear line (9,10). It is a nonspecific indicator of atelectasis,
fibrosis, inflammation, or even edema. It was first described in patients with
asbestosis (128).
It was originally suggested that a subpleural line reflected the presence of
fibrosis associated with honeycombing (128), and in some patients, a confluence
of honeycomb cysts can result in a somewhat irregular subpleural line (Figs. 339 to 3-42). A subpleural line representing fibrosis is much more common in
patients who have asbestosis than in those who have IPF or other causes of UIP
(54,83). Indeed, the presence of a subpleural line in nondependent lung has been
reported in as many as 41% of patients with clinical findings of asbestosis (8).
However, the presence of this finding is nonspecific and can be seen in a variety
of lung diseases (Fig. 3-1). The presence of subpleural lines has also been
reported as common in patients with scleroderma who have interstitial disease
(Fig. 3-41) (129,130); this may reflect the common occurrence of NSIP in
patients with scleroderma and the tendency of NSIP to spare the immediate
subpleural lung (Fig. 3-42). Subpleural lines may also be seen in ankylosing
spondylitis (53).
FIGURE 3-39 Subpleural line in a patient with asbestosis. An ill-defined subpleural line
(arrows) on a prone scan reflects subpleural fibrosis and honeycombing. Other findings of
pulmonary fibrosis are also present.
FIGURE 3-40 Bilateral subpleural lines (arrows) in a patient with early IPF.
FIGURE 3-41 Subpleural lines in a patient with scleroderma who likely has NSIP. Supine (A)
and prone (B). HRCT shows bilateral subpleural lines (arrows). C: Sagittal reconstruction also
shows a posterior subpleural line.
FIGURE 3-42 Subpleural line in a patient with NSIP. On an axial HRCT obtained in the prone
position, bilateral subpleural lines are visible. In this patient, this may reflect the tendency of NSIP
to spare the immediate subpleural lung.
A subpleural line also has been reported to occur as a result of the confluence
of peribronchiolar interstitial abnormalities in patients with asbestosis,
representing early fibrosis with associated alveolar flattening and collapse
(11,96). In these patients, honeycombing was not present. Also, in patients with
asbestos exposure, a subpleural line may be seen adjacent to focal pleural
thickening or plaques. These most likely represent focal atelectasis or localized
areas of scarring.
It is common to see a subpleural line or focal areas of reticulation adjacent to
thoracic spine osteophytes or other causes of chest wall distortion, such as
prominent healed rib fractures or at the site of postsurgical lung hernia. The
subpleural line or reticulation reflects the presence of localized alveolar collapse
and fibrosis (131). In addition, in some patients with asbestos exposure, a
subpleural line may be seen adjacent to pleural plaques, representing focal
atelectasis.
A subpleural line can also be seen in normal patients as a result of atelectasis
within the dependent lung (e.g., the posterior lung when the patient is positioned
supine); the presence of dependent atelectasis has been confirmed
experimentally (132). Also, a thicker, less well-defined subpleural opacity, a socalled dependent density (8) or dependent opacity (133) can also be seen in
normal subjects as a result of volume loss. In a study by Lee et al. (133),
dependent lung opacity was significantly more common at reduced lung
volumes, with studies using spirometrically gated HRCT. Such normal posterior
lines or opacities are transient and disappear in the prone position. In a study of
patients with asbestos exposure by Aberle et al. (8), neither transient subpleural
lines nor transient dependent densities correlated with the clinical suspicion of
pulmonary fibrosis.
In patients with early interstitial lung disease, there may be a greater tendency
for atelectasis to develop in the peripheral lung, resulting in the appearance of a
subpleural line. As such, the presence of this abnormality could reflect an
increased closing volume (i.e., an increased tendency for the lung to collapse)
that is known to occur as a result of early interstitial lung disease. The
association of platelike atelectasis at the junction of “cortical” and “medullary”
lung regions, air trapping in the lung peripheral to the atelectasis, and decreased
compliance of lung because of interstitial infiltration was first reported by
Kubota et al. (134).
NORMAL RETICULAR OPACITIES IN THE ELDERLY
The presence of fine reticular opacities in the peripheral, posterior, lower lobes
can be seen as a normal finding in older subjects. In a study by Copley et al.
(17), a limited subpleural reticular pattern was identified in the majority (24 of
40, 60%) of individuals older than 75 years, and was absent in a group younger
than 55 years (p < 0.001) (17). The reticulation was fine or coarse, and was
unassociated with honeycombing or traction bronchiectasis. Interlobular septal
thickening was also seen in some patients. These findings are presumably due to
an increase in lung collagen in older patients.
DISTRIBUTION OF LINEAR AND RETICULAR OPACITIES IN
THE DIAGNOSIS OF LUNG DISEASE
When attempting to reach a diagnosis or differential diagnosis of lung disease
using HRCT, the overall distribution of pulmonary abnormalities should be
considered along with their morphology, HRCT appearance, and distribution
relative to lobular structures (3,59,84,135). Many lung diseases show specific
regional distributions or preferences, a fact that is likely related to their
underlying pathogenesis and pathophysiology (136).
An important caveat to keep in mind when reading the following section is
that significant variations in classical patterns of lung involvement can be seen in
individual patients. A specific diagnosis should not be excluded because of an
atypical distribution of abnormalities.
Central Lung Versus Peripheral Lung
Some diseases have a central, perihilar, bronchocentric, or peribronchovascular
distribution (59,100), whereas others favor the peripheral or subpleural
parenchyma, or lung cortex (Table 3-10).
TABLE 3-10 Predominance of Lung Disease on HRCT: Central Lung
Versus Peripheral Lung
Lung disease
Findings
Central Lung
Sarcoidosis
Silicosis
Talcosis
Lymphangitic spread of
carcinoma
HP
NSIP
Peribronchovascular nodules; conglomerate fibrosis with
traction bronchiectasis
Conglomerate masses of fibrosis
Conglomerate masses of fibrosis
Peribronchovascular interstitial thickening or nodules
Peribronchovascular fibrosis in some
Peribronchovascular fibrosis in some
Peripheral Lung
UIP, IPF, collagen diseases,
asbestosis
Subpleural fibrosis; honeycombing
NSIP in 50%
Subpleural ground-glass opacity; reticulation; subpleural
sparing
Diseases associated with reticular opacities on HRCT that can have a central
or perihilar predominance include end-stage sarcoidosis, silicosis, fibrotic NSIP,
chronic HP (137), and lymphangitic spread of carcinoma (138). In a study by
Grenier et al. (138), a predominantly central distribution of abnormalities was
visible in 16% of patients with sarcoidosis, 31% of patients with silicosis, and
8% of those with lymphangitic spread of carcinoma. In another study (84), a
central or peribronchovascular predominance was seen in 70% of patients with
sarcoidosis and 60% of patients with lymphangitic spread of carcinoma. A
predominantly peribronchial distribution of fibrosis is considered inconsistent
with UIP and IPF (63); in patients with HRCT findings of fibrosis, this
distribution would be more typical of NSIP (95), chronic HP, or sarcoidosis.
A peripheral, cortical, or subpleural predominance of abnormalities is typical
of UIP and has been reported in nearly all patients with asbestosis (58); 81% to
94% of patients with IPF (58,84,85); and a similar high percentage of patients
with scleroderma, rheumatoid lung disease, or other collagen-vascular diseases.
Other fibrotic IPs, such as NSIP, commonly show a peripheral predominance,
although subpleural sparing is present in about half. A peripheral predominance
of abnormalities is visible in approximately half of patients with OP and DIP
(58,84,138–141), although these entities uncommonly present with a
predominantly reticular pattern. Peripheral predominance is occasionally present
in patients with chronic HP and end-stage sarcoidosis, ranging from a few
percent to 20% in different studies. Subpleural predominance is also typical of
diffuse amyloidosis, although this disease is quite rare.
In a study by Silva et al. (137) of HRCT findings in patients with IPF, NSIP,
and chronic HP with fibrosis, patients with IPF and NSIP were more likely to
have peripheral predominance of abnormalities (78% and 72%, respectively) (p<
0.001) and fibrosis (100% and 92%, respectively) than those with chronic HP
(25% and 78%, respectively) (p< 0.002).
Upper Lung Versus Lower Lung
The relative extent and severity of abnormalities in the upper lungs and midlungs
and at the lung bases can be determined on HRCT by using coronal or sagittal
reconstruction of volumetric HRCT, or by comparing the severity of
abnormalities on transaxial scans at different levels. Some diseases tend to
predominate in the upper lobes, whereas others predominate in the mid-or lower
lobes (Table 3-11) (142).
TABLE 3-11 Predominance of Lung Disease on HRCT: Upper Lung
Versus Lower Lung
Lung disease
Findings
Upper Lung
Sarcoidosis
Silicosis
Talcosis
Chronic HP
Langerhans cell
histiocytosis
Pleuroparenchymal
fibroelastosis
Nodules, fibrosis, conglomerate masses
Nodules, conglomerate masses
Conglomerate masses of fibrosis
Mid-to upper-lung predominance typical
Reticulation in a few percent
Rare, reticulation traction bronchiectasis, honeycombing; pleural
thickening
Lower Lung
Pulmonary edema
Lymphangitic
carcinoma and
lymphoproliferative
diseases
UIP, IPF, collagen
diseases, asbestosis
NSIP
Other IPs
Septal thickening
Septal thickening
Subpleural fibrosis; honeycombing
Peripheral reticulation
Findings of fibrosis in a few
Diseases that can result in reticular opacities and have been recognized to
have upper-lobe predominance on HRCT include sarcoidosis, silicosis, and CWP
chronic HP (48,50,84,85,135,138,143–145), and Langerhans cell histiocytosis, in
the small percentage cases presenting with reticulation. An upper-lobe
predominance of abnormalities is present in nearly equal percentages of patients
with sarcoidosis (47%–50%) and silicosis (55%–69%), whereas a lower-lobe
predominance is present in less than 10% of patients with these diseases
(85,138). According to recent criteria, a predominantly upper-or midlung
predominance of fibrosis is considered inconsistent with a diagnosis of UIP and
IPF (63); however, some patients with a diagnosis of UIP may show this
distribution. In patients with HRCT findings of fibrosis, an upper-or midlung
predominance would be more typical of chronic HP or sarcoidosis.
A basal distribution is most typical of lymphangitic metastasis (46%), UIP,
IPF (68%), collagen-vascular diseases such as rheumatoid lung disease and
scleroderma (80%), and asbestosis (3,5,8,58,84,85,122,138,141). A basal
predominance of abnormalities is typical of fibrotic NSIP (95). Pulmonary
fibrosis of any cause has a basal predominance in approximately 60% of cases
(84,85). Although HP may show an upper-lobe predominance, it more often
appears to be diffuse or preponderant in the mid- (58,74) or lower lung zones
(30%) (138).
In a study by Silva et al. (137) comparing the HRCT findings in patients with
IPF, NSIP, and chronic HP with fibrosis, a lower-zone predominance of
abnormalities was more common in patients with IPF (83%) and NSIP (94%)
than in those with chronic HP (31%) (p < 0.001). Also, although no significant
difference was observed in the frequency of honeycombing in patients with
chronic HP (64%) and IPF (67%), patients with IPF were more likely to have
basal predominance of honeycombing (52%) than were those with chronic HP
(11%) (p < 0.001).
Upper-lobe fibrosis was seen in all patients with chronic HP, compared to 96%
in IPF and 62% in NSIP (p < 0.001), and although an upper-zone predominance
of abnormalities was uncommon, it was seen more frequently in patients with
chronic HP (11%) than in those with IPF (2%) or NSIP (0%) (p = 0.02) (137).
Uniform involvement of upper-and lower-lung zones was more common in
patients with chronic HP (58%) than in those with IPF (15%) or NSIP (6%) (p <
0.001).
Anterior Lung Versus Posterior Lung
Some diseases produce their initial or most extensive abnormalities in the
posterior lung (Table 3-12). The distinction between anterior and posterior, of
course, is easily made on HRCT. However, it is important to recognize the value
of using both prone and supine scans in this regard. Areas of increased
attenuation that are limited to the posterior lung on scans obtained in the supine
position can reflect normal dependent volume loss; prone scans are essential in
making a confident diagnosis of early posterior lung disease. Although the
percentages vary in different series, a posterior preponderance of disease is
particularly common in scleroderma (60%), sarcoidosis (32%–36%), silicosis
(31%–38%) HP (23%), IPF (9%–21%) and other causes of UIP, and NSIP
(50,84,85,138,145). A posterior predominance of abnormalities is also common
in patients with asbestosis, lymphangitic carcinomatosis, and pulmonary edema
(3,8,84,85,122,138,141,145). In patients with pulmonary edema, the
predominant abnormality is more appropriately referred to as dependent rather
than posterior.
TABLE 3-12 Predominance of Lung Disease on HRCT: Posterior
Lung Versus Anterior Lung
Lung disease
Findings
Posterior
lung
UIP, NSIP
Asbestosis
Collagen-vascular
disease
Silicosis
Sarcoidosis
Pulmonary edema
Lymphangitic
carcinoma and
lymphoproliferative
disease
HP
Fibrosis
Fibrosis
Fibrosis
Fibrosis; conglomerate masses
Fibrosis; conglomerate masses
Septal thickening
Septal thickening
Findings of fibrosis
Anterior
lung
Post-ARDS fibrosis
Radiation fibrosis in
some patients (e.g.,
those with breast
cancer)
Subpleural fibrosis; honeycombing; traction bronchiectasis
Reticulation; volume loss; traction bronchiectasis; honeycombing in
some
An anterior predominance of lung disease is unusual but has been reported in
adult survivors of ARDS (78). In this study, HRCT was obtained during the
acute illness and at follow-up in 27 patients with ARDS. At follow-up CT, a
reticular pattern was the most prevalent abnormality (85%), with a striking
anterior distribution. This finding was related to the duration of mechanical
ventilation and was inversely correlated with the extent of parenchymal
opacification on scans obtained during the acute illness. Anterior lung fibrosis is
common in patients having radiation therapy for breast cancer.
Unilateral Disease Versus Bilateral Disease
A unilateral predominance of abnormalities is most typical of lymphangitic
spread of carcinoma, which is often asymmetric in distribution; this was seen in
nearly 40% of patients with lymphangitic spread of carcinoma in one series (84).
Asymmetry or unilateral predominance of findings is also common in patients
with sarcoidosis, ranging from 9% to 21%. It is somewhat less frequent in
association with silicosis (2%–21%), IPF (3%–14%), and HP (5%) (84,85). Drug
reactions resulting in lung fibrosis or other abnormalities may appear
asymmetrical or predominantly unilateral.
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4
HRCT Findings: Multiple Nodules and Nodular Opacities
IMPORTANT TOPICS
NODULE SIZE
NODULE APPEARANCE AND ATTENUATION
NODULE DISTRIBUTION AND PATTERN
Perilymphatic or Lymphatic Distribution
Random Distribution
Centrilobular Distribution
ALGORITHMIC APPROACH TO NODULE PATTERN AND DIAGNOSIS
LARGE NODULES AND MASSES
Abbreviations Used in This Chapter
ABPA
allergic bronchopulmonary aspergillosis
AIDS
acquired immunodeficiency syndrome
CWP
coal worker’s pneumoconiosis
DPB
diffuse panbronchiolitis
FB
follicular bronchiolitis
HP
hypersensitivity pneumonitis
GGO
ground-glass opacity
LIP
lymphoid interstitial pneumonia
MAC
Mycobacterium avium-intracellulare complex
OP
organizing pneumonia
RB
respiratory bronchiolitis
RB-ILD
respiratory bronchiolitis-interstitial lung disease
A number of lung diseases are characterized by the presence of multiple nodules
as the primary abnormality. In general, the term nodule is used to describe a
rounded pulmonary opacity, well-defined or ill-defined, and no more than 3 cm
in diameter (1,2). An approach to the high-resolution computed tomography
(HRCT) assessment and differential diagnosis of multiple nodular opacities is
based on a consideration of their size (small or large), appearance (well-defined
or ill-defined), attenuation (soft-tissue or ground-glass opacity [GGO]), and
distribution.
NODULE SIZE
In this chapter, the term small nodule is used to define a rounded opacity smaller
than 1 cm in diameter, whereas large nodule is used to refer to nodules 1 cm or
larger in diameter. A rounded lesion 3 cm or more in diameter is usually termed
a mass (1,2).
Some authors have used the term micronodule to describe nodules that are
smaller than 3 mm (3), 5 mm (4), or 7 mm in diameter (5,6). The Nomenclature
Committee of the Fleischner Society has recommended that “micronodule” be
used to refer to nodules less than 3 mm in diameter (1,2). However, patients with
multinodular lung disease often show nodules of various sizes, and it is
uncommon to see cases characterized solely by micronodules, except in the
presence of miliary disease. A nodular pattern indicates the presence of
numerous nodules, usually small in size (2).
A consideration of nodule size can be important in differential diagnosis,
although it is not always of value. For example, the nodules seen in patients with
miliary tuberculosis are usually quite small, and uncommonly exceed 5 mm. On
the other hand, nodules in patients with hematogenous metastases are often
larger than this.
NODULE APPEARANCE AND ATTENUATION
The appearance of lung nodules (well-defined or ill-defined) and their
attenuation, being solid (of soft-tissue attenuation) or of ground-glass opacity,
can be important in differential diagnosis.
Differences in the appearance of nodules that are predominantly interstitial or
predominantly airspace in origin have been emphasized by several authors.
Nodules considered to be interstitial are usually well-defined despite their small
size (Table 4-1; Figs. 4-1 and 4-2). Nodules as small as 1 to 2 mm in diameter
can be detected by HRCT in patients with interstitial diseases such as miliary
tuberculosis (Fig. 4-1) (7–10), sarcoidosis (Fig. 4-2) (11–16), Langerhans
histiocytosis (17,18), silicosis and coal worker’s pneumoconiosis (CWP) (5,19–
22), and metastatic tumor (23–25). Interstitial nodules usually appear to be of
soft-tissue attenuation (i.e., solid) and obscure the edges of vessels or other
structures that they touch (Fig. 4-2; Table 4-2) (26–30).
TABLE 4-1 Differential Diagnosis of Multinodular Lung Disease
Based on the Sharpness of the Nodule Margins
FIGURE 4-1 Interstitial nodules in a patient with miliary tuberculosis. Nodules are sharply
defined despite their small size.
FIGURE 4-2 Interstitial nodules in a patient with sarcoidosis. Nodules a few millimeters in
diameter are sharply marginated and are of soft-tissue attenuation. In regions of confluence, the
nodules obscure vessels.
TABLE 4-2 Differential Diagnosis of Multinodular Lung Disease
Based on Nodule Attenuation
Airspace nodules (nodules associated with alveolar filling) are more likely to
be ill-defined (Table 4-1) (7,31–34); they can be of homogeneous soft-tissue
attenuation (solid) (Figs. 4-3 and 4-4) or hazy and less dense than vessels (socalled ground-glass opacity) (Table 4-2) (Fig. 4-4). A cluster or rosette of small
nodules can also be seen in patients who have airspace diseases (32). Airspace
nodules have also been termed acinar nodules because they approximate the size
of acini, but these nodules are not usually acinar histologically and instead tend
to be centrilobular and peribronchiolar (33); ill-defined nodule or airspace
nodule are preferable terms (2).
FIGURE 4-3 Airspace nodules in a lung transplant patient with bronchopneumonia. Nodules
are ill-defined. Some are of soft-tissue attenuation, and some are of ground-glass opacity.
FIGURE 4-4 Airspace nodules in a patient with cryptogenic organizing pneumonia. Numerous
ill-defined nodules of soft-tissue attenuation are visible, most centrilobular in location. Some of the
nodules are of ground-glass opacity (arrows). Focal consolidation is also visible in the anterior
right upper lobe.
Despite these differences in appearance, a distinction between interstitial and
airspace nodules on the basis of HRCT findings can be quite difficult, and in
fact, is somewhat arbitrary because many nodular diseases affect both the
interstitial and alveolar compartments histologically.
The differential diagnosis of multinodular lung disease based on the
appearance and attenuation of nodules is shown in Tables 4-1 and 4-2. Nodules
of ground-glass opacity are often poorly marginated. Soft-tissue attenuation
nodules may be sharply marginated or poorly defined. The differential diagnosis
of centrilobular nodules based on attenuation is discussed in detail.
NODULE DISTRIBUTION AND PATTERN
The anatomic distribution or location of small nodules is generally of more value
in differential diagnosis than their appearance, although both features are usually
taken into account (Table 4-3). In different conditions, a nodular pattern can
appear perilymphatic (lymphatic) in distribution, randomly distributed, or
predominantly centrilobular (2). Although there may be some overlap between
these appearances, in most cases, a predominant distribution of nodules is
usually evident on HRCT (35,36). Once this pattern is determined, the overall
distribution of nodules (i.e., upper lobe or lower lobe) and symmetry may be
considered in differential diagnosis.
TABLE 4-3 Differential Diagnosis and Characteristics of Small
Nodules
Perilymphatic or Lymphatic Distribution
Several diseases are characteristically associated with nodules that occur
predominantly in relation to pulmonary lymphatics. These diseases have been
termed perilymphatic or lymphatic (2,5,37) (Table 4-3). A perilymphatic pattern
is most typical of patients with sarcoidosis, silicosis and CWP, other
pneumoconioses such as berylliosis and those caused by talc and rare earths,
lymphangitic spread of carcinoma or lymphoma, lymphoproliferative diseases
such as lymphoid interstitial pneumonia (LIP) (Fig. 4-5), and rarely amyloidosis
or light-chain deposition disease (5,38–43).
FIGURE 4-5 Appearance of small nodules with a perilymphatic distribution. Nodules
predominate in relation to the perihilar peribronchovascular interstitium, centrilobular interstitium,
interlobular septa, and subpleural regions. Conglomerate subpleural nodules can form
pseudoplaques.
In patients with a perilymphatic distribution, nodules predominate, both
histologically and on HRCT, in relation to (a) the perihilar peribronchovascular
interstitium, (b) the interlobular septa, (c) the subpleural regions, and (d) the
centrilobular peribronchovascular interstitium. Lymphatics are numerous in each
of these locations. Because the nodules occur in these specific regions, the
overall involvement of lung usually appears patchy, with some lung regions
normal and others quite abnormal.
Peribronchovascular nodules can be seen individually, or in groups or clusters,
in relation to the central, parahilar bronchi and arteries. Among diseases
resulting in this distribution, peribronchovascular nodules are most typical of
sarcoidosis. Since lymphatics accompany the bronchi and arteries from the hila
into the lung periphery, peribronchovascular nodules can also be seen in the
peripheral lung, and in a centrilobular location, in relation to the centrilobular
artery. Interlobular septal nodules, resulting in the appearance of “beaded” septa
or nodular septal thickening (see Chapter 3), are most frequent in patients with
lymphangitic spread of carcinoma, but may also be seen in the other diseases
responsible for this pattern.
Subpleural nodules are usually seen in patients with a perilymphatic
distribution of nodules. These are most easily recognized in relation to the
fissures, where they can be easily distinguished from pulmonary vessels (Figs. 46 to 4-8). Subpleural nodules have been reported in approximately 80% of
patients with silicosis or CWP and at least 50% of patients with sarcoidosis, and
are also common with lymphangitic spread of carcinoma (5). Confluent
subpleural nodules can result in the appearance of pseudoplaques: linear areas of
subpleural opacity several millimeters in thickness that mimic the appearance of
asbestos-related parietal pleural plaques (Figs. 4-5 and 4-8). The presence of
pseudoplaques in these diseases correlates significantly with the profusion of
subpleural nodules (5).
FIGURE 4-6 Sarcoidosis showing a perilymphatic distribution of nodules on HRCT and open
lung biopsy and in lung specimens. A: HRCT through the upper lobe shows small nodules in
relation to the peribronchovascular regions and small vessels. Vessels and bronchi show a
nodular appearance. B: At a lower level, small nodules are seen in the subpleural regions along
the fissure (small white arrows), in the centrilobular region (black arrows), and interlobular septa
(long white arrows). C and D: Open lung biopsy shows that the small nodules correspond to
groups of granulomas that are subpleural (C, black arrows), septal (C, red arrows), and
centrilobular and peribronchiolar (D, arrows). E: View of the lung in a different patient with
sarcoidosis. Clusters of granulomas immediately beneath the visceral pleura are visible (arrows).
These correspond to the subpleural nodules seen on HRCT. F: Cut surface of lung in a patient
with sarcoidosis shows granulomas (arrows) in relation to a central bronchus. (C–F: Courtesy of
Martha Warnock, MD.)
FIGURE 4-7 Sarcoidosis with a perilymphatic distribution of nodules. Numerous small
nodules are seen in relation to the peribronchovascular interstitium adjacent to vessels in the
perihilar lung and more peripherally in the centrilobular regions (arrows). Subpleural nodules are
also seen bordering the major fissures.
FIGURE 4-8 A–C: HRCT at three levels in a patient with sarcoidosis and a typical
perilymphatic distribution of nodules. Numerous nodules are predominant in relation to the major
fissure (small arrows) and perihilar bronchovascular interstitium (large arrows). Subpleural
nodules and pseudoplaques are also seen bordering the costal pleural surfaces. Confluence of
granulomas in the left lower lobe (B and C) results in consolidation or large masses. As in this
patient, lung involvement in patients with sarcoidosis is often patchy, with some areas appearing
relatively normal.
Although sarcoidosis, silicosis and CWP, and lymphangitic spread of
carcinoma all typically show a perilymphatic distribution of nodules, these
diseases usually show different patterns of involvement of the perilymphatic
interstitium. HRCT findings allow their differentiation in many cases.
Sarcoidosis
The large majority of patients, perhaps 95%, showing a perilymphatic
distribution of nodules on HRCT have sarcoidosis. In nearly all patients with
sarcoidosis, HRCT shows nodules ranging in size from several millimeters to 1
cm or more in diameter (13,15,42,44). The nodules often appear sharply defined
despite their small size, but they can be ill-defined (Figs. 4-2 and 4-6 to 4-8).
Nodules are most frequently seen in relationship to the perihilar
peribronchovascular interstitium and the subpleural interstitium; histologically,
small clusters of granulomas are visible in these locations (13,15,26). A
preponderance of nodules in relation to the major fissures and central bronchi
and vessels is very typical of sarcoidosis. Nodules recognizable as centrilobular
or septal in location are less frequently seen on HRCT (Fig. 4-6) (45), but they
also correlate with typical histologic abnormalities.
Large nodules or masses measuring from 1 to 4 cm in diameter or larger are
seen in 15% to 25% of patients (Figs. 4-8 and 4-9) (15,27,28) and represent a
conglomeration of granulomatous lesions, each granuloma being less than 0.4
mm in diameter (26). These large nodules or masses tend to have irregular
margins or may be associated with adjacent small satellite nodules (Figs. 4-8 and
4-9) (46); this occurrence in sarcoidosis has been termed the galaxy sign (46).
Nodules and masses can cavitate, but this is uncommon; Grenier et al. (3)
reported this finding in only 3% of cases. Occasionally, nodules visible on
HRCT represent nodular areas of fibrosis rather than active granulomas (13).
FIGURE 4-9 A and B: Large peribronchovascular nodules in a patient with sarcoidosis,
representing clusters of granulomas. These have irregular margins. Small nodules are also
visible, as are nodules involving the fissures.
An upper lobe predominance of nodules is typical of sarcoidosis (5), but a
diffuse distribution or lower lobe predominance may sometimes be seen. The
lung is characteristically involved in a patchy fashion, with groups of
granulomas occurring in some regions of the lung, whereas other regions appear
normal (Fig. 4-8). Asymmetry is very common.
Silicosis and Coal Worker’s Pneumoconiosis
Silicosis and CWP are associated with the presence of small, well-defined
nodules, usually measuring from 2 to 5 mm in diameter, which predominantly
appear centrilobular and subpleural in location on HRCT (Fig. 4-10)
(5,19,21,22,29,43,47,48). These correlate, respectively, with areas of fibrosis
surrounding centrilobular respiratory bronchioles and involving the subpleural
interstitium, caused by the accumulation of particulate material in these regions
(5,21). Parenchymal nodules are visible in 80% of patients with CWP, whereas
subpleural nodules are seen in 87% (5,22). Nodules occurring in relation to the
perihilar peribronchovascular interstitium and thickened interlobular septa are
less frequent and less conspicuous than in patients with sarcoidosis or
lymphangitic spread of tumor. Also, nodules appear more evenly distributed than
in patients with sarcoidosis. In patients who have silicosis, the nodules can
calcify.
FIGURE 4-10 A and B: Perilymphatic nodules in a patient with silicosis. Nodules
predominate in the subpleural (A, black arrows) and centrilobular (B, white arrows) regions.
Peribronchovascular nodules are less frequent in patients with silicosis than in those with
sarcoidosis, and the nodules appear more evenly distributed. The nodules often predominate
posteriorly and in the upper lobes in patients with this disease. (Courtesy of Raymond Glyn
Thomas, MD, The Rand Mutual Hospital, Johannesburg, South Africa.)
Nodules may be diffuse, but in patients with mild silicosis or CWP, they are
usually visible only in the upper lobes. Typically, nodules are bilateral and
symmetric. A posterior predominance of nodules is often present (19,22).
Lymphangitic Spread of Tumor
In patients with lymphangitic spread of tumor (carcinoma or lymphatic
neoplasms), when nodules are present, they are most often visible within
thickened peribronchovascular interstitium and interlobular septa (Figs. 4-11 to
4-13) (20,24,49–52). Peribronchovascular and subpleural nodules are typically
not as profuse as in patients with sarcoidosis. Septal thickening results in the
appearance of a “beaded” septum (Figs. 4-11 to 4-13) (11,24,30).
FIGURE 4-11 Radiograph of a 1-mm-thick lung slice in a patient with lymphangitic spread of
tumor. Note the nodular thickening of interlobular septa (S) and the centrilobular interstitium
surrounding arteries (A). Bar = 1 cm. (Courtesy of Harumi Itoh, MD, Chest Disease Research
Institute, Kyoto University, Kyoto, Japan.)
FIGURE 4-12 Lymphangitic spread of carcinoma. There is nodular thickening (red arrows) of
the interlobular septa surrounding a lobule in the right upper lobe. The centrilobular artery (yellow
arrow) is abnormally prominent because of thickening of the peribronchovascular interstitium by
tumor.
FIGURE 4-13 Lymphangitic spread of thyroid carcinoma. HRCT at three levels (A–C) shows
subpleural nodules along the fissures (small arrows) and peribronchovascular nodules (large
arrow) resulting in a nodular appearance of pulmonary artery branches. Interlobular septal
thickening is inconspicuous in this patient. Subpleural nodules are easy to see in the periphery.
Note the presence of right hilar lymph node enlargement.
In an HRCT study of postmortem lung specimens (11,24,30), 19 of 22 cases
with interstitial pulmonary metastases showed the appearance of beaded or
nodular septal thickening on HRCT. The beaded septa corresponded directly to
the presence of tumor growing in pulmonary capillaries, lymphatics, and septal
interstitium. In this study (24), beaded septa were not noted in any of the
specimens of patients with pulmonary edema, fibrosis, or in normal lungs. In
clinical practice, however, septal thickening in patients with lymphangitic spread
of tumor is usually smooth (see Chapter 3).
In patients with lymphangitic carcinomatosis, the abnormalities may be
unilateral, patchy, bilateral, or symmetric. They may predominate in the upper or
lower lobes or may be diffuse. Often a central or perihilar predominance of
abnormalities is present in lymphangitic spread of neoplasm.
Differential Diagnosis
A perilymphatic distribution of nodules may also be seen in other diseases, but
these are uncommon. In patients with diffuse amyloidosis, interstitial thickening
with nodules, visible in relation to vessels, bronchi, interlobular septa, and the
subpleural interstitium, has been reported (Fig. 4-14) (36,53). In smokers, a few
small subpleural and centrilobular nodules can be seen, probably related to the
presence of fibrosis and accumulated particulate material in the peribronchial
regions and at the bases of interlobular septa, and related to pathways of
lymphatic drainage (54,55). LIP, occurring primarily in patients with
dysproteinemia; autoimmune disease, particularly Sjögren syndrome;
multicentric Castleman disease; and AIDS can result in the presence of
lymphocytic and plasma cell infiltrates in relation to the peribronchovascular
interstitium and interlobular septa, and in the subpleural and centrilobular
regions (56–59). On HRCT, LIP may result in a variety of appearances
(39,41,60), but in some patients, it closely mimics the appearance of
lymphangitic spread of carcinoma, with subpleural, peribronchovascular, and
septal nodules. This is particularly common in patients with AIDS (61) (Fig. 415).
FIGURE 4-14 Amyloidosis with perilymphatic nodules. Small subpleural nodules (large
arrows) and interlobular septal nodules (small arrows) were found on biopsy to represent small
nodular deposits of amyloid. Nodules are also seen along the right major fissures (open arrows).
FIGURE 4-15 Perilymphatic nodules in a patient who has AIDS with lymphoid interstitial
pneumonia. Small subpleural nodules (small arrows) are visible along the major fissure. Nodules
within interlobular septa (large arrows) are also visible.
Random Distribution
Small nodules that appear randomly distributed in relation to structures of the
secondary lobule and lung are often seen in patients with miliary tuberculosis
(Fig. 4-16) (9,10,36), miliary fungal infections, and hematogenous metastases
(36,37) (Table 4-3).
FIGURE 4-16 A: Appearance of small nodules with a random distribution in miliary
tuberculosis. The nodules involve the lungs in a diffuse manner, without predominance to any
structure. A uniform distribution is most typical of random nodules. B: Miliary tuberculosis with
small nodules. Nodules a few millimeters in diameter have a random distribution and appear
widely and evenly distributed throughout the lung. Some nodules do not predominate in relation to
these structures. (From Im JG, Itoh H, Shim YS, et al. Pulmonary tuberculosis: CT findings—early
active disease and sequential change with antituberculosis therapy. Radiology 1993;186:653, with
permission.)
As with a lymphatic distribution, the nodules can be seen in relation to the
pleural surfaces, small vessels, and interlobular septa but do not appear to have a
consistent or predominant relationship to any of these. On HRCT, a uniform
distribution of nodules throughout the lung, without respect for anatomical
structures, is most typical. Lung involvement tends to be bilateral and
symmetrical. An upper or lower lobe predominance in size and number of
nodules may be seen.
Miliary Infections
In miliary tuberculosis (Fig. 4-16) or fungal infections (Fig. 4-17), the nodules
tend to be well-defined, sharply marginated, and up to several millimeters in
diameter (10). They are visible in relation to fissures and the peripheral pleural
surfaces, but are diffuse and uniform in distribution on transaxial images. In
some patients, particularly those with miliary tuberculosis, there may be an
upper lobe predominance of nodules.
FIGURE 4-17 Miliary coccidioidomycosis with numerous very small nodules that have a
random distribution. A and B: Two different patients with miliary coccidioidomycosis show a
diffuse distribution of nodules. Nodules involving the major fissures are well seen in B.
Metastatic Neoplasm
Hematogenous metastases also tend to be well-defined and of soft-tissue
attenuation (Fig. 4-18) (62). As with miliary tuberculosis, the nodules can be
seen in relation to small vessels, a fact that likely reflects their mode of
dissemination. Although random in distribution, they have a recognized
tendency to predominate in the lung periphery and at the lung bases (62). Also,
in patients with metastatic tumor, nodules are often larger than a few millimeters
when first detected.
FIGURE 4-18 Hematogenous metastases from a rectal carcinoma. A: HRCT obtained in a
patient with an abnormal chest radiograph and no known tumor. Multiple, small well-defined
nodules are visible, with involvement of the peripheral pleural surfaces (arrow). The overall
pattern of distribution is random. B: Spiral CT obtained 6 months later following diagnosis of the
patient’s tumor shows progression of the metastases. A random distribution, with diffuse and
uniform lung involvement, is well demonstrated.
In a study correlating HRCT and pathologic findings in patients with
metastatic tumor (62), nodules less than 3 mm in diameter had no consistent
relationship to lobular structures. Eleven percent of nodules were seen in relation
to the centrilobular pulmonary arteries, 21% were related to interlobular septa,
and 68% were located in between. On examination of specimen radiographs and
pathology, a similar distribution was noted. Nodules resulting from
hematogenous metastasis are characteristically well-defined. Some overlap
between a random pattern, and a perilymphatic pattern may be seen in patients
with metastatic tumor.
Differential Diagnosis
When numerous, nodules in patients with sarcoidosis (Fig. 4-19), Langerhans
cell histiocytosis (Fig. 4-20), or silicosis may appear to be randomly and
diffusely distributed (37) and may be difficult to distinguish from the nodules of
miliary infection or metastasis. An appearance of small well-and ill-defined
random nodules has also been reported with varicella-zoster pneumonia (63).
FIGURE 4-19 Diffuse sarcoidosis with a random distribution of nodules. Very small nodules
are seen in relation to the major fissure, but the overall distribution is diffuse and uniform. Findings
typical of sarcoidosis, such as patchy distribution or a predominance of nodules in relation to
peribronchovascular regions, are not seen. (Courtesy of Luigia Storto, Chieti, Italy.)
FIGURE 4-20 Langerhans cell histiocytosis with small nodules, cavitary nodules, and cysts in
a 21-year-old smoker. Some nodules involve the pleural surfaces and fissures, but many nodules
appear to be centrilobular in location.
Centrilobular Distribution
Nodules limited to the centrilobular regions (Fig. 4-21) can reflect the presence
of either interstitial or airspace abnormalities, and the histologic correlations
reported to occur in association with centrilobular nodules vary with the disease
entity (45). Centrilobular nodules may be dense (i.e., solid) and of homogeneous
opacity or ground-glass opacity (Figs. 4-22 and 4-23), and may range from a few
millimeters to about 1 cm in size. Either a single centrilobular nodule or a
centrilobular rosette of nodules may be visible (7,32,33). Although they are often
ill-defined, this is not always the case.
FIGURE 4-21 HRCT appearances of centrilobular nodules are usually separated from the
interlobular septa and pleural surfaces by a distance of at least several millimeters; in the lung
periphery, the nodules are usually centered 5 to 10 mm from the pleural surface. Also,
centrilobular nodules may be associated with small pulmonary artery branches. Because of the
similar size of secondary lobules, centrilobular nodules often appear to be evenly spaced.
Although they are often ill-defined, this is not always the case. Either a single centrilobular nodule
or a centrilobular rosette of nodules may be seen. In occasional cases, the air-filled centrilobular
bronchiole can be recognized as a rounded lucency with a centrilobular distribution, representing
impaction of centrilobular bronchioles.
FIGURE 4-22 Ill-defined centrilobular nodules in a patient with hypersensitivity pneumonitis.
A: HRCT shows ground-glass opacity nodules that are separated from the plural surfaces and
fissures by a distance of several millimeters. As is typical, the nodules often appear to be evenly
spaced and, in this case, are diffusely distributed. This is a common appearance in HP. B:
Histologic section in a patient with HP shows a centrilobular bronchiole (Br) and ill-defined regions
of peribronchiolar inflammation. (Courtesy of Martha Warnock, MD.)
FIGURE 4-23 Centrilobular nodules in infection. A: In a patient with bacterial
bronchopneumonia, clusters of centrilobular nodules are present in the lower lobes. The most
peripheral of these are centered a few millimeters from the pleural surface. B: Endobronchial
spread of infection in a patient with multidrug-resistant tuberculosis. A cavity is associated with
multiple centrilobular nodules. The largest of these touch the pleural surface, but they are
centered about 5 mm from it.
Centrilobular nodules are usually separated from the pleural surfaces, fissures,
and interlobular septa by a distance of at least several millimeters. In the lung
periphery, the nodules are usually centered 5 to 10 mm from the pleural surface,
a fact that reflects their centrilobular origin (Figs. 4-22 and 4-23). They are not
usually seen occurring in relation to interlobular septa or the pleural surfaces, as
do random or perilymphatic nodules, and the subpleural lung is typically spared.
This difference can be particularly valuable in distinguishing diffuse
centrilobular nodules from diffuse random nodules. Although centrilobular
nodules, when large, may touch the pleural surface, they do not appear to arise at
the pleural surface. Because of the similar size of secondary lobules,
centrilobular nodules often appear to be evenly spaced. They may appear patchy
or diffuse in different diseases.
The term centrilobular nodule is best thought of as indicating that the nodule
is related to centrilobular structures, such as small vessels, even if they cannot be
precisely localized to the lobular core (Figs. 4-4, 4-22, and 4-23). Indeed, in
some cases, centrilobular nodules can be correctly identified by noting their
association with small pulmonary artery branches. It is typical for centrilobular
nodules to appear perivascular on HRCT, surrounding or obscuring the smallest
visible pulmonary arteries. In occasional cases, the air-filled centrilobular
bronchiole can be recognized as a rounded lucency within a centrilobular nodule
(Figs. 4-24 and 4-25).
FIGURE 4-24 A and B: Ill-defined centrilobular nodules in a patient with chronic airways
disease and bronchopneumonia. A number of the ill-defined nodules surround an air-filled
bronchus or bronchiole (A, arrows). C: Open lung biopsy in another patient shows a pulmonary
lobule (black arrows) and a nodular region of inflammation (blue arrows) surrounding the
centrilobular bronchiole. This abnormally represents panbronchiolitis.
FIGURE 4-25 Centrilobular nodules in a patient with bronchopneumonia. A: Scattered illdefined nodules represent peribronchiolar consolidation and may contain a visible bronchiole
(arrow). B: At the lung bases, consolidated lobules surround air-filled bronchioles in several
locations. Bronchopneumonia is also termed lobular pneumonia because of this appearance.
As indicated earlier, centrilobular nodules can be seen in patients having a
perilymphatic or lymphatic distribution of disease. Pulmonary lymphatics are
located in the peribronchovascular interstitial compartment in the centrilobular
region. However, in patients with a perilymphatic distribution, nodules will also
be seen in other locations (i.e., subpleural regions or interlobular septa). Sarcoid
granulomas are typically distributed along lymphatics in the peribronchovascular
interstitial space in both the perihilar and centrilobular regions (Fig. 4-6)
(5,13,14). In some cases, centrilobular clusters of granulomas are a predominant
feature of the disease, but nodules involving the subpleural regions are also
present in most cases. Small centrilobular nodules are also characteristic of both
silicosis and CWP (21,22). In patients with silicosis, early lesions are
centrilobular and peribronchiolar; the nodules are a few millimeters in diameter
and consist of layers of lamellated connective tissue. Subpleural nodules are also
typically present (Fig. 4-10). The characteristic lesion of CWP is the so-called
coal macule, which consists of a focal accumulation of coal dust surrounded by a
small amount of fibrous tissue, occurring in a centrilobular, peribronchiolar
location. 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 are
commonly seen (Fig. 4-11) (45). Other findings include thickening of the
peribronchovascular interstitium in the perihilar lung. LIP or follicular
bronchiolitis (FB) in AIDS patients can result in the presence of ill-defined
centrilobular opacities. LIP is associated with a lymphocytic and plasma cell
infiltrate in relation to lymphatics; it may predominate in the centrilobular
regions or mimic the appearance of lymphangitic spread of carcinoma.
Nodules limited to centrilobular regions (i.e., a centrilobular distribution) are
most commonly seen in patients with a variety of diseases that primarily affect
centrilobular bronchioles and result in inflammation, infiltration, or fibrosis of
the surrounding interstitium and alveoli (Table 4-3) (37,45,64). Angiocentric
diseases are less frequent as a cause of centrilobular nodules (36). Diseases
resulting in this appearance may be classified as bronchiolar and peribronchiolar
or vascular and perivascular.
The differential diagnosis of centrilobular nodules is long. Once a
centrilobular pattern is identified, the presence of tree-in-bud should be sought.
If tree-in-bud is present, infection is likely. If not, then a consideration of the size
of the nodules, their appearance and attenuation (i.e., well-defined or ill-defined,
solid or of ground-glass opacity), distribution (e.g., diffuse or patchy; localized
or bilateral; upper, mid, or lower lung predominant), and, if available, associated
history (e.g., acute or chronic symptoms, fever, exposures) should be used to
limit the differential diagnosis to the most likely causes.
Tree-in-bud, representing impaction of centrilobular bronchioles by fluid,
mucus, or pus and often appearing as a branching opacity in the peripheral lung
(Figs. 4-26 and 4-27), may be present in patients with a centrilobular distribution
of nodules (65). Tree-in-bud almost always indicates the presence of bronchiolar
infection (66). The appearance and significance of tree-in-bud are discussed in
detail later.
FIGURE 4-26 Tree-in-bud. A: A centrilobular tree-in-bud (arrow) is visible in a patient with
cystic fibrosis and chronic airway infection. Also note bronchial wall thickening and
inhomogeneous lung attenuation due to airways obstruction and air trapping with mosaic
perfusion. B: In a patient with chronic airway infection, a thick-walled bronchus is seen, leading to
impacted bronchioles in the lung periphery (arrows). This appearance represents tree-in-bud.
FIGURE 4-27 Centrilobular nodules and tree-in-bud in a patient with tuberculosis. A:
Radiograph of a resected lung in a patient with endobronchial spread of tuberculosis shows a
branching centrilobular opacity (solid arrows) and rosettes of small nodular opacities producing a
tree-in-bud appearance (open arrows). B: On pathologic examination, the branching centrilobular
opacity represents caseous material filling bronchioles and alveolar ducts (red arrows). (From Im
JG, Itoh H, Shim YS, et al. Pulmonary tuberculosis: CT findings—early active disease and
sequential change with antituberculosis therapy. Radiology 1993;186:653, with permission.)
Bronchiolar and Peribronchiolar Diseases
Bronchiolar diseases secondarily involving the peribronchiolar interstitium,
alveoli, or both are the most frequent causes of centrilobular opacities seen on
HRCT (67). Their histologic correlates and HRCT appearances vary with the
nature of the disease. The differential diagnosis of airway diseases associated
with centrilobular abnormalities includes the following entities.
Endobronchial
Spread
of
Tuberculosis,
Nontuberculous
Mycobacterial Disease, and Other Granulomatous Infections.
Bronchogenic dissemination of infection can occur in patients with active
tuberculosis and nontuberculous mycobacterial disease (Figs. 4-23B, 4-27, and
4-28 to 4-30) (7,14,33,68–71). Nodules, or clusters of nodules, that reflect
peribronchiolar consolidation or granulomas are common, visible on HRCT in as
many as 97% of patients with active tuberculosis, and are also common in
patients with nontuberculous mycobacterial infection; tree-in-bud is commonly
associated (70,72). Bronchioles filled with infected material can also result in the
appearance of a tree-in-bud (Figs. 4-27 and 4-29) (68). Fungal infections may
result in similar findings (73). Specifically, Aspergillus bronchiolitis and
bronchopneumonia (airway-invasive aspergillosis) are characterized by patchy
consolidation, centrilobular nodules, and the finding of a tree-in-bud (74,75).
Nodules are most often solid appearing, but may also be of ground-glass opacity.
They are typically focal or multifocal and patchy in distribution, and may be
unilateral or bilateral. An upper lobe predominance is typical of tuberculosis.
Nontuberculous mycobacteria, particularly Mycobacterium avium-intracellulare
complex (MAC), may predominate in the lung bases, middle lobe, and lingula.
On occasion, they may be diffuse. In tuberculosis, nodules may predominate in
relation to a cavitary infection.
FIGURE 4-28 Centrilobular nodules and rosettes in a patient with endobronchial spread of
tuberculosis. Multiple small nodules occurring in clusters (arrows) are common in patients with
this disease. The nodules, being centrilobular, spare the pleural surfaces.
FIGURE 4-29 A–C: Centrilobular rosettes and tree-in-bud in a patient with endobronchial
spread of tuberculosis. Multiple small nodules occurring in clusters and the appearance of tree-inbud (arrows) are seen in association with several larger nodules in the right lung apex. The
appearance of tree-in-bud almost always indicates infection. Mycobacterium tuberculosis was
found in this patient’s sputum.
FIGURE 4-30 Nontuberculous mycobacterial infection with endobronchial spread. Coned
view of the left lower lobe in a patient with MAC infection on sputum cultures. Clusters of
centrilobular nodules are visible (arrows).
Bronchopneumonia. Bronchopneumonia resulting from various organisms,
most commonly bacteria, is associated with the presence of bronchial and
peribronchiolar inflammatory exudates, which also involve surrounding alveoli.
HRCT findings are quite similar to those of endobronchial spread of tuberculosis
(Figs. 4-23A, 4-24, 4-25, and 4-31) (14,31,32). Viral infections (Fig. 4-32)
(76–80) and Chlamydia pneumoniae, Mycoplasma pneumoniae, and
Pneumocystis jiroveci pneumonia can also result in the appearance of
centrilobular nodules (81). Nodules often appear solid, but may be of groundglass opacity, particularly with infection by atypical organisms. They are
typically focal or multifocal and patchy in distribution, and may be unilateral or
bilateral.
FIGURE 4-31 Supine (A) and prone (B and C) HRCT in a patient with bronchopneumonia
due to Haemophilus influenzae. Ill-defined centrilobular nodules are visible bilaterally, with a
predominance on the left. An appearance of tree-in-bud is visible in many locations C, arrows).
FIGURE 4-32 Viral bronchiolitis. Two-dimensional HRCT reconstructions (A, coronal; B,
sagittal) in an immunosuppressed renal transplant patient show ill-defined centrilobular nodules
due to viral bronchiolitis. The arrows outline secondary lobules that show a rosette of centrilobular
nodules.
Infectious Bronchiolitis. Infectious bronchiolitis is seen most often in
children, and presents with fever, dyspnea, and wheezing. It is often due to
respiratory syncytial virus, although other viruses and bacteria, particularly
mycoplasma, may be involved. Centrilobular nodules or tree-in-bud may be
visible (Fig. 4-32) (82,83). Nodules are often of ground-glass opacity.
Cystic Fibrosis. In patients with cystic fibrosis, thick-walled, mucus-or pusfilled bronchioles are seen as rounded or branching centrilobular opacities (i.e.,
tree-in-bud), usually in association with central bronchiectasis (Figs. 4-26A and
4-33) (14,84,85). The centrilobular bronchiolar abnormalities can be an early
finding and can be patchy in distribution. Nodules usually appear solid. They
typically predominate in the upper lobes.
FIGURE 4-33 Centrilobular bronchiolar abnormality with tree-in-bud in a patient with cystic
fibrosis. Fluid-, mucus-, or pus-filled centrilobular bronchioles result in a tree-in-bud appearance in
several lung regions (arrows). These are associated with findings of bronchiectasis.
Bronchiectasis. Findings similar to those of cystic fibrosis can be seen in
patients with chronic bronchiectasis of any cause, including congenital
immunodeficiency states, ciliary dysmotility syndrome, and the syndrome of
yellow nails and lymphedema (Figs. 4-34 and 4-35). Nodules are usually seen in
regions with abnormal bronchi.
FIGURE 4-34 A and B: Centrilobular bronchiolar abnormality and tree-in-bud in a patient with
yellow nails, lymphedema syndrome, and chronic bronchial sepsis. A tree-in-bud appearance and
small well-defined centrilobular nodules (arrows) are visible in the posterior right lower lobe.
These reflect the presence of pus-filled centrilobular bronchioles. This appearance is easily
contrasted with the appearance of normal lung more medially.
FIGURE 4-35 A and B: Prone scans in a patient with chronic bronchiectasis and small airway
infection by pseudomonas. Small centrilobular nodules, rosettes, and tree-in-bud are visible
throughout the lower lobes.
Panbronchiolitis. In patients with Asian panbronchiolitis, aggregates of
histiocytes, lymphocytes, and plasma cells infiltrate the walls of respiratory
bronchioles and extend into the peribronchiolar tissues. HRCT can show (a)
prominent branching centrilobular opacities representing dilated bronchioles
with inflammatory bronchiolar wall thickening and abundant intraluminal
secretions (i.e., tree-in-bud), (b) bronchiolar dilatation that tends to occur late in
the disease process (36,86–88) and is typically proximal to the nodular
peribronchiolar opacities, and (c) centrilobular nodules that reflect bronchiolar
and peribronchiolar inflammation and fibrosis (Figs. 4-24C and 4-36) (87).
Abnormalities are typically diffuse and bilateral but predominate in the lung
periphery and lung bases.
FIGURE 4-36 Bronchiolar abnormalities in Asian panbronchiolitis. Dilated and thick-walled
bronchioles (white arrows) are seen in association with a tree-in-bud appearance (black arrows)
and multiple centrilobular nodules. These findings correlate pathologically with the presence of
dilated bronchioles, inflammatory bronchiolar wall thickening, abundant intraluminal secretions,
and peribronchiolar inflammation. (Courtesy of Harumi Itoh, MD, Chest Disease Research
Institute, Kyoto University, Kyoto, Japan.)
Asthma and Allergic Bronchopulmonary Aspergillosis. Patients with
asthma and allergic bronchopulmonary aspergillosis (ABPA) may develop
mucoid impaction of centrilobular bronchioles visible as centrilobular nodules or
tree-in-bud (89). These are more common in patients with ABPA (93%) than in
those who have asthma (28%) (89). Nodules usually appear solid. An upper lobe
predominance may be present, and a bilateral patchy distribution is most typical.
A central predominance may be seen.
Hypersensitivity Pneumonitis. An immunologic response to a variety of
inhaled allergens in sensitized persons, subacute hypersensitivity pneumonitis
(HP), is characterized by a peribronchiolar and perivascular lymphocytic and
plasma cell infiltrate with formation of poorly defined granulomas (90).
Centrilobular nodules of ground-glass opacity seen on HRCT are typical (Figs.
4-22 and 4-37), reflecting the histologic abnormality (4,66,90–94). Nodules are
diffuse and bilateral. Often there is a predominance in the mid or upper lung
zones.
FIGURE 4-37 Centrilobular nodules of ground-glass opacity in a patient with hypersensitivity
pneumonitis. The ill-defined opacities are visible in relation to small vascular branches throughout
the lung. The most peripheral nodules are centered about 5 mm from the pleural surface. The
subpleural lung region appears spared.
Langerhans Histiocytosis. Initially, granulomas form in the peribronchiolar
tissues and adjacent alveolar interstitium. Mononuclear Langerhans cells are
present in the early stages of the disease; later, the cellular response diminishes
and fibrosis dominates. Centrilobular nodules on HRCT reflect the
peribronchiolar abnormality (Fig. 4-20) (18). Nodules appear solid, and have an
upper lobe predominance. Later in the course of the disease, cavitation of
nodules, cyst formation, and centrilobular bronchiolectasis can be seen (95). A
combination of nodules, cavitary nodules, and cysts is common.
Organizing Pneumonia. OP, also known as organizing pneumonia or, when
idiopathic, cryptogenic organizing pneumonia, is characterized by the presence
of inflammatory cells lining the walls of the terminal and respiratory bronchioles
with plugs of granulation tissue within airways and alveoli (96,97). Because the
abnormality is distributed in the peribronchiolar airspaces, ill-defined solid or
ground-glass opacity centrilobular nodules up to 1 cm in diameter can be present
in patients with OP (Fig. 4-4). These may be patchy or bilateral and symmetrical,
and may show a lower lobe predominance. Frank consolidation or larger areas of
ground-glass opacity are more common in OP (98,99). Tree-in-bud may
occasionally be seen (82). Chronic eosinophilic pneumonia, a disease related to
OP, may also show centrilobular nodules (100).
Bronchiolitis Obliterans. Bronchiolitis obliterans, also known as constrictive
bronchiolitis, is characterized primarily by concentric bronchiolar and
peribronchiolar fibrosis and luminal narrowing or obliteration. In an acute phase,
ill-defined centrilobular nodules may sometimes be seen, reflecting
peribronchiolar inflammation (45,101,102). In the later obliterative stage,
centrilobular opacities may occasionally be seen, but they are not a common
feature of this disease (14). Airway obstruction with air trapping is much more
frequent.
Respiratory Bronchiolitis. RB is believed to represent a nonspecific reaction
to inhaled irritants, usually in association with cigarette smoking. Inflammation
of the respiratory bronchioles, with filling of the bronchioles by brownpigmented macrophages, plasma cells, and lymphocytes, is present
histologically. In symptomatic patients, macrophages and inflammatory cells
extend into the peribronchiolar airspaces and alveolar walls. When associated
with symptoms, the term respiratory bronchiolitis-interstitial lung disease (RBILD) is used. HRCT findings in symptomatic patients include multifocal groundglass nodules with a centrilobular distribution that reflects the peribronchiolar
nature of this disease (55,103–106). During follow-up, centrilobular nodules
may evolve into areas of centrilobular emphysema (106). Patchy ground-glass
opacities can also be seen and tend to increase in frequency with follow-up
(106). An upper lobe predominance is typical. Distinct centrilobular opacities
(e.g., so-called crack lung) may be seen in patients who use inhalational drugs.
Cigarette Smoking. A few small subpleural and centrilobular nodules can be
seen in subjects who smoke or have a history of smoking. Ill-defined
centrilobular nodules have been reported in as many as 12% to 27% of smokers
studied using HRCT, reflecting the presence of bronchiolectasis and
peribronchiolar fibrosis or respiratory bronchiolitis (RB) (54,55,106–108).
Aspiration. Aspiration of a variety of materials, including gastric contents,
water, or blood, associated with a variable inflammatory response may result in
ill-defined centrilobular opacities (101,102,109). Tree-in-bud may be seen,
particularly with chronic aspiration. A posterior and basal predominance is
typical. Abnormalities are usually patchy.
Asbestosis. In patients with early asbestosis, the histologic abnormality is
nearly identical to that seen in patients with RB, but asbestos fibers can be
identified in the peribronchiolar tissues. Fiber deposition in the respiratory
bronchioles results in a peribronchiolar cellular response and fibrosis that
eventually extends to involve the contiguous airspaces and alveolar interstitium.
Ill-defined centrilobular opacities have been reported on HRCT in as many as
half of patients with early asbestosis (110,111). Nodules predominate posteriorly
and at the lung bases, probably due to the gravitational effects of fiber deposition
(110,112).
Pneumoconiosis. Centrilobular nodules are most typical of silicosis or CWP,
but can also be seen with other pneumoconioses. Centrilobular nodules in
patients with silicosis or CWP may reflect a perilymphatic distribution of lesions
or a peribronchiolar abnormality. Small nodular or branching centrilobular
opacities are common in silicosis and may be an early sign of disease (113). In a
study by Antao et al. (113), centrilobular opacities were seen using HRCT in
68.3% of 41 workers with silica exposure, including 20 of 22 with abnormal
radiographs consistent with silicosis and 4 of 15 who had normal chest
radiographs. This appearance has been shown to correlate with the presence of
irregular fibrosis occurring in relation to respiratory bronchioles. Nodules are
often solid in appearance and sharply marginated. CWP and pneumoconiosis
associated with other inhaled minerals (e.g., siderosis) can result in similar
histologic and imaging abnormalities, but nodules may be less dense (i.e.,
ground-glass opacity) and less well-defined than those of silicosis.
Pneumoconioses associated with ground-glass opacity nodules are usually
associated with substances that are less fibrogenic than silica (38,43). An upper
lobe predominance is typical of both silicosis and CWP, and symmetry is usual.
Follicular Bronchiolitis. This entity, defined as lymphoid hyperplasia of
bronchus-associated lymphoid tissue, is characterized by hyperplastic lymphoid
follicles along the walls of centrilobular bronchioles. It may be seen in patients
with nonspecific inflammation or infection, termed secondary follicular
bronchiolitis. It may also represent a focal manifestation of LIP in patients with
collagen-vascular diseases, particularly rheumatoid arthritis, AIDS, or other
diseases; this is termed primary follicular bronchiolitis. Small, well-defined
centrilobular nodules, often smaller than 3 mm in diameter, are commonly seen,
and large airway abnormalities and peribronchial nodules may also be present
(Fig. 4-38) (73,114–117). Nodules may be of ground-glass opacity or solid.
Tree-in-bud may be present.
FIGURE 4-38 Follicular bronchiolitis with centrilobular nodules. A: A patient with secondary
FB shows ill-defined centrilobular nodules, some surrounding airways. B: A patient with
rheumatoid arthritis and primary FB shows ill-defined centrilobular nodules.
Endobronchial Spread of Neoplasm. Centrilobular nodules can be seen in
patients with invasive mucinous pulmonary adenocarcinoma (formerly diffuse
bronchioloalveolar carcinoma) (Fig. 4-39) or tracheobronchial papillomatosis,
when endobronchial spread of tumor occurs (118,119). Nodules in patients with
mucinous adenocarcinoma are typically patchy and unilateral or bilateral. They
can be well-defined or ill-defined, and solid or of ground-glass opacity; larger
areas of consolidation may be associated with the nodules. Large airway
papillomas or cystic lesions may also be visible in patients with tracheobronchial
papillomatosis.
FIGURE 4-39 Invasive mucinous adenocarcinoma with centrilobular nodules. In addition to a
large nodule, multiple centrilobular nodules (arrows) are present in the left lower lobe.
Vascular and Perivascular Diseases
Vascular abnormalities, localized either to the walls of arteries or to perivascular
tissues, can cause a centrilobular opacity. Because airways are not involved,
bronchiolectasis and tree-in-bud are typically absent, although if the cellular
response extends into the peribronchiolovascular interstitium, apparent
bronchiolar wall thickening or a tree-in-bud appearance may result.
Pulmonary Edema. Mild cases of edema may show hazy, ill-defined
centrilobular opacities, usually of ground-glass opacity (33,120,121). Increased
prominence of the centrilobular artery resulting from perivascular interstitial
thickening is also commonly visible. Septal thickening is variably associated, but
in some patients, centrilobular opacities predominate. This appearance has also
been reported in pulmonary venoocclusive disease and pulmonary capillary
hemangiomatosis (122).
Vasculitis. Processes resulting in a vascular and perivascular inflammation,
including vasculitis and reaction to injected substances, such as talc or cellulose
(talcosis) (21,45,66,123–126), can result in ill-defined centrilobular opacities on
HRCT. Hemorrhage can also result in this appearance in patients with vasculitis
(125). Connolly et al. (127) reported hazy or fluffy centrilobular and
perivascular opacities in eight children with vasculitis, including five with
Granulomatosis with polyangiitis (Wegener granulomatosis), one with systemic
lupus erythematosus, one with scleroderma-polymyositis overlap syndrome, and
one with Churg-Strauss syndrome. In these eight children, centrilobular opacities
were associated with the onset of active disease or with an exacerbation of
preexisting disease. In four of five patients, this abnormality disappeared on
treatment.
Pulmonary Hemorrhage. Ill-defined centrilobular nodules may occasionally
be seen in patients with acute pulmonary hemorrhage (128). In children with
idiopathic pulmonary hemorrhage, also known as idiopathic pulmonary
hemosiderosis, recurrent episodes of pulmonary hemorrhage may result in illdefined centrilobular nodules (74). This finding may be related to deposition of
hemosiderin-laden macrophages in relation to small vessels and bronchioles.
Nodules are usually of ground-glass opacity.
Metastatic Calcification. In patients with metastatic calcification, calcium
deposits typically involve the interstitium and alveolar septa in a centrilobular
perivascular location. Ill-defined nodules of ground-glass opacity or obvious
calcifications may be seen. These may be lobular or centrilobular (66,129–131).
They tend to predominate in the upper lobes and appear symmetrical.
Pulmonary Hypertension. Ill-defined centrilobular nodules, usually of
ground-glass opacity, may be seen in patients with pulmonary hypertension,
particularly those with venoocclusive disease and capillary hemangiomatosis
(122,132,133). These are likely related to edema or hemorrhage. Also,
cholesterol granulomas may be seen in a centrilobular location in patients with
pulmonary hypertension. In one study, histopathologic evidence of cholesterol
granulomas was found in 5 of 20 (25%) patients with severe pulmonary
hypertension (134). In 3 of these 5 patients, the granulomas manifested on
HRCT as small centrilobular nodules. These may result from prior episodes of
pulmonary hemorrhage.
Tree-in-Bud
A centrilobular distribution of nodular opacities may be associated with an
important finding, termed tree-in-bud, which is of great value in differential
diagnosis (Table 4-3) (45,64,68,101,102,135–138). The finding of tree-in-bud
typically reflects the presence of dilated centrilobular bronchioles with their
lumina impacted with mucus, fluid, or pus, and is often associated with
peribronchiolar inflammation (Table 4-4). Because of the branching pattern of
the dilated bronchiole and the presence of ill-defined nodules of peribronchiolar
inflammation, its appearance has been likened to a budding or fruiting tree
(68,86), or children’s toy jacks (135) (Figs. 4-21, 4-26, 4-27, 4-29, 4-31, 4-33 to
4-36, and 4-40 to 4-42). The term budding tree has also been used to describe the
appearance of small airway filling on bronchography (139).
FIGURE 4-40 Tree-in-bud in a patient with airway infection. Branching, impacted, pus-filled
bronchioles (arrows) are visible in the peripheral lung. A parenchymal band seen more anteriorly
represents focal atelectasis.
FIGURE 4-41 Tree-in-bud in bronchopneumonia. A: Bacterial bronchopneumonia is
associated with ill-defined centrilobular nodules and tree-in-bud. B: In a different patient with
bronchiectasis and bronchopneumonia, tree-in-bud is visible in the right lower lobe (arrows). C:
Lung slice in a patient with bronchopneumonia. Multiple examples of tree-in-bud are visible
(arrows). (Courtesy of Martha Warnock, MD.)
FIGURE 4-42 Tree-in-bud in a patient with Mycobacterium avium-intracellulare complex
infection. A: In addition to patchy consolidation, branching centrilobular structures (arrows) in the
right lung are typical of tree-in-bud and strongly suggest the presence of infection. Tree-in-bud
can be distinguished from normal branching arteries because of their more irregular appearance,
lack of tapering, and a knobby or bulbous appearance. B: At a lower level, centrilobular nodules
and tree-in-bud are visible in several locations.
TABLE 4-4 Differential Diagnosis of the Tree-in-Bud Pattern and Its
Mimics
Infections
Bacterial infection
Mycobacterial infection
Fungal infection
Viral infection
Disease associated with infection
Bronchiectasis (various causes)
Cystic fibrosis
Ciliary disorders
Immunodeficiency
Panbronchiolitis
ABPA
Noninfectious bronchiolar diseases
Vascular abnormalities
Perilymphatic disease
Invasive mucinous adenocarcinoma
FB
Aspiration
Injection talcosis
Intravascular metastases
Sarcoidosis
On HRCT, tree-in-bud is usually easy to recognize, but several different
appearances may be seen alone or in combination. In the lung periphery, tree-inbud may be associated with a typical branching appearance, with the most
peripheral branches or nodular opacities being several millimeters from the
pleural surface. Tree-in-bud may also appear as a centrilobular cluster of
nodules, depending on the relationship of the bronchiole to the plane of scan. If
the centrilobular bronchiole is sectioned across its axis, as is typical in the
costophrenic angles, the impacted bronchiole may appear to be a single, welldefined, centrilobular nodule a few millimeters in diameter.
Abnormal bronchioles producing a tree-in-bud pattern can usually be
distinguished from normal centrilobular vessels by their more irregular
appearance, a lack of tapering, and a knobby or bulbous appearance at the tips of
small branches (Figs. 4-40 to 4-42). Normal centrilobular arteries are
considerably thinner than the branching bronchioles seen in patients with this
finding and are much less conspicuous. Furthermore, because tree-in-bud is
often patchy in distribution, it is easy to contrast its appearance with that of
adjacent normal lung regions.
Tree-in-bud is usually associated with other HRCT findings of airways
disease. Bronchiolar dilatation and wall thickening can sometimes be seen in
association with tree-in-bud if the dilated bronchioles are air filled; normal
bronchioles should not be visible in the peripheral 1 cm of the lung. Tree-in-bud
may also be associated with ill-defined centrilobular nodules representing areas
of bronchiolar or peribronchiolar inflammation. Large airway abnormalities with
wall thickening or bronchiectasis are also often present (45). For example, in a
study by Aquino et al. (102), 26 of 27 (96%) patients showing tree-in-bud on
HRCT also showed bronchiectasis or bronchial wall thickening.
The finding of tree-in-bud is usually indicative of small airways disease.
Furthermore, a tree-in-bud appearance is associated with airway infection in the
large majority of cases, although it may also be seen in patients with mucoid
impaction of centrilobular bronchioles in absence of infection and in some
patients with bronchiolar wall infiltration (67,114). In the study by Aquino et al.
(102), 25% of patients with bronchiectasis and 18% of patients with infectious
bronchitis showed tree-in-bud, but this finding was not visible in patients with
other diseases involving the airways, such as emphysema, RB, bronchiolitis
obliterans, OP, or HP. Similarly, in patients with active tuberculosis, a tree-inbud appearance was visible in 72% of patients in one study (68), correlating with
the presence of solid caseous material within terminal and respiratory
bronchioles (Fig. 4-27). In patients with Asian panbronchiolitis, prominent,
branching centrilobular opacities represent dilated bronchioles with
inflammatory bronchiolar wall thickening and abundant intraluminal secretions
(Fig. 4-36) (86,87).
Thus, in patients with a centrilobular distribution of nodules, if tree-in-bud can
be recognized, the differential diagnosis is limited, and infection should be
strongly considered (Table 4-4) (66). Among the larger group of diseases
causing centrilobular nodules listed in the previous section, tree-in-bud may be
seen in patients with endobronchial spread of tuberculosis (68) or
nontuberculous mycobacterial disease (45,71,140,141), bronchopneumonia of
any cause (including bacteria, fungus, and virus) (77–80,142–144), infectious
bronchiolitis (82), cystic fibrosis (84), bronchiectasis of any cause (45,101,102),
and Asian panbronchiolitis (86,87).
The appearance of tree-in-bud can be seen in noninfectious diseases, but it is
less common in this setting (Table 4-4). Tree-in-bud may be seen in airway
diseases that result in the accumulation of mucus within small bronchi, such as
asthma or ABPA (66,101). It is rarely seen in patients with constrictive
bronchiolitis, presumably related to impaction of bronchioles (101). An
appearance resembling tree-in-bud has been reported in patients with FB, an
entity in which hyperplasia of lymphoid follicles occurs in relation to
centrilobular airways; FB is often seen in association with collagen-vascular
disease or AIDS (66,114). Aspiration bronchiolitis or inhalation of toxic fumes
or gases may be associated with the appearance of tree-in-bud (66,109,137).
Invasive mucinous adenocarcinoma may occasionally show tree-in-bud,
although nodules are more typical (119). In some patients with sarcoidosis,
nodules occurring in relation to centrilobular arteries may mimic the appearance
of tree-in-bud, although other typical features of sarcoidosis are usually present
(45,101). Vascular abnormalities associated with perivascular inflammation or
fibrosis, such as may occur with talcosis, may occasionally result in this
appearance (124), as may intravascular tumor embolism (137,145–148).
Okada et al. (66) reviewed the HRCT in 553 patients with predominant
centrilobular opacities or preferential centrilobular disease and compared the
scan findings to those of histology in 141 patients who underwent biopsy.
Centrilobular opacities with a tree-in-bud appearance were highly predictive of
an infectious cause. Tree-in-bud was observed in a large percentage of patients
who (a) were carriers of human T-lymphotropic virus type 1 (HTLV-1; 88 of 99
patients) or (b) had M. pneumoniae pneumonia (44 of 52 patients),
Mycobacterium tuberculosis (MTB; 38 of 52 patients), MAC (22 of 37 patients),
Mycobacterium kansasii (27 of 33 patients), ABPA (6 of 9 patients), diffuse
panbronchiolitis (DPB; all of 12 patients), diffuse aspiration bronchiolitis (12 of
13 patients), or FB (5 of 7 patients). Pathologically, the tree-in-bud pattern
correlated with plugging of small airways with mucus, pus, or fluid; dilated
bronchioles; and bronchiolar wall thickening; although the specific histologic
correlate varied with the disease. In all 55 patients with HTLV-1, abnormalities
correlated with lymphocytic infiltration along respiratory bronchioles. In patients
with MTB, MAC, and M. kansasii, the histologic abnormalities associated with
tree-in-bud included caseous material in terminal bronchioles along with airway
dilatation and wall thickening. In patients with ABPA, fragments of fungal
hyphae, mucin, and inflammatory cells were identified. In patients with DPB,
centrilobular abnormalities corresponded to thickened and dilated airway walls
with intraluminal mucous plugs. In patients with FB, histologic findings
consisted of hyperplastic lymphoid follicles with reactive germinal centers
distributed along bronchioles, and thickened and dilated airway walls.
The distribution of tree-in-bud may be of some value in diagnosis. In the study
by Okada et al. (66), tree-in-bud predominated in the peripheral lungs in about
70% of patients. Patients with ABPA were an exception; abnormal findings were
predominantly central in 77.8%. In patients with HTLV-1 and DPB, a diffuse
distribution of tree-in-bud was observed in 72 patients (72.7%) and 10 patients
(83.3%), respectively. In patients with M. pneumoniae pneumonia and DAB,
lower lobe distribution was observed in 30 patients (57.7%) and 12 patients
(92.3%), respectively. In patients with MTB, MAC, and M. kansasii, abnormal
findings were predominantly seen in the upper lung zones (76.9%, 51.4%, and
60.6%, respectively). Tree-in-bud associated with acute or chronic bacterial
infection often shows a lower lobe predominance, and is often patchy in
distribution.
ALGORITHMIC APPROACH TO NODULE PATTERN AND
DIAGNOSIS
A simple algorithm may be used to help localize small nodules as perilymphatic,
random, or centrilobular and classify them for the purpose of differential
diagnosis (Fig. 4-43A) (149,150).
FIGURE 4-43 Algorithmic approach to the differential diagnosis of multinodular lung disease.
Distinguishing these three distributions is most easily accomplished by
looking first for subpleural nodules and nodules arising in relation to the
fissures. A few subpleural nodules that look different (i.e., smaller, denser, or
better defined) than other visible nodules or are much less numerous are likely
unrelated to the patient’s disease and should be ignored. If only a few subpleural
nodules are visible, a determination of the distribution and differential diagnosis
should generally be based on other findings, such as tree-in-bud (i.e.,
centrilobular airways disease), a patchy distribution (i.e., perilymphatic or
centrilobular disease), predominant involvement of the peribronchovascular
interstitium or interlobular septa (i.e., perilymphatic disease).
If numerous subpleural or fissural nodules are present, then the pattern is
either perilymphatic or random. These two patterns are distinguished by looking
at the distribution of other nodules. If other nodules are patchy in distribution,
and particularly if a distinct predominance is noted relative to the
peribronchovascular interstitium, interlobular septa, or subpleural regions, then
the nodules are perilymphatic. The specific structures involved and the overall
nodule distribution, being upper lobe or lower lobe, and symmetrical or
asymmetrical, may suggest the correct diagnosis (Table 4-5). If pleural nodules
are present and the overall nodule distribution is diffuse and uniform, then the
pattern is random, and hematogenous disease is likely.
TABLE 4-5 Overall Distribution of Common Perilymphatic Diseases
If subpleural nodules are absent or less numerous than nodules elsewhere in
the lung, the pattern is centrilobular. Keep in mind that large centrilobular
nodules may touch the pleura but do not appear to arise from it; nodules a few
millimeters in diameter that touch the pleura are not centrilobular. If a
centrilobular distribution is present, the finding of tree-in-bud should be sought.
If tree-in-bud is present, then nearly all cases will represent airway disease,
which is infectious in nature (Fig. 4-43B).
The differential diagnosis of centrilobular nodules unassociated with tree-inbud is long and varies depending on several additional findings, including (a) the
nodule attenuation (whether they are of ground-glass opacity, Table 4-6, or solid
[of homogeneous soft-tissue attenuation], Table 4-7), (b) their overall
distribution (e.g., upper or lower lobe, diffuse, symmetrical, or patchy) (Table 48), and (c) any available history (e.g., acuity of symptoms, fever, exposures).
TABLE 4-6 Diseases Usually Associated with Ground-Glass
Opacity Centrilobular Nodules
Airways diseases
Bronchopneumonia or bronchiolitis (atypical organisms)
HP
RB or RB-ILD
FB
Pneumoconioses (also solid)
Invasive mucinous adenocarcinoma (also solid)
OP (also solid)
Aspiration (also solid)
Panbronchiolitis (also solid)
Vascular diseases
Pulmonary edema
Pulmonary hemorrhage
Pulmonary arterial hypertension
Vasculitis
Metastatic calcification
TABLE 4-7 Diseases Usually Associated with Solid (Soft-Tissue
Attenuation) Centrilobular Nodules
Bronchopneumonia (bacterial, mycobacterial, fungal)
Asthma and ABPA
Langerhans cell histiocytosis
Pneumoconioses (also GGO)
Invasive mucinous adenocarcinoma (also GGO)
OP (also GGO)
Aspiration (also GGO)
Panbronchiolitis (also GGO)
TABLE 4-8 Differential Diagnosis of Centrilobular Nodules Based
on Overall Distribution
Diffuse distribution
HP
RB or RB-ILD
FB
Atypical/viral infections
Pneumoconioses
Pulmonary edema
Pulmonary hemorrhage
Pulmonary arterial hypertension
Patchy distribution
Endobronchial infection (bacterial, mycobacterial, fungal)
Invasive mucinous adenocarcinoma
Aspiration
Langerhans cell histiocytosis
Upper-or mid-lung
predominance
Lower lobe distribution
HP
RB (RB or RB-ILD)
Langerhans cell histiocytosis
Pneumoconioses
Metastatic calcification
Endobronchial infection (bacterial, mycobacterial, fungal)
Aspiration
Ground-Glass Opacity Centrilobular Nodules
Centrilobular nodules of ground-glass opacity (GGO) may result from
bronchiolar or vascular abnormalities, but bronchiolar disease is more likely
(Table 4-6). Centrilobular nodules with this appearance typically reflect
processes that produce peribronchiolar inflammation, infiltration, or fibrosis
without consolidation or obliteration of alveoli. In patients with a diffuse
distribution of GGO nodules and chronic symptoms, HP is most likely, but RBILD should be considered if there is a history of cigarette smoking and the
nodules predominate in the upper lobes. FB is a consideration if there is a history
of connective tissue disease or immune suppression. If the GGO nodules are
patchy, consider invasive mucinous adenocarcinoma. In patients with acute
symptoms, GGO centrilobular nodules suggest pulmonary edema, pulmonary
hemorrhage, pneumonia (particularly atypical pneumonia), or occasionally HP.
Soft-Tissue Attenuation Centrilobular Nodules
Centrilobular nodules of homogenous soft-tissue attenuation usually result from
peribronchiolar inflammation or infiltration, with consolidation of alveoli or
dense fibrosis (Table 4-7). Bronchiolar filling or impaction (i.e., tree-in-bud)
may be present. As the disease progresses, the entire lobule may be involved.
The differential diagnosis of centrilobular nodules of soft-tissue attenuation
includes processes that are associated with endobronchial spread, such as
bronchopneumonia (caused by any organism, although bacteria or mycobacteria
are most common), aspiration, tumor (invasive mucinous adenocarcinoma), and
Langerhans histiocytosis. In patients with bronchopneumonia, symptoms are
generally acute, and the nodules are focal, multifocal, or patchy in distribution.
Invasive mucinous adenocarcinoma may result in multifocal or patchy nodules,
sometimes associated with larger areas of consolidation or ground-glass opacity.
Multiple lobes and both lungs may be involved.
Vascular diseases may produce either ground-glass or soft-tissue attenuation
centrilobular nodules depending on the severity and confluence of alveolar
involvement. Pulmonary edema and pulmonary hemorrhage are the most
common vascular diseases to appear as soft-tissue attenuation nodules.
Overall Distribution of Centrilobular Nodules in Differential
Diagnosis
The overall distribution of centrilobular nodules may be helpful in diagnosis
(Table 4-8). In general, a diffuse and symmetrical distribution of centrilobular
nodules is seen in patients with HP, RB (RB or RB-ILD), FB, atypical infections,
pneumoconioses, pulmonary edema, and other vascular abnormalities.
A symmetrical distribution of nodules with an upper or mid lung
predominance may be seen in HP, RB, Langerhans histiocytosis,
pneumoconioses (e.g., CWP, silicosis, siderosis), and metastatic calcification.
Patchy or multifocal nodules are most frequent with endobronchial spread of
infection (e.g., bacterial, mycobacterial, fungal), invasive mucinous
adenocarcinoma, aspiration, and Langerhans histiocytosis. Such nodules are
often asymmetric.
Accuracy of High-Resolution Computed Tomography in
Determining Nodule Distribution
HRCT is accurate in localizing nodules according to their anatomical
distribution (i.e., perilymphatic, random, or centrilobular), thus limiting the
differential diagnosis. In a study by Gruden et al. (35), the interobserver
variability and accuracy of the algorithm described (i.e., Algorithm 4) were
assessed; four experienced chest radiologists independently evaluated HRCT
images in 58 patients with nodular lung disease (35). Nodules were classified as
perilymphatic, random, centrilobular, or associated with tree-in-bud and small
airways disease. The observers were correct in 218 of 232 (94%) localizations in
the 58 cases. Three of four observers agreed in 56 of 58 (97%) cases, and all four
observers agreed in 79% (46 of 58) of the cases. The most noteworthy source of
error and disagreement between observers was the confusion of perilymphatic
and small airways disease–associated nodules in a limited number of cases.
In another study (36), HRCT findings were compared to those from
pathologic examination in 40 consecutive patients with diffuse micronodular
lung disease. HRCT scans were analyzed, with particular attention to the
location of nodules (i.e., centrilobular, perilymphatic, random) and their zonal
distribution. HRCT scans showed centrilobular nodules in patients with DPB (n
= 4), infectious bronchiolitis (n = 4), HP (n = 3), endobronchial spread of
tuberculosis (n = 3), pneumoconiosis (n = 1), primary lymphoma of the lung (n =
1), and foreign body–induced necrotizing vasculitis (n = 1). They demonstrated
perilymphatic nodules in patients with pneumoconiosis (n = 5), sarcoidosis (n =
2), and amyloidosis (n = 2). HRCT demonstrated micronodules of random
distribution in patients with miliary tuberculosis (n = 9) and pulmonary
metastasis (n = 5). An upper-and middle-zonal predominance was seen in
patients with sarcoidosis and in two of six patients with pneumoconiosis.
LARGE NODULES AND MASSES
The term large nodule is used in this book to refer to rounded opacities that are 1
cm or more in diameter. The term mass is generally used to describe nodular
lesions larger than 3 cm in diameter (1,151). Nodules approximating 1 cm may
be seen in many nodular lung diseases and are nonspecific.
In patients who have diseases characterized by small nodules (e.g.,
sarcoidosis, silicosis, CWP, talcosis, Langerhans histiocytosis), conglomeration
or confluence of many small nodules can result in large nodules or mass-like
opacities (Table 4-9) (12). Also, neoplasms and several subacute or chronic lung
diseases may be characterized by large nodules or masses as the primary
manifestation of disease.
TABLE 4-9 Differential Diagnosis of Large Nodules and Masses
Diagnosis
Comments
Sarcoidosis
Silicosis/CWP
Common; upper lobe and peribronchovascular predominance;
confluent masses of granulomas (active disease) or fibrous tissue
(end-stage disease)
Common in advanced disease; upper lobe; associated with
surrounding emphysema
Conglomerate masses of fibrous tissue; upper lobe and perihilar
Talcosis
Langerhans cell
histiocytosis
Metastatic carcinoma
Invasive mucinous
adenocarcinoma
Lymphoma
Lymphoproliferative
disease
OP
Granulomatosis with
polyangiitis (Wegener
granulomatosis)
Churg-Strauss syndrome
Amyloidosis
Infection
Rounded atelectasis
predominance; high attenuation common
Large nodules in 20%
Peripheral and basal predominance common
Large nodules in 30%; ill-defined; basal predominance
Commonly contain air bronchograms
Large nodules common; air bronchograms; often
peribronchovascular or subpleural
Uncommon, may be associated with the atoll sign
Common manifestation; cavitation common
Cavitation may be present
Smooth or lobulated; cavitation in 20%
Fungal infection in immunosuppressed patient
Associated with asbestos pleural disease
Sarcoidosis
Sarcoidosis may be associated with the presence of large nodules or masses in
half of all patients; these are made up of numerous confluent granulomas or
fibrous tissue (3,44). In our experience, these predominate in the upper lobes and
the peribronchovascular regions (Figs. 4-8, 4-9, and 4-44). These nodules or
masses are often irregular in shape and surround central bronchi and vessels,
with air bronchograms often being visible (Fig. 4-44).
FIGURE 4-44 Conglomerate masses of nodules in a patient with sarcoidosis. A and B: Large
masses representing confluent granulomas show small discrete nodules at their margins.
Scattered nodules with a perilymphatic distribution are also visible in less abnormal regions.
Bronchi are visible within the masses.
In patients with end-stage sarcoidosis, it is not uncommon to see conglomerate
masses in the upper lobes associated with central crowding of vessels and
bronchi as a result of peribronchovascular fibrosis (Fig. 4-45). Traction
bronchiectasis is often visible within the masses of fibrous tissue, and posterior
displacement of upper lobe bronchi is commonly present. Adjacent areas of
emphysema or bullae are visible in some cases. Similar upper lobe masses
associated with bronchiectasis have been reported in patients with tuberculosis
and are most frequent after treatment (68).
FIGURE 4-45 Sarcoidosis with peribronchovascular fibrosis associated with traction
bronchiectasis. Volume loss, interlobular septal thickening, and parenchymal bands are also
evident. There is posterior displacement of the bronchi.
Small satellite nodules adjacent to the large nodules are often seen. This
occurrence in patients with sarcoidosis has been termed the galaxy sign (46),
although satellite nodules may be seen in several granulomatous diseases (152);
tuberculosis and mycobacterial infections (153,154), OP (155); and silicosis,
CWP, and other pneumoconioses.
Silicosis and Coal Worker’s Pneumoconiosis
Patients who have silicosis and coal workers who have complicated
pneumoconiosis or progressive massive fibrosis also show conglomerate masses
in the upper lobes, but these are typically of homogeneous opacity and tend to be
unassociated with visible traction bronchiectasis, as seen in sarcoidosis (Fig. 446) (19,22). Also, areas of emphysema peripheral to the conglomerate masses
are common (47,48). This finding is present in as many as 48% of patients with
CWP (22).
FIGURE 4-46 Conglomerate masses of fibrosis in silicosis. Central areas of
peribronchovascular fibrosis (arrows) are associated with small nodules, typical of silicosis, and
distortion of lung architecture.
Talcosis
An appearance of progressive massive fibrosis very similar to that occurring in
patients with silicosis or sarcoidosis can be seen in intravenous drug users who
develop talcosis from injection of talc-containing substances (123). The fibrotic
masses can show high attenuation at soft-tissue windows, indicating the presence
of talc (see Chapter 13). Perihilar and upper lobe predominance has been
reported. A similar appearance may also be seen in patients with inhalational
talcosis (156).
Langerhans Cell Histiocytosis
Large nodules have been seen in as many as 24% of patients with Langerhans
histiocytosis, although masses are not generally seen in this disease (3).
Metastatic Carcinoma
Metastatic carcinoma commonly results in large nodules or masses
(119,157,158). They may be well-defined or ill-defined, and they typically have
a peripheral and basal predominance.
Invasive Mucinous Adenocarcinoma
Invasive mucinous adenocarcinoma, formerly termed diffuse bronchioloalveolar
carcinoma, often shows a pattern of multiple nodules or masses (119,159,160).
Small nodules may be centrilobular in location. Nodules are often ill-defined and
may be of ground-glass opacity or may appear solid, and often occur in
association with larger areas of ground-glass opacity or consolidation. Half of
the cases have a peripheral or lower lobe predominance. They often appear
patchy and multifocal, and unilateral or bilateral, but in some cases, nodules
appear diffuse and random in distribution.
Lymphoma
Lymphoma involving the lung most commonly results in airspace consolidation
(66% of cases) and large nodules (41% of cases) (60), often ill-defined and
sometimes containing air bronchograms (161). In most instances, spiral CT,
rather than HRCT, is most appropriate in evaluation of a patient with lymphoma
(162,163).
Lymphoproliferative Disorders
Lymphoproliferative disorders, often associated with the Epstein-Barr virus, may
range from benign lymphoid hyperplasia to high-grade lymphoma and occur in
immunosuppressed patients (e.g., those with AIDS, congenital immune
deficiency, or receiving immunosuppressive therapy). The most common CT
manifestation consists of multiple nodules, 2 to 4 cm in diameter, frequently in a
predominantly peribronchovascular or subpleural distribution (164). In a review
of 246 patients who had lung transplantation (165), 9 patients (4%) were
diagnosed with posttransplantation lymphoproliferative disorders. The most
common abnormality visible on CT was the presence of multiple, well-defined
pulmonary nodules ranging up to 3 cm in diameter. These nodules, when
multiple, had a basilar and peripheral predominance. Other abnormal findings
included hilar or mediastinal lymphadenopathy. Three patients had nodules with
a surrounding area of ground-glass opacity (“halo sign”).
Organizing Pneumonia
Multiple large nodules or masses may be seen in patients with OP (Fig. 4-47)
(166). Akira et al. (166) reviewed the HRCT scans and clinical records of 59
consecutive patients with histologically proven OP, and 12 patients had multiple
large nodules or masses. Of 60 lesions found in the 12 patients, 53 (88%) had an
irregular margin, 27 (45%) had an air bronchogram, 23 (38%) had a pleural tail,
and 21 (35%) had a spiculated margin. Ancillary findings included focal
thickening of the interlobular septa in 5 of the 12 (42%) patients, pleural
thickening in 4 (33%) patients, and parenchymal bands in 3 (25%) patients.
FIGURE 4-47 Irregular masses in organizing pneumonia. A: Masses in the lower lobes are
very irregular in contour and contain air bronchograms. OP tends to predominate in the lung
periphery and peribronchial regions. B: At a different level, one mass (arrow) shows an atoll sign
or reversed halo sign, which is suggestive of this diagnosis.
Nodules, masses, or focal regions of consolidation in OP may be associated
with the “reversed halo sign” (167,168) or “atoll sign” (169) in which a region of
ground-glass opacity is surrounded or marginated by a denser ring or crescent of
consolidation (thus resembling a coral atoll, or the opposite of the halo sign)
(Fig. 4-47) (170). This appearance is highly suggestive of OP and has been seen
in as many as 12% to 19% of cases in two different studies (167,168). In several
reports of this unusual finding, areas of ground-glass opacity primarily
corresponded to alveolar septal inflammation, while denser areas of
consolidation represented intra-alveolar inflammatory infiltrates.
The reversed-halo or atoll sign has also been reported in other diseases, such
as chronic eosinophilic pneumonia, which is similar to OP histologically;
granulomatosis
with
polyangiitis
(Wegener
granulomatosis);
paracoccidioidomycosis and other infections; sarcoidosis; and pulmonary
infarction (171–175). Each of these entities may be associated with OP on
biopsy.
Granulomatosis with Polyangiitis (Wegener
Granulomatosis)
Wegener granulomatosis, also referred to as granulomatosis with polyangiitis, is
typically manifested by multiple nodules or masses that are limited in number,
range in size from a few millimeters to 10 cm in diameter, have no zonal
predominance, and have a random distribution (Fig. 4-48) (176–178). Masses
may also appear peribronchial or peribronchovascular in distribution (179). In a
study of 10 patients (178), CT scans revealed multiple pulmonary nodules in 7
patients and a single nodule in 1. The nodules ranged in diameter from 2 mm to
7 cm, and most had irregular margins. Ill-defined centrilobular nodules, likely
reflecting the presence of vasculitis, have also been reported (127). Cavitation of
nodules is common, being present in all nodules larger than 2 cm in one study
(178); the cavity walls are often thick and irregular or shaggy, although thinwalled cavities may also be seen. Consolidation, ground-glass opacity, or crazy
paving may also be seen, usually related to pulmonary hemorrhage (125).
FIGURE 4-48 Large lung nodules in Wegener granulomatosis. These are nonspecific in
appearance.
Churg-Strauss Syndrome
Churg-Strauss syndrome is most often characterized by parenchymal
opacification (consolidation or ground-glass attenuation), but pulmonary nodules
may be present with or without cavitation (125,180,181).
Amyloidosis
Large pulmonary nodules are common in patients with localized amyloidosis
(246 cases), ranging in size from 8 mm to 3 cm (182). Nodules may be solitary
(60% of cases) or multiple, with a smooth or lobular contour, and are often
subpleural or peripheral. Calcification may occur (20% of cases) (183).
Infections
Infections, particularly in immunosuppressed patients and usually representing a
fungus, may be manifested by multiple large nodules or masses (184). Nodules
are often ill-defined and may be associated with cavitation, air bronchograms, or
a surrounding halo of ground-glass opacity (i.e., the halo sign). In a study of
immunosuppressed patients with fever, large nodules shown on CT predicted the
presence of a fungal infection (185). Invasive aspergillosis is most common in
neutropenic patients, typically showing scattered nodules that are often
associated with vessels, the halo sign, and cavitation during later stages of the
infection (186). Although the halo sign can be associated with a variety of
infectious processes, including tuberculosis (187), candidiasis, Legionella
pneumonia, cytomegalovirus, or herpes simplex (188) in a neutropenic patient, it
should suggest invasive aspergillosis (189).
Rounded Atelectasis
Rounded atelectasis represents a focal, collapsed, and often folded region of lung
(190–193). It almost always occurs in association with ipsilateral pleural disease
and typically contacts the pleural surface. Rounded atelectasis occurs most
commonly in the paravertebral regions of the posterior lung and may be
bilateral. Bending or bowing of adjacent bronchi and arteries toward the area of
atelectasis because of volume loss or folding of lung is characteristic. This
appearance has been likened to a comet tail. Air bronchograms within the mass
can sometimes be seen. The presence of pleural disease and these typical
findings is usually suggestive of this condition. Focal fibrotic masses, usually
irregular in shape, have been described as occurring in the peripheral lung in
relation to pleural abnormalities in patients with asbestos exposure (193). These
represent focal areas of scarring or rounded atelectasis.
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5
HRCT Findings: Parenchymal Opacification
IMPORTANT TOPICS
GROUND-GLASS OPACITY
CONSOLIDATION
LUNG CALCIFICATION AND HIGH-ATTENUATION OPACITIES
Abbreviations Used in This Chapter
AIP
acute interstitial pneumonia
ARDS
acute respiratory distress syndrome
COP
cryptogenic organizing pneumonia
DAD
diffuse alveolar damage
DIP
desquamative interstitial pneumonia
GGO
ground-glass opacity
HP
hypersensitivity pneumonitis
IPF
idiopathic pulmonary fibrosis
LIP
lymphoid interstitial pneumonia
NSIP
nonspecific interstitial pneumonia
OP
organizing pneumonia
PAP
pulmonary alveolar proteinosis
P. jirovecii
Pneumocystis jirovecii
PJP
Pneumocystis jirovecii pneumonia
RB-ILD
respiratory bronchiolitis-interstitial lung disease
UIP
usual interstitial pneumonia
Parenchymal opacification, either focal or diffuse, or a multifocal increase in
lung attenuation, is a common finding on high-resolution computed tomography
(HRCT) in patients with chronic lung disease. Increased lung opacity or
attenuation is generally described as either ground-glass opacity (GGO) or
consolidation (1–4) (Fig. 5-1). Some lung diseases may result in lung
calcification or other high-attenuation lung abnormalities. These are also
discussed in this chapter.
FIGURE 5-1 HRCT appearances of increased lung opacity. Ground-glass opacity does not
result in obscuration of underlying vessels, whereas consolidation does. Both can be associated
with air bronchograms and can be nodular, lobular, or patchy and geographic.
GROUND-GLASS OPACITY
Ground-glass opacity is a nonspecific term that refers to the presence of a hazy
increase in lung opacity on HRCT that, somewhat arbitrarily, is not associated
with obscuration of underlying vessels or bronchial margins (Figs. 5-1 to 5-3); if
vessels are obscured, the term consolidation is generally used (1–4). This finding
can reflect the presence of a number of abnormalities and can be seen in patients
with airspace disease (Fig. 5-3), interstitial thickening (Fig. 5-4), partial alveolar
collapse (atelectasis), increased capillary blood volume, or a combination of
these (5–12).
FIGURE 5-2 Ground-glass opacity in a 16-year-old boy with Goodpasture syndrome and
pulmonary hemorrhage.
FIGURE 5-3 Patchy ground-glass opacity in a patient with PJP with ground-glass opacity.
Pulmonary vessels remain visible within the abnormal lung regions.
FIGURE 5-4 Ground-glass opacity associated with interstitial fibrosis. A: HRCT shows patchy
areas of ground-glass opacity. B: Biopsy specimen shows the abnormality to consist of alveolar
wall thickening and fibrosis, with little airspace abnormality. (From Leung AN, Miller RR, Müller
NL. Parenchymal opacification in chronic infiltrative lung diseases: CT-pathologic correlation.
Radiology 1993;188:209, with permission.)
Ground-glass opacity results from the volume averaging of morphologic
abnormalities, too small to be clearly resolved by HRCT (9–12). It can reflect
the presence of minimal thickening of the “septal” or alveolar interstitium;
thickening of alveolar walls; interstitial inflammation, infiltration, or fibrosis; or
the presence of cells or fluid partially filling the alveolar spaces (7,13,14). When
a small amount of fluid is present within the alveoli, as can occur in the early
stages of an airspace-filling disease, the fluid tends to layer against the alveolar
walls and is indistinguishable on HRCT from alveolar wall thickening (15). In a
study comparing the results of lung biopsy with HRCT in 22 patients who
showed ground-glass opacity, 14% had diseases primarily affecting airspaces,
32% had a mixed interstitial and airspace abnormality, and 54% had a primarily
interstitial abnormality (7). Partial alveolar collapse also results in increased lung
attenuation (16), which has the appearance of ground-glass opacity.
The term ground-glass opacity may be used to refer to increased lung density
resulting from increased capillary blood volume, although this is better termed
mosaic perfusion if the etiology of the lung attenuation abnormality is known or
suspected (16). The appearance of mosaic perfusion is described in Chapter 7.
Ground-glass opacity is difficult to recognize if it is minimal and diffuse in
distribution, involving the entire lung to an equal degree. However, ground-glass
opacity is almost always patchy in distribution, affecting some lung regions and
sparing others; this “geographic” appearance of the lung parenchyma makes it
easier to detect and diagnose with confidence (Figs. 5-3 and 5-5). In some
patients, entire lobules may appear abnormally dense, whereas adjacent lobules
appear normal (13). In others, the abnormal ground-glass opacities are
centrilobular and peribronchiolar in location, resulting in the appearance of illdefined centrilobular nodules (5,13,15,17–20). Ground-glass opacity can involve
individual segments and lobes, can involve nonsegmental regions of lung (Fig.
5-6), or may be diffuse (13) (Fig. 5-7). The presence of air-filled bronchi that
appear “too black” within an area of lung can also be a clue as to the presence of
ground-glass opacity; this dark bronchus appearance is essentially that of an air
bronchogram.
FIGURE 5-5 A and B: Patchy ground-glass opacity associated with HP. Abnormalities had an
upper-lobe predominance.
FIGURE 5-6 Extensive perihilar ground-glass opacity associated with acute lung injury and
DAD related to smoking cocaine. This abnormality was transient and cleared within 2 weeks.
FIGURE 5-7 A–C: HRCT at three levels in a patient with PJP associated with AIDS. Diffuse
ground-glass opacity predominates in the upper lobes and perihilar regions (A). In the lower lobes
(C), ground-glass opacity is more patchy in distribution.
Significance of Ground-Glass Opacity
Ground-glass opacity is a highly significant finding because it often indicates the
presence of an ongoing, active, and potentially treatable process. In patients with
acute symptoms, the association of ground-glass opacity with active disease is
very high. For example, in patients with AIDS and acute respiratory distress,
ground-glass opacity visible on HRCT accurately predicts the presence of
Pneumocystis jirovecii pneumonia (previously called Pneumocystis carinii
pneumonia) (21).
In patients who have subacute or chronic symptoms, ground-glass opacity also
suggests the likelihood of active disease, although in this setting, lung fibrosis
can also result in this finding. Of 22 patients with ground-glass opacity studied
by Leung et al. (7), 18 (82%) were considered to have active or potentially
reversible disease on lung biopsy. In a similar study by Remy-Jardin et al. (14),
HRCT findings were correlated with histology at 37 biopsy sites in 26 patients.
In 24 of the 37 (65%) biopsies, they found that ground-glass opacity
corresponded to the presence of inflammation that exceeded or was equal to
fibrosis in degree. In 8 biopsies (22%), inflammation was present but fibrosis
predominated, whereas in the remaining 5 (13%), fibrosis was the sole histologic
finding. Because of its association with active lung disease, the presence of
ground-glass opacity often leads to further diagnostic evaluation, including lung
biopsy, depending on the clinical status of the patient. Also, when a lung biopsy
is performed, areas of ground-glass opacity can be targeted by the surgeon or
bronchoscopist. Because such areas are most likely to be active, they are most
likely to yield diagnostic material.
However, since ground-glass opacity can reflect the presence of either fibrosis
or inflammation, one should be careful to diagnose an active process only when
ground-glass opacity is unassociated with HRCT findings of fibrosis or is the
predominant finding (Figs. 5-5 to 5-8). If ground-glass opacity is seen only in
lung regions that also show HRCT findings of fibrosis, such as traction
bronchiectasis or honeycombing, it is likely that fibrosis will be the predominant
histologic abnormality (Figs. 5-4 and 5-9). For example, in a study by RemyJardin et al. (14), all patients showing traction bronchiectasis or bronchiolectasis
on HRCT in regions of ground-glass opacity had fibrosis on lung biopsy.
However, among patients without traction bronchiectasis in the areas of groundglass opacity, 92% were found to have active inflammatory disease on lung
biopsy.
FIGURE 5-8 Subtle patchy ground-glass opacity in a patient with NSIP. A posterior and
subpleural predominance is present. Findings of fibrosis, such as traction bronchiectasis, are
absent. Note sparing of the immediate subpleural lung. This is seen in about half of patients with
NSIP.
FIGURE 5-9 Ground-glass opacity associated with lung fibrosis in two patients with IPF. A: In
a patient with early lung fibrosis, ground-glass opacity in the posterior lung is associated with
reticulation and traction bronchiectasis. B: In a patient with extensive lung fibrosis with
reticulation, honeycombing, and traction bronchiectasis, ground-glass opacity is also visible.
When ground-glass opacity is associated with findings of fibrosis, such as traction bronchiectasis
or bronchiolectasis, it is likely that the ground-glass opacity also reflects fibrosis.
Differential Diagnosis of Ground-Glass Opacity
A large number of diseases can be associated with ground-glass opacity on
HRCT. In many, this reflects the presence of similar histologic reactions in the
early or active stages of disease, with inflammatory exudates involving the
alveolar septa and alveolar spaces, although this pattern can be the result of a
variety of pathologic processes.
When considering the differential diagnosis of ground-glass opacity, it is
important to know whether the patient’s symptoms are acute, subacute, or
chronic (Table 5-1). Among those causes of ground-glass opacity typically
having an acute presentation are pulmonary edema of various causes (22,23);
pulmonary hemorrhage (Fig. 5-2) (24); pneumonias of all types, but particularly
atypical pneumonias, such as Pneumocystis jirovecii pneumonia (PJP) (Figs. 5-3,
5-7, and 5-10) (13,21,22,25–31), viral pneumonia (e.g., cytomegalovirus)
(32–40), and mycoplasma pneumonia (41); acute interstitial pneumonia (AIP)
(42,43) and other causes of diffuse alveolar damage (DAD) (Fig. 5-6) and the
acute respiratory distress syndrome (ARDS) (44), including acute exacerbation
of a chronic interstitial pneumonia (45); acute eosinophilic pneumonia (46,47);
acute hypersensitivity pneumonitis, aspiration, and early radiation pneumonitis
(20,48,49).
FIGURE 5-10 Pneumonia with ground-glass opacity in two patients. A: In a patient with
Pneumocystis pneumonia, patchy ground-glass opacity is associated with septal thickening, the
appearance termed “crazy paving.” B: In another patient with pneumonia, ground-glass opacity is
associated with focal consolidation.
TABLE 5-1 Differential Diagnosis of Ground-Glass Opacity
The most common causes of ground-glass opacity in patients having subacute
or chronic symptoms (Table 5-1) include interstitial pneumonias such as
nonspecific interstitial pneumonia (NSIP) (Figs. 5-8 and 5-11), either idiopathic
or associated with specific diseases, such as scleroderma or other collagenvascular diseases (7,13,14,50–54), desquamative interstitial pneumonia (DIP)
(Fig. 5-12) (55–57), respiratory bronchiolitis-interstitial lung disease (RB-ILD)
(56,58–60), hypersensitivity pneumonitis (HP) (Figs. 5-5 and 5-13)
(14,19,61,62), organizing pneumonia (OP) (7,14,54,63), drug reactions (13,64),
chronic eosinophilic pneumonia (Fig. 5-14) (47,64,65), lymphoid interstitial
pneumonia (LIP) (66,67), Churg-Strauss syndrome (47,68), lipoid pneumonia
(Fig. 5-15) and chronic or recurrent aspiration (69,70), nonmucinous and
mucinous pulmonary adenocarcinomas (Fig. 5-16) (71,72), sarcoidosis (7,14,73–
75), and pulmonary alveolar proteinosis (PAP) (Fig. 5-17) (29,76–80).
FIGURE 5-11 Ground-glass opacity in cellular NSIP. Ground-glass opacity predominates in
the posterior lung. Although it predominates in the peripheral lung, there is subpleural sparing,
and finding that suggests NSIP.
FIGURE 5-12 DIP in a 39-year-old smoker. Ground-glass opacity predominates in the
peripheral lung, with some subpleural sparing. Cysts are visible within the areas of ground-glass
opacity. Cysts are visible in some patients with DIP.
FIGURE 5-13 Subacute HP. Patchy and geographic areas of ground-glass opacity are visible,
with relative sparing of some lobules.
FIGURE 5-14 Two patients with chronic eosinophilic pneumonia. A: Patchy and geographic
areas of ground-glass opacity are visible in the upper lobes. B: In a different patient, patchy areas
of ground-glass opacity and consolidation are visible.
FIGURE 5-15 Lipoid pneumonia associated with chronic mineral oil aspiration. A and B:
Parahilar areas of ground-glass opacity are visible.
FIGURE 5-16 Invasive mucinous adenocarcinoma. Patchy and nodular areas of ground-glass
opacity are visible in both lungs, although the left lung is more severely involved.
FIGURE 5-17 PAP with crazy paving. A and B: Geographic ground-glass opacities and
interlobular septal thickening are visible in the same lung regions. This pattern is termed crazy
paving. It is nonspecific, but characteristic of alveolar proteinosis. C: Lung biopsy in a patient with
alveolar proteinosis shows parts of three adjacent pulmonary lobules. The lobule on the left (PAP)
shows alveoli filled with proteinaceous material; ground-glass opacity would be visible in this
region on HRCT. The lobule in the middle (NL) is normal, accounting for the geographic
appearance of this abnormality on HRCT. Enlargement of lymphatics within interlobular septa by
the proteinaceous material (arrows) results in interlobular septal thickening. (Courtesy of Martha
Warnock, MD.)
Correlation with Histology
In patients with ground-glass opacity, the nature of the histologic abnormalities
associated with this finding varies according to the typical histologic features of
the disease; no specific histology is associated with this finding (Table 5-2)
(7,19,60,81–83). In patients with NSIP, scleroderma, or other collagen-vascular
diseases, a number of studies have correlated the presence of ground-glass
opacity on HRCT with biopsy results, response to treatment, and patient survival
(6,10–12,50,55,84–87). In histologic studies of patients with interstitial
pneumonia, ground-glass opacity has been shown to be associated with the
presence of alveolar wall or intra-alveolar inflammation in most. For example, in
a study of scleroderma patients by Wells et al. (10), increased opacity on HRCT
correlated with predominant inflammation on biopsy in 4 of 7 cases, whereas
reticulation on HRCT indicated fibrosis in 12 of 13. In another study of 14
patients with idiopathic pulmonary fibrosis (IPF) and ground-glass opacity on
HRCT, 12 had inflammation on biopsy (7). In patients with usual interstitial
pneumonia (UIP), ground-glass opacity is variably associated with lung fibrosis;
ground-glass opacity in patients with DIP largely reflects the presence of
macrophages within alveoli (7,10,55,85).
TABLE 5-2 Histologic Abnormalities Associated with Ground-Glass
Opacity
Diagnosis
Histologic findings
UIP
NSIP
DIP
Respiratory bronchiolitis
AIP
HP
OP
Eosinophilic pneumonia
PJP
Sarcoidosis
Alveolar proteinosis
Mucinous and nonmucinous
adenocarcinoma
Fibrosis is usually present
Alveolar septal inflammation; intra-alveolar cellular infiltrate;
fibrosis
Alveolar macrophages; interstitial inflammatory infiltrate; mild
fibrosis
Pigment-containing alveolar macrophages
Interstitial inflammatory exudate; edema; DAD with hyaline
membranes
Alveolitis; interstitial infiltrates; poorly defined granulomas;
cellular bronchiolitis
Alveolar septal inflammation; alveolar cellular desquamation
Eosinophilic interstitial infiltrate; alveolar eosinophils and
histiocytes
Alveolar inflammatory exudate; alveolar septal thickening
Largely due to numerous small granulomas; alveolitis less
important
Intra-alveolar lipoproteinaceous material
Lepidic tumor growth; alveolar collapse; intra-alveolar mucin
(in mucinous tumors)
Crazy-Paving Pattern
In some patients with ground-glass opacity visible on HRCT, superimposition of
a reticular pattern results in an appearance termed crazy paving (65,78,88–90).
This pattern was first recognized in patients with PAP (Fig. 5-17) (78) and is
quite typical of PAP, but may also be seen in patients with a variety of other
diseases (65,88,89). In patients with crazy paving, ground-glass opacity may
reflect the presence of airspace or interstitial abnormalities; the reticular
opacities may represent interlobular septal thickening, thickening of the
intralobular interstitium, irregular areas of fibrosis, or a preponderance of an
airspace-filling process at the periphery of lobules or acini (65).
The differential diagnosis of crazy paving includes diseases considered to be
primarily airspace or interstitial and mixed (Table 5-3) (65,88,89). These include
PAP, both primary and secondary (Fig. 5-17) (78–80); silicoproteinosis (acute
silicosis) (91); pulmonary edema (23,92); pulmonary hemorrhage (Fig. 5-18)
(24,88); ARDS (88,89); AIP; DAD; pneumonias due to P. jirovecii (Figs. 5-10A
and 5-19), virus (e.g., cytomegalovirus, adenovirus, severe acute respiratory
syndrome) (Fig. 5-20) (30,39,93–95), mycoplasma, bacteria, and tuberculosis
(88,96); interstitial pneumonias, including NSIP and OP (Fig. 5-21) (88); chronic
eosinophilic pneumonia; acute eosinophilic pneumonia (46); Churg-Strauss
syndrome (68); radiation pneumonitis (49); drug-related pneumonitis (88,97);
sarcoidosis (88); pulmonary adenocarcinoma (Fig. 5-22) (71,88); Kaposi
sarcoma (92); lipoid pneumonia (69,70); aspiration, and type B Niemann-Pick
disease (98). Clearly, the differential diagnosis of a crazy-paving pattern must be
based on a consideration of both clinical and HRCT findings, as well as
knowledge of whether symptoms are acute or chronic (Table 5-3).
FIGURE 5-18 Ground-glass opacity and crazy paving in a patient with pulmonary
hemorrhage. A and B: Vessels are visible within the area of opacity, as are thickened interlobular
septa.
FIGURE 5-19 A and B: PJP in an immunosuppressed patient with leukemia. Patchy areas of
ground-glass opacity are associated with distinct interlobular septal thickening.
FIGURE 5-20 A and B: Pneumonia due to respiratory syncytial virus. HRCT at two levels
shows patchy ground-glass opacity associated with some interlobular septal thickening (arrows).
FIGURE 5-21 A and B: Patchy areas of ground-glass opacity and interlobular septal
thickening (crazy paving) in a patient with OP associated with aspiration. Note the presence of a
dilated fluid-filled esophagus (E).
FIGURE 5-22 A and B: Patchy areas of ground-glass opacity and interlobular septal
thickening in a patient with pulmonary adenocarcinoma. Nodules within the left lung and nodular
thickening of the subpleural interstitium adjacent to the left major fissure also reflect tumor spread.
Focal lucencies within the upper lobes are caused by underlying emphysema.
TABLE 5-3 Differential Diagnosis of Crazy Paving
In the study by Johkoh et al. (65) of 46 patients showing the crazy-paving
pattern on HRCT, the most common causes included ARDS (n = 8), bacterial
pneumonia (n = 7), AIP (n = 5), and, despite its rarity, alveolar proteinosis (n =
5). Of these common causes of crazy paving, it is worth noting that only PAP
presents with subacute or chronic symptoms, and ARDS, bacterial pneumonia,
and AIP are not commonly studied using HRCT in clinical practice. Also, the
highest prevalences of crazy paving in this study were seen in PAP (100%),
DAD (67%), AIP (31%), and ARDS (21%) (65).
In a prospective study of patients showing this pattern (89), a variety of causes
of crazy paving were identified. These included PJP, alveolar proteinosis, UIP,
pulmonary hemorrhage, acute radiation pneumonitis, ARDS, and drug-induced
pneumonitis. Of these, PJP was most common.
In very general terms, the differential diagnosis of crazy paving is similar to
that of ground-glass opacity, with a consideration of whether associated
symptoms are acute or chronic. In patients with crazy paving and chronic
symptoms, PAP should be considered more likely than when ground-glass
opacity without crazy paving is visible.
Approach to the Diagnosis of Ground-Glass Opacity
If ground-glass opacity is associated with significant reticulation, the reticular
pattern should be identified (Fig. 5-23). If reticulation with honeycombing or
traction bronchiectasis is present in areas of increased attenuation, fibrosis is
very likely the cause of the ground-glass opacity, and the differential diagnosis
generally is that of fibrotic disease. If the reticular pattern represents interlobular
septal thickening, crazy paving is present (Table 5-3). If the only reticular pattern
present is that of intralobular interstitial thickening (intralobular lines), and
traction bronchiectasis or bronchiolectasis is absent, the pattern is nonspecific
and may reflect lung infiltration, inflammation, or mild fibrosis.
FIGURE 5-23 Algorithmic approach to the diagnosis of ground-glass opacity.
Ground-glass opacity unassociated with reticulation and findings of fibrosis
likely represents active disease. Knowing whether a patient with this HRCT
appearance has acute, subacute, or chronic symptoms is fundamental to
differential diagnosis.
Acute Symptoms
In patients with acute symptoms, the appearances of pulmonary edema,
pulmonary hemorrhage, DAD, atypical pneumonias, and other causes of groundglass opacity show considerable overlap, and considering the distribution of
abnormalities is of little value in diagnosis. PJP, cytomegalovirus pneumonia,
pulmonary edema, pulmonary hemorrhage, ARDS, and AIP may show a diffuse
distribution, a central, peripheral, centrilobular, diffuse, patchy, upper-or lowerlobe predominance in different situations, and generally, clinical information or
ancillary findings such as interlobular septal thickening (in edema) or
pneumatoceles (in PJP) are more valuable in limiting the diagnostic possibilities.
For example, HRCT abnormalities in pulmonary edema and DAD may appear
peripheral or central and “bat wing,” and atypical pneumonia may also have this
appearance. A multifocal posterior and dependent distribution suggests the
possibility of aspiration.
Subacute or Chronic Symptoms
In patients with subacute or chronic symptoms, the distribution of ground-glass
opacity in cross section, upper-lobe, mid-lung, or lower-lobe predominance, the
appearance of ground-glass opacity, associated nodules, and ancillary findings
can be helpful in differential diagnosis (Table 5-4).
TABLE 5-4 Associated Findings in the Differential Diagnosis of
Ground-Glass Opacity Associated with Chronic Symptoms
HRCT finding associated with
Most likely diagnosis(es)
GGO
Fibrosis (honeycombing, traction
bronchiectasis, irregular reticulation)
Peripheral distribution
Peripheral distribution with sparing of the
immediate subpleural interstitium
Patchy and geographic distribution
Upper-, mid-lung predominance
Lower-lobe predominance
Significant mosaic perfusion and/or air trapping
Centrilobular nodules
Interlobular septal thickening
NSIP, HP, UIP
NSIP, DIP
NSIP
HP, NSIP, OP
HP, respiratory bronchiolitis
NSIP, DIP, OP, UIP
HP
HP, respiratory bronchiolitis/DIP, follicular
bronchiolitis/LIP, invasive mucinous
adenocarcinoma
Alveolar proteinosis, mucinous and
nonmucinous adenocarcinoma, lipoid
pneumonia
Ground-glass opacity with a peripheral and subpleural predominance is most
likely due to an interstitial pneumonia (NSIP, DIP, or OP) or eosinophilic
pneumonia. NSIP is particularly likely if sparing of the immediate subpleural
lung is present. Patchy and geographic ground-glass opacity is most typical of
HP, OP, eosinophilic pneumonia, alveolar proteinosis, sarcoidosis, lipoid
pneumonia, and LIP. Diffuse and extensive ground-glass opacity may be seen
with HP.
If ground-glass opacity is associated with centrilobular nodules, the
differential diagnosis of centrilobular ground-glass opacity nodules (see Chapter
4) should be considered. This differential diagnosis includes HP, respiratory
bronchiolitis, follicular bronchiolitis, OP, and mucinous adenocarcinoma. A
patchy and lobular distribution is nonspecific (13), and can be seen in a variety
of diseases, but is most common in HP and metastatic calcification. Patchy or
nodular opacities in association with larger regions of ground-glass opacity or
consolidation suggest mucinous adenocarcinoma, particularly if the abnormality
is asymmetrical or unilateral. Patchy ground-glass opacity in sarcoidosis
generally reflects the presence of numerous small nodules, and satellite nodules
surrounding the areas of GGO, or nodules seen in other locations, may suggest
the diagnosis.
In patients with subacute or chronic symptoms, an upper-lobe predominance
of abnormalities suggests HP (an upper-to mid-lung predominance is most
likely), metastatic calcification, eosinophilic pneumonia, RB-ILD, or
sarcoidosis. A lower-lobe predominance may be seen with interstitial
pneumonias (NSIP, DIP, and OP), LIP, follicular bronchiolitis, and some patients
with HP.
Ground-glass opacity associated with areas of mosaic perfusion or air trapping
suggests HP as most likely, although in patients with subacute or chronic
symptoms, this combination may also be seen in sarcoidosis, DIP and RB-ILD,
and LIP.
Pitfalls in Diagnosis of Ground-Glass Opacity
There are several potential pitfalls in the recognition and diagnosis of groundglass opacity. First, it is important to keep in mind that because ground-glass
opacity reflects the volume averaging of subtle morphologic abnormalities, the
thicker the collimation used for scanning, the more likely volume averaging will
occur, regardless of the nature of the anatomical abnormality present. Thus,
ground-glass opacity should be diagnosed only on scans obtained with thin
collimation.
The diagnosis of ground-glass opacity is largely subjective and based on a
qualitative assessment of lung attenuation (9). The use of lung attenuation
measurements to determine the presence of increased lung density in patients
with ground-glass opacity is difficult because of variations in attenuation
measurements that are known to be associated with gravitational density
gradients in the lung, the level of inspiration, and that occur as a result of
differences in patient size, position, chest wall thickness, and the kilovolt peak
(kV(p)). Using consistent window settings for the interpretation of HRCT is very
important. Using too low a window mean in conjunction with a relatively narrow
window width can give the appearance of diffuse ground-glass opacity (9). In
addition, using a wider window width than one is accustomed to without
changing window mean can give the impression of increased lung attenuation. In
assessing the attenuation of lung parenchyma, it is often helpful to compare its
appearance to that of air in the trachea or bronchi; if tracheal air appears gray
instead of black, then increased attenuation or “grayness” of the lung
parenchyma may not be significant.
Also, as previously indicated, increased lung opacity is commonly seen in the
dependent lung on HRCT, largely as a result of volume loss in the dependent
lung parenchyma; this is so-called dependent density (16,99). This can result in a
stripe of ground-glass opacity several centimeters thick in the posterior lung of
supine patients; prone scans allow this transient finding to be distinguished from
a true abnormality. Similarly, on expiration, because of a reduction of the amount
of air within alveoli, lung regions increase in attenuation and can mimic the
appearance of ground-glass opacity resulting from lung disease.
Furthermore, in patients who have patchy emphysema or other causes of lung
hyperlucency, such as airways obstruction and air trapping, normal lung regions
can appear relatively dense, thus mimicking the appearance of ground-glass
opacity. This pitfall can usually be avoided if consistent window settings are
used for interpretation of scans, and the interpreter is accustomed to the
appearances of normal lung, lung of increased attenuation, and lung of decreased
attenuation. Also, air bronchograms will not be seen within the relatively dense,
normal lung regions, as they are in patients with true ground-glass opacity. The
use of expiratory HRCT can also be of value in distinguishing the presence of
heterogeneous lung attenuation resulting from emphysema or air trapping from
that representing ground-glass opacity. This is described further in the section on
Mosaic Attenuation Pattern.
CONSOLIDATION
Increased lung attenuation with obscuration of underlying pulmonary vessels is
referred to as consolidation (Figs. 5-1 and 5-24 to 5-28) (1,2,4); air
bronchograms may be present (Fig. 5-28). HRCT has little to add to the
diagnosis of patients with clear-cut evidence of consolidation visible on chest
radiographs. However, HRCT can allow the detection of consolidation before it
becomes diagnosable radiographically. Focal areas of ground-glass opacity and
centrilobular nodules may be seen in association with areas of consolidation
(Figs. 5-28 and 5-29).
FIGURE 5-24 A and B: OP with patchy areas of consolidation. A peripheral or peribronchial
distribution is typical. Areas of consolidation in OP are typically irregular in contour, and may
contain air bronchograms.
FIGURE 5-25 OP with patchy peribronchial consolidation and ground-glass opacity. Air
bronchograms are visible.
FIGURE 5-26 A and B: Eosinophilic pneumonia with focal areas of consolidation and groundglass opacity. As in patients with OP, a peripheral distribution is typical. Note the presence of air
bronchograms and obscuration of vessels in the apical opacity (arrow).
FIGURE 5-27 A and B: Eosinophilic pneumonia with focal areas of consolidation having a
peripheral and subpleural distribution. Eosinophilic pneumonia and OP are often indistinguishable.
FIGURE 5-28 Consolidation in a lung transplant recipient with acute symptoms. A and B:
Focal consolidation is associated with an air bronchograms and adjacent centrilobular nodules
(arrows, B).
FIGURE 5-29 Angioinvasive aspergillosis in a 17-year-old patient with leukemia and
neutropenia. HRCT shows focal consolidation with adjacent ground-glass opacity (arrows).
Ground-glass opacity surrounding a nodule or focal area of consolidation is termed the halo sign,
and in this clinical setting suggests angioinvasive aspergillosis.
By definition, diseases that produce consolidation are characterized by a
replacement of alveolar air by fluid, cells, tissue, or some other substance
(1,4,15,77). Most are associated with airspace filling, but diseases that produce
an extensive, confluent interstitial abnormality, such as NSIP or sarcoidosis, can
also result in this finding (7,100). In patients who show consolidation in
association with another pattern that is predominant, such as small nodules, the
other pattern should be used for differential diagnosis. In such patients,
consolidation probably represents confluent disease.
Differential Diagnosis
The differential diagnosis of consolidation overlaps considerably with that listed
for ground-glass opacity (Table 5-1), and, in fact, many of the diseases listed in
Table 5-1 can show a mixture of both findings (Table 5-5). The differential
diagnosis of consolidation includes pneumonia of different causes, most
typically bacterial (Fig. 5-28) but including mycobacteria, fungal pneumonia
(Fig. 5-29), mycoplasma, P. jirovecii and viral pneumonia (15,26,38–40,101);
OP ((Figs. 5-24 and 5-25) (63,102,103); eosinophilic pneumonia (Figs. 5-26 and
5-27) (64,104), interstitial pneumonias such as NSIP, and DIP; HP Fig. 5-30)
(61); radiation pneumonitis (20,48,49,105,106), invasive mucinous
adenocarcinoma ((Figs. 5-16 and 5-31) (72); LIP, lymphoma Fig. 5-32), and
lymphoproliferative disease (7,15,107); alveolar proteinosis (76); sarcoidosis
(108); drug reactions (28,109), pulmonary edema or hemorrhage; and AIP
(42,90), DAD, and ARDS (15). Exogenous lipoid pneumonia, related to
aspiration of animal or vegetable fats or mineral oil may result in ground-glass
opacity or consolidation; consolidation, when present may be low in attenuation
because of contained fat (Fig. 5-33) (70).
FIGURE 5-30 Hypersensitivity pneumonitis. Irregular areas of consolidation represent OP
occurring in association with HP.
FIGURE 5-31 Invasive mucinous adenocarcinoma. A and B: Focal areas of consolidation
involve both lungs. Ground-glass opacity is seen surrounding with the right lower lobe nodule in
B.
FIGURE 5-32 Primary pulmonary non-Hodgkin lymphoma. Nodular areas of consolidation are
visible bilaterally. Air bronchograms are visible in both lungs.
FIGURE 5-33 Low-attenuation consolidation in lipoid pneumonia. Low attenuation (arrow)
within an area of consolidation in the right upper lobe is due to chronic mineral oil aspiration.
TABLE 5-5 Differential Diagnosis of Consolidation
Consolidation and the “Halo Sign”
Focal areas of consolidation (or lung nodules) may be associated with groundglass opacity. This is a nonspecific finding. If focal consolidation or a lung
nodule is surrounded by a “halo” of ground-glass opacity, the “halo sign” is
present. The halo sign, in and of itself, is nonspecific and may be seen in a
variety of infections, including tuberculosis (110), candidiasis, Legionella
pneumonia, cytomegalovirus, or herpes simplex (111), infarction,
granulomatosis with polyangiitis (Wegener granulomatosis), and various tumors
(Fig. 5-31A). However, in neutropenic patients, the halo sign is typical and
suggestive of angioinvasive aspergillosis (Fig. 5-29) (112,113).
Consolidation and the “Reversed Halo Sign” or “Atoll
Sign”
Focal regions of consolidation or ground-glass opacity may be associated with
the so-called reversed halo or atoll sign (114–117) in which a region of groundglass opacity is surrounded or marginated by a denser ring or crescent of
consolidation (thus resembling a coral atoll, or the opposite of the “halo sign”)
(Figs. 4-47, 5-34, and 5-35) (118). This appearance is highly suggestive of OP
and has been seen in as many as 12% to 19% of cases in two different studies
(115,116), and is also common in chronic eosinophilic pneumonia, which may
closely resemble OP. The reversed halo or atoll sign has also been reported in
other diseases, such as Wegener granulomatosis (granulomatosis with
polyangiitis); various infections, specifically paracoccidioidomycosis,
mucormycosis, aspergillosis, bacterial infections, and tuberculosis; sarcoidosis;
neoplasm; lymphomatoid granulomatosis, and infarcts (117,119–122). Of note,
each of these diseases may be associated with OP histologically. In several
reports of this unusual finding, areas of ground-glass opacity primarily
corresponded to alveolar septal inflammation, while denser areas of
consolidation represented intra-alveolar inflammatory infiltrates.
FIGURE 5-34 The reversed halo sign or atoll sign in OP. A and B: In a patient with
dematomyositis, OP is manifested by the reversed halo sign (arrows). A rim of consolidation
surrounds a region of ground-glass opacity. This appearance also resembles a coral atoll.
FIGURE 5-35 The reversed halo sign or atoll sign in chronic eosinophilic pneumonia. A and
B: Multiple patchy areas of ground-glass opacity and consolidation are visible in a peripheral and
peribronchial distribution. A number are associated with a crescent of peripheral consolidation
(arrows). A complete ring of consolidation need not be present.
Although this sign suggests OP, it may be associated with a variety of
infectious and noninfectious diseases. The presence of this sign should not
preclude an otherwise straightforward diagnosis. A thorough analysis of
associated HRCT findings may help with the differential diagnosis, and
histologic assessment is often needed for a definitive determination of the cause
(122).
In a recent study (121), the morphologic characteristics of the reversed halo
sign associated with tuberculosis were compared to those caused by cryptogenic
organizing pneumonia (COP). HRCT in all 12 patients with active tuberculosis
showed reversed halos with nodular walls, and in most cases (10/12), nodules
were also visible within the halos. None of the 10 patients with COP showed
halos with nodular walls or associated nodules.
Algorithmic Approach to the Diagnosis of Consolidation
As with ground-glass opacity, the duration of symptoms associated with
consolidation is important in differential diagnosis. Consolidation in a patient
with acute symptoms suggests pulmonary edema, hemorrhage, pneumonia (most
commonly bacterial) (Fig. 5-28), DAD, or AIP as most likely. Subacute or
chronic symptoms would generally suggest an alternate diagnosis (Table 5-5).
Lung diseases causing consolidation can have widely differing appearances
and distributions, depending on the nature of the pathologic process responsible
(Fig. 5-36). Diffuse consolidation is most typical of pneumonia, OP, invasive
mucinous adenocarcinoma, DAD and ARDS (44), AIP, pulmonary edema, and
pulmonary hemorrhage. A subpleural distribution is most suggestive of
eosinophilic pneumonia and OP, but may also be seen with an interstitial
pneumonia such as NSIP.
FIGURE 5-36 Algorithmic approach to the diagnosis of common causes of consolidation.
Patchy consolidation can show a nonanatomical and nonsegmental
distribution, but can also appear lobar, lobular, or centrilobular on HRCT
(5,15,123,124). Patchy abnormalities can be seen with almost any cause of
consolidation, but are most typical of OP, eosinophilic pneumonia, invasive
mucinous adenocarcinoma, sarcoidosis, and bronchopneumonia. Lobular
consolidation is often due to infection (i.e., lobular pneumonia or
bronchopneumonia), but is nonspecific and may be seen with a variety of
diseases (123). This appearance has been termed the panlobular pattern (124).
Focal consolidation is most typical of pneumonia, mucinous adenocarcinoma,
lymphoma, OP, and lipoid pneumonia.
LUNG CALCIFICATION AND HIGH-ATTENUATION
OPACITIES
Lung opacities with an attenuation greater than that of soft tissue has a limited
differential diagnosis, including causes of lung calcification or the deposition of
other high-attenuation substances in the lung (Table 5-6).
TABLE 5-6 High-Attenuation Lung Opacity
Multifocal lung calcification, often associated with lung nodules, is common,
and has been reported in association with infectious granulomatous diseases such
as tuberculosis (123), histoplasmosis, and varicella pneumonia (125); sarcoidosis
(Fig. 5-37) (126); silicosis (91,126,127); amyloidosis (128); and fat embolism
associated with ARDS (129).
FIGURE 5-37 Calcification within nodular lung disease in a patient with sarcoidosis. Densely
calcified nodules are visible bilaterally. Mediastinal lymph node enlargement is also present.
Diffuse and dense lung calcification can be seen in the presence of metastatic
calcification, disseminated pulmonary ossification, and alveolar microlithiasis
(125,130,131). High lung attenuation can be seen in patients with talcosis
(131,132) associated with fibrotic masses, although this may represent the
injected material rather than calcification, or inhalation of metals such as iron,
tin, or barium (125). Small focal areas of increased attenuation may be seen in
the presence of injection and embolized radiodense materials such as mercury,
iodinated oil, or acrylic cement (125). Diffuse, increased lung attenuation in the
absence of calcification can be seen as a result of amiodarone lung toxicity or
embolization of iodinated oil after chemoembolization (125,131).
Metastatic Calcification
Deposition of calcium within the lung parenchyma (metastatic calcification) can
occur as a result of hypercalcemia in patients with abnormal calcium and
phosphate metabolism, and is most common in patients with chronic renal
failure and secondary hyperparathyroidism (Fig. 5-38) (130,133–135).
Metastatic calcification is typically interstitial, involving the alveolar septa,
bronchioles, and arteries, and can be associated with secondary lung fibrosis.
Plain radiographs are relatively insensitive in detecting this calcification,
whereas HRCT can show calcification in the absence of radiographic findings.
Calcifications can be focal, centrilobular, lobular, or diffuse (125) (Fig. 5-38).
Ground-glass opacities with a centrilobular distribution have been reported in
association with metastatic calcification (134). Often, the calcification
predominates in the upper lobes (Fig. 5-38).
FIGURE 5-38 A 42-year-old man with chronic renal failure and metastatic calcification. A:
HRCT shows nodular areas of opacity that appear centrilobular, as well as some ground-glass
opacities, predominating in the upper lobes. B: Soft-tissue window scan shows multiple areas of
calcification within these opacities. C: Lung specimen in a patient with metastatic calcification
shows a centrilobular and lobular distribution (arrows), with a predominance in the upper lobes.
(Courtesy of Martha Warnock, MD.)
Hartman et al. (135) reviewed the chest radiographs and CT and HRCT scans
of seven patients with hypercalcemia and biopsy-proven metastatic calcification.
In five patients, the radiographic findings were nonspecific, consisting of poorly
defined nodular opacities and patchy areas of parenchymal consolidation,
whereas in two patients calcified nodules were visible. CT and HRCT findings
consisted of numerous fluffy and poorly defined nodules measuring 3 to 10 mm
in diameter. The nodules primarily involved the upper lobes in three patients,
were diffuse in three, and were predominant in the lower lung zones in one.
Areas of ground-glass opacity were present in three of the seven patients, and
patchy areas of consolidation were present in two. Calcification of some or all of
the nodules was seen on CT in four of the seven patients. Six of the seven
patients also had evidence of calcification in the vessels of the chest wall, and
one had calcification of the left atrial wall.
Alveolar Microlithiasis
The HRCT appearances of several patients with pulmonary alveolar
microlithiasis have been reported, corresponding closely to pathologic findings
in this disease (136–139). Alveolar microlithiasis is characterized by widespread
intra-alveolar calcifications, representing so-called microliths or calcospheres.
HRCT shows a posterior and lower-lobe predominance of the calcifications, with
a high concentration in the subpleural parenchyma and in association with
bronchi and vessels (Fig. 5-39). A perilobular and centrilobular distribution of
the calcifications may be seen, or calcifications may be associated with
interlobular septa. Intraparenchymal cysts or paraseptal emphysema may be
associated (136,137). In children or patients with early disease, ground-glass
opacity or reticulation may be the predominant finding, with calcification being
inconspicuous (138).
FIGURE 5-39 HRCT in a patient with alveolar microlithiasis, with lung (A) and soft-tissue (B)
windows. Calcifications that are very small and diffuse show a subpleural predominance.
(Courtesy of Joseph Cherian, MD, Al-Sabah Hospital, Kuwait.)
In a study of 10 patients with alveolar microlithiasis, HRCT findings included
parenchymal bands, ground-glass opacity, and subpleural interstitial thickening
(10 patients each); interlobular septal thickening (9 patients); paraseptal
emphysema (8 patients); centrilobular emphysema (7 patients); confluent
micronodules (6 patients); peribronchovascular interstitial thickening (5
patients); panacinar emphysema (3 patients); and pleural calcification (2
patients). Significant correlations were found between HRCT scores for these
findings and results of pulmonary function tests (139).
Amiodarone Pulmonary Toxicity
Amiodarone is a tri-iodinated drug used to treat refractory tachyarrhythmias. It
accumulates in lung, largely within macrophages and type 2 pneumocytes, where
it forms lamellar inclusion bodies and has a very long half-life. In some patients,
accumulation of the drug results in pulmonary toxicity with interstitial
pneumonia and fibrosis, although the mechanisms of disease are unclear. CT in
patients with amiodarone can show high-attenuation areas of consolidation or
high-attenuation nodules or masses, sometimes in association with an abnormal
reticulation or ground-glass opacity (Fig. 5-40) (109,140). High-attenuation
consolidation or masses were seen in 8 of 11 patients in one series (140),
correlating with the presence of numerous foamy macrophages in the
interstitium and alveolar spaces. Unconsolidated lung parenchyma does not
appear abnormally dense. Because the drug also accumulates in the liver and
spleen, these also appear abnormally dense on scans obtained through the lung
bases.
FIGURE 5-40 HRCT in amiodarone toxicity. A: On an unenhanced HRCT, a focal area of
dense lung consolidation (arrows) is present in the posterior lung. A pleural effusion is also visible,
because of cardiac decompensation. B: In another patient with OP occurring because of
amiodarone toxicity, focal areas of lung consolidation (arrows) appear higher in attenuation than
soft tissue.
Talcosis
An appearance of progressive massive fibrosis very similar to that occurring in
patients with silicosis or sarcoidosis can be seen in intravenous drug users who
develop talcosis from injection of talc-containing substances (132). The fibrotic
masses can show high attenuation at soft-tissue windows, because of the
presence of talc (see Chapter 13). Perihilar and upper-lobe predominance has
been reported. A similar appearance may also be seen in patients with
inhalational talcosis (141).
Heavy Metal Pneumoconiosis
Inhalation of radiodense material, such as iron oxide, tin, and barium, may result
in dense pulmonary lesions (91,142). The HRCT appearance of dense lung
lesions secondary to inhaled iron oxide has been reported in welders;
centrilobular nodules are common (143).
Disseminated Pulmonary Ossification
Disseminated pulmonary ossification is a rare condition in which very small
deposits of mature bone form within the lung parenchyma (144). It can be
associated with chronic heart disease, such as mitral stenosis, or chronic
interstitial fibrosis, such as IPF or asbestosis, or be related to drugs.
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6
HRCT Findings: Air-Filled Cystic Lesions
IMPORTANT TOPICS
LUNG CYST: DEFINITION
HONEYCOMBING
CYSTIC LUNG DISEASE
INCIDENTAL LUNG CYSTS
EMPHYSEMA
PNEUMATOCELE
CAVITARY NODULES
BRONCHIECTASIS
ALGORITHMIC APPROACH TO THE DIAGNOSIS OF CYSTIC AIRSPACES
Abbreviations Used in This Chapter
CLE
centrilobular emphysema
COPD
chronic obstructive pulmonary disease
DIP
desquamative interstitial pneumonia
HP
hypersensitivity pneumonitis
HU
Hounsfield units
LAM
lymphangio(leio)myomatosis
LCH
Langerhans cell histiocytosis
LIP
lymphoid interstitial pneumonia
PFT
pulmonary function test
PLE
panlobular emphysema
RB-ILD
respiratory bronchiolitis-interstitial lung disease
TS-LAM
tuberous sclerosis complex-associated LAM
UIP
usual interstitial pneumonia
A variety of abnormalities result in air-filled cystic lesions on high-resolution
computed tomography (HRCT). These include honeycombing, lung cysts,
emphysema, bullae, pneumatoceles, cavitary nodules, and bronchiectasis (Fig. 61). In most cases, these can be readily distinguished on the basis of HRCT
findings (1). This chapter provides a brief introduction to this topic. Subsequent
chapters discuss cystic lung diseases, emphysema, and airways disease in greater
detail.
FIGURE 6-1 HRCT appearances of abnormalities associated with air-filled lucencies,
including cysts, emphysema, and bronchiectasis. Mosaic perfusion, decreased lung attenuation
resulting from perfusion abnormalities, can mimic some of these appearances. It is discussed in
Chapter 7.
LUNG CYST: DEFINITION
The term lung cyst is used to refer to a well-defined and well-circumscribed
rounded or irregular lesion, with a visible wall, that may be uniform or variable
in thickness, but which is usually thin (less than 2–3 mm) (1,2). A cyst usually
contains air but may also contain liquid, semisolid, or solid material (1–3).
Lung cysts are also defined as having a wall composed of one of a variety of
cellular elements, usually fibrous or epithelial in nature (4). For example, in
patients with end-stage pulmonary fibrosis, honeycomb cysts are lined by
bronchiolar epithelium; on the other hand, in patients with
lymphangio(leio)myomatosis (LAM), the cysts are lined by abnormal spindle
cells resembling smooth muscle. The term cystic airspace may also be used to
describe a peripheral air-containing lesion surrounded by a wall of variable
thickness that may be thin as in LAM, or thick as in honeycombing (3). The term
cyst is not usually used to describe dilated airspaces in patients with emphysema,
although these may be cystic in appearance.
HONEYCOMBING
Honeycombing in patients with interstitial fibrosis is characterized on HRCT by
the presence of air-filled cysts, usually ranging from several millimeters to 1 cm
in diameter, which often predominate in a peripheral and subpleural location and
are characterized by clearly definable fibrous walls 1 to 3 mm in thickness
(2,5,6) (Figs. 6-1 to 6-4). Honeycombing reflects the presence of alveolar
disruption, dilatation of alveolar ducts, and bronchiolar dilatation (7–9). In
examples of early honeycombing, only a few clustered subpleural cysts are
visible; in advanced cases, cysts occur in multiple layers. It is important to
emphasize that in order to diagnose honeycombing with certainty, air-filled
cystic spaces must have thick and easily seen walls, must be seen in the
immediate subpleural lung, and must be seen in a row or cluster. In
contradistinction to the lung cysts seen in patients with LAM, Langerhans cell
histiocytosis (LCH), lymphoid interstitial pneumonia (LIP), other cystic lung
diseases, and the lucencies seen in patients with centrilobular emphysema
(CLE), extensive honeycomb cysts tend to share walls. The presence of
honeycombing on HRCT indicates the presence of severe lung fibrosis, and in
patients with a posterior, lower-lobe predominance, suggests usual interstitial
pneumonia (UIP). Other findings of fibrosis are also visible.
FIGURE 6-2 Honeycombing in a patient with idiopathic pulmonary fibrosis. On HRCT,
honeycombing cysts have clearly definable walls a few millimeters in thickness. When numerous,
the cysts occur in several layers and share walls.
FIGURE 6-3 Honeycombing with large lung cysts. In a patient with idiopathic pulmonary
fibrosis, peripheral honeycombing, traction bronchiectasis, and several large lung cysts (arrows)
are visible.
FIGURE 6-4 Idiopathic pulmonary fibrosis with asymmetric honeycombing and large lung
cysts. Peripheral honeycombing and irregular reticular opacities are associated with large lung
cysts. These are predominantly subpleural in location.
Large cystic spaces, several centimeters in diameter, can be associated with
honeycombing (Figs. 6-3 and 6-4). These large cysts tend to predominate in the
subpleural regions of the upper lobes, but may be seen at the lung bases as well;
they are most frequent in patients who have emphysema in combination with
fibrotic lung disease. These cysts may represent bullae or large honeycomb cysts
or a combination of both. In a patient with emphysema and UIP, although
emphysema predominates in the upper lobes and honeycombing in the lower
lobes, it is often difficult to determine where emphysema stops and
honeycombing starts. These large cysts may decrease in size on expiratory scans
(10–12).
CYSTIC LUNG DISEASE
A variety of diseases may result in lung cysts, either as a predominant feature or
in association with other abnormalities (Table 6-1). Although uncommon, three
diseases are responsible for most cases in which lung cysts are the predominant
HRCT finding; these are LCH (Figs. 6-5 to 6-8), LAM (including tuberous
sclerosis complex-associated LAM [TS-LAM]) (Figs. 6-9 to 6-11), and LIP (Fig.
6-12) (or follicular bronchiolitis) particularly associated with Sjögren syndrome
and other collagen-vascular diseases. Other causes of lung cysts include BirtHogg-Dube syndrome (Fig. 6-13) (13), amyloidosis (which may be associated
with lymphoproliferative disease in Sjögren syndrome) (14,15), light-chain
deposition disease (Fig. 6-14) (16,17), cystic metastases, benign metastasizing
leiomyoma (18), tracheobronchial papillomatosis (19), neurofibromatosis,
barotrauma in deep sea or scuba divers (Fig. 6-15), and Proteus syndrome (Fig.
6-16) (20). Cysts may be seen in association with other lung abnormalities in
hypersensitivity pneumonitis (HP), desquamative interstitial pneumonia (DIP)
and respiratory bronchiolitis-interstitial lung disease (RB-ILD), and interstitial
pneumonias with honeycombing.
FIGURE 6-5 LCH with lung cysts in a 47-year-old woman. A and B: HRCT shows numerous
lung cysts, of varying size and shape, involving the upper lobes. C: HRCT at the lung bases
shows the cysts to be smaller and less numerous. D: Section of this patient’s lung shows
extensive cystic disease with upper lobe predominance. The lung bases are relatively spared.
This distribution is typical of histiocytosis.
FIGURE 6-6 HRCT in a man with LCH. The cysts vary in size, and many are irregular in
shape. These findings are typical of this disease. (Courtesy of Marcia McCowin, San Francisco,
CA.)
FIGURE 6-7 A and B: LCH with upper lobe predominance. A: Multiple thin-walled cysts are
visible in the upper lobes. Confluence of cysts is visible, with some appearing clover leaf shaped.
B: Cysts are smaller and less numerous at the lung bases.
FIGURE 6-8 Early LCH in a 21-year-old patient who had been smoking for 5 years. A and B:
HRCT through the upper lobes shows small lung cysts, some irregular in shape associated with
small sharply marginated lung nodules. Some thick-walled cystic spaces may reflect cavitary
nodules. This combination is characteristic of early disease. The lung bases were normal.
FIGURE 6-9 HRCT in a patient with tuberous sclerosis and LAM. Cystic airspaces have
clearly defined walls measuring up to 2 mm in thickness.
FIGURE 6-10 HRCT in a woman with LAM. Cysts are rounder and more regular in size than
those seen in patients with Langerhans histiocytosis.
FIGURE 6-11 HRCT in a young woman with LAM. A: Cysts are round and very thin walled.
Intervening lung parenchyma appears normal. B: The lung bases are equally involved, as is
typical for LAM. C: HRCT 5 years later at the same level as A shows significant progression, with
the cysts appearing larger and more confluent. D: Sagittal slice of this patient’s lung removed at
transplantation shows a diffuse cystic abnormality involving the lung bases to the same degree as
the upper lobes.
FIGURE 6-12 Lung cysts in a 72-year-old woman with Sjögren syndrome and LIP. Cysts in
LIP are usually thin walled and less numerous than in patients with histiocytosis or LAM. Often,
vessels can be seen in association with the cyst walls.
FIGURE 6-13 Birt-Hogg-Dube syndrome in a 46-year-old woman, with multiple lung cysts
and pneumothorax. A and B: Cysts may involve the fissures and pleural surfaces, may be large,
and may be round or lenticular in shape, particularly when involving a pleural surface. They
predominate in the lower lobes.
FIGURE 6-14 Light-chain deposition disease with lung cysts. A and B: Multiple thin-walled
lung cysts are visible. As with LIP, vessels may be seen in relation to the cyst walls. There is a
small right pneumothorax.
FIGURE 6-15 Lung cysts in a 49-year-old scuba diver. Multiple thin-walled lung cysts are
visible, some involving the pleural surface and fissures.
FIGURE 6-16 Extensive cystic lung disease in a 20-year-old with Proteus syndrome.
TABLE 6-1 Differential Diagnosis of Cystic Lung Disease and Lung
Cysts
LAM, LCH, LIP, and other cystic lung diseases often show multiple discrete
lung cysts on HRCT, with intervening lung appearing normal or nearly normal
(Table 6-1) (15,21–32). The cysts have a thin but easily discernible wall in most
instances, ranging up to a few millimeters in thickness. Associated findings of
fibrosis are usually absent or much less conspicuous than they are in patients
with honeycombing and end-stage lung disease. Lung cysts may show a decrease
in size on expiratory scans, while this is characteristically absent in patients with
paraseptal emphysema and bullae (10–12). A decrease in cyst size has been
found on expiration in patients with honeycombing, LCH, LAM, cystic
bronchiectasis, and CLE.
Although several of the various causes of cystic lung diseases may have a
characteristic appearance that allows their distinction, overlap exists among the
HRCT findings in different diseases (33). In a study (33) of patients with chronic
cystic lung diseases, including Langerhans histiocytosis, LAM, UIP with
honeycombing, LIP, emphysema, and DIP and RB-ILD, interpreters made a
correct first-choice diagnosis in 80% of all readings, and they were confident in
93% of readings (which represented 57% of interpretations). The correct
diagnosis was made in 100% of cases of UIP, 81% of DIP or RB-ILD, 81% of
cases of LIP, 77% of emphysema, 72% of LAM, and 72% of LCH. Four cystic
lung diseases that may have characteristic features are described briefly in what
follows; cystic lung diseases are reviewed in greater detail in Chapter 16.
Langerhans Cell Histiocytosis
In adult patients with LCH, lung cysts can appear irregular or bizarre in shape,
with double cysts or clover leaf shapes seen in some patients (Figs. 6-5 to 6-7)
(34–37). Although irregularly shaped cysts can also be seen with LAM, they are
much less common and less numerous; also, cysts associated with LAM are
characteristically thin walled, while in LCH, cysts may be thick (Fig. 6-6) or thin
walled (Figs. 6-5 and 6-7). In early LCH, the cysts may be associated with small
nodules (Fig. 6-8), and a characteristic progression from nodules to cavitary
nodules to thick-walled cysts to thin-walled cysts may be seen in a patient over
time. In Langerhans histiocytosis, cysts (or cysts and nodules) have a distinct
upper-lobe predominance in size and number, and sparing of the costophrenic
angles is often seen in adults (38).
Lymphangiomyomatosis (Lymphangioleiomyomatosis)
In patients with LAM and TS-LAM, HRCT typically shows bilateral, thinwalled, rounded cysts, with a diffuse distribution, involving both upper and
lower lobes, and with involvement of the costophrenic angles (Figs. 6-9 to 6-11)
(39). In one study (30), CT showed diffuse lung involvement by cysts in 50%,
relative sparing of lung apices in 39%, and relative sparing of lung bases in 11%.
Cysts generally range from a few millimeters to 2 cm in diameter, and tend to be
larger and more numerous in patients with severe disease. Pleural effusion and
pneumothorax may be seen in as many as 22% of patients with LAM (30). Small
lung nodules may be associated with the cysts in some patients, and
abnormalities in the upper abdomen (e.g., angiomyolipoma) may also be seen.
CT quantitation of low-attenuation lung and cyst volume has shown significant
correlations with pulmonary function test (PFT) results in LAM (40).
Although LAM and TS-LAM are similar in appearance, some differences
have been reported. Avila et al. (39) compared the thoracic, abdominal, and
pelvic CT findings in 256 patients with LAM to those in 67 patients with TSLAM. Patients with LAM had more extensive lung involvement and higher
frequency of lymphangioleiomyoma (29% vs. 9%, p < 0.001), thoracic duct
dilatation (4% vs. 0, p = 0.3), pleural effusion (12% vs. 6%, p = 0.2), and ascites
(10% vs. 6%, p = 0.3). Patients with TS-LAM had higher frequency of
noncalcified pulmonary nodules (12% vs. 1%, p < 0.01), hepatic (33% vs. 2%, p
< 0.001) and renal (93% vs. 32%, p < 0.001) angiomyolipomas, nephrectomy
(25% vs. 7%, p < 0.001), or renal artery embolization (9% vs. 2%, p < 0.05)
(39). Another study found pleural effusion and pneumothorax to be somewhat
more common in TS-LAM (30).
Lymphoid Interstitial Pneumonia
Multiple thin-walled lung cysts are seen in some patients with LIP (Fig. 6-12) or
follicular bronchiolitis (15,28,29), particularly in patients with Sjögren
syndrome. Cysts tend to be less numerous than cysts occurring in patients with
histiocytosis or LAM, often limited to a few dozen or fewer (41). In one study of
22 patients with LIP, cystic airspaces were seen in 15; other findings of LIP
included small subpleural nodules, centrilobular nodules, interlobular septal
thickening, and ground-glass attenuation, but these findings do not usually occur
in combination with cysts (28). In patients with LIP, the cysts tend to
predominate in the lower lobes, and vessels are often associated with the walls of
cysts, a finding that can be helpful in diagnosis.
In some patients with Sjögren syndrome, cysts may show a combination of
lymphocytic infiltrate and deposition of amyloid or light chains, or amyloid or
light-chain deposition disease may be the primary abnormality contributing to
cyst formation (Fig. 6-14) (14,15,17). Solid nodules may also be associated (14).
Birt-Hogg-Dube Syndrome
This rare autosomal-dominant disorder is characterized by (a) lung cysts; (b)
fibrofolliculomas distributed over the face, neck, and upper trunk; and (c) renal
tumors ranging from benign oncocytoma to renal cell carcinoma (19). Lung
cysts are often thin walled, subpleural in location, and may be rounded or
lenticular in shape. Subpleural cysts, which may involve the fissures, are more
frequent than in other cystic diseases (Fig. 6-13). Cysts are often larger than
those in LAM and LCH, and predominate in the lower and medial lung zones
(42). Pneumothorax may result (13,42,43).
In one study (43), CT images of 17 patients with Birt-Hogg-Dube syndrome
were reviewed. Fifteen patients had cystic lung disease; the cysts varied in size
from 0.2 to 7.8 cm. Bilateral cysts were typical (87%). Cysts predominated in
the lower lobes in 87% and cysts were larger in this location. Cyst shape varied,
ranging from round to oval, lentiform, and multiseptated. Large lung cysts were
frequently multiseptated. Among the 15 patients, 5 (33%) had more than 20
cysts.
INCIDENTAL LUNG CYSTS
It is not uncommon to see a few thin-walled lung cysts in an otherwise normal
subject, unassociated with other HRCT abnormalities and without a history of
lung disease or symptoms. Lung cysts have been reported as a normal finding in
some elderly patients (44). In a study by Copley et al. (44), cysts were seen in 10
of 40 (25%) subjects in a group of subjects older than 75, but no subjects
younger than 55. The cysts ranged from 5 to 22 mm in diameter, and were seen
in all lobes. In this study, there was no correlation between the presence of cysts
and pulmonary function abnormalities or smoking history.
EMPHYSEMA
Emphysema is defined as a permanent, abnormal enlargement of airspaces distal
to the terminal bronchiole and accompanied by the destruction of the walls of the
involved airspaces (1,45). Emphysema can be accurately diagnosed using HRCT
(6,46–51) and results in focal areas of very low attenuation that can be easily
contrasted with surrounding higher-attenuation normal lung parenchyma if
sufficiently low window means (–600 to –800 Hounsfield units [HU]) are used.
Although some types of emphysema can have walls visible on HRCT, these are
usually inconspicuous. In many patients, it is possible to classify the type of
emphysema on the basis of its HRCT appearance (6,48).
Centrilobular Emphysema
CLE (proximal or centriacinar) is defined by preferential loss of alveolar septa in
the centers of pulmonary acini and pulmonary lobules, in relation to respiratory
bronchioles (45). The process affects the upper lungs more than lower lungs, and
posterior segments more than anterior. Cigarette smoking is the most common
cause of CLE.
CLE is characterized on HRCT by the presence of multiple small lucencies
that predominate in the upper lobes and, in some subjects or regions, may appear
centrilobular (Figs. 6-1 and 6-17 to 6-19). Even if the centrilobular location of
these lucencies is not visible, a spotty distribution is typical of CLE. In most
cases, the areas of low attenuation seen on HRCT in patients with CLE lack a
visible wall, although very thin walls are occasionally visible. Some smokers
with emphysema develop fibrosis in relation to emphysematous spaces, giving
rise to the presence of cysts with visible walls (36,37). The combination of
smoking-related emphysema and lung fibrosis is well recognized (36,37). In
severe cases, the areas of CLE may become confluent, resulting in bullae or in
regions of panlobular (panacinar) emphysema (PLE).
FIGURE 6-17 Centrilobular emphysema. A: In an inflated lung specimen, severe, but patchy,
emphysema is visible on the HRCT. The areas of destruction cluster around the centrilobular
arteries (arrows). (From Webb WR, Stein MG, Finkbeiner WE, et al. Normal and diseased isolated
lungs: HRCT. Radiology 1988;166:81, with permission.) B: On a slice of the inflated lung, some
lobules (large arrows) show extensive destruction. In some, the centrilobular artery remains
visible (small arrow) within the area of emphysema. C: Lung slice in a patient with CLE (arrows).
D: Histologic appearance of CLE. The areas of emphysema (E) surround the centrilobular
structures (arrow).
FIGURE 6-18 Centrilobular emphysema on HRCT. A: Spotty areas of lucency predominate in
the upper lobes. This appearance is typical and diagnostic. B: Detail view of the left upper lobe.
The focal lucencies of CLE lack visible walls, and the centrilobular artery (arrows) is visible in the
centers of some lucencies.
FIGURE 6-19 A–C: CLE on HRCT showing an upper lobe predominance. Spotty areas of
lucency predominate in the upper lobes (A), and some are centrilobular in location, surrounding
small vessels. At lower levels (B and C), lucencies are smaller in size and more normal lung is
visible.
Panlobular Emphysema
PLE is defined by uniform loss of alveolar septa throughout secondary lobules
(45). It typically results in an overall decrease in lung attenuation and a reduction
in size of pulmonary vessels, often without the focal areas of lucency typically
seen in patients with CLE (Figs. 6-1 and 6-20). Areas of panlobular emphysema
typically lack visible walls. This form of emphysema has been aptly described as
a diffuse simplification of lung architecture. Severe or confluent CLE also
results in this appearance (Figs. 6-21 and 6-22).
FIGURE 6-20 Panlobular emphysema in two patients. A: On HRCT, lung volumes are
increased, the lungs appear lucent, and the size of pulmonary vessels is diminished. Focal
lucencies, as seen in patients with CLE, are not visible. B: Panlobular emphysema in a patient
who has had a right lung transplantation. The right lung is normal in appearance and attenuation.
The emphysematous left lung is abnormally lucent, increased in volume, and contains fewer and
smaller visible vessels.
FIGURE 6-21 Panlobular emphysema due to confluent CLE. Areas of CLE have coalesced in
the posterior right lung (arrows), resulting in an area of very low attenuation typical of panlobular
emphysema. Mild interlobular septal thickening is also visible, usually indicative of some
associated fibrosis.
FIGURE 6-22 Confluent CLE in an isolated lung. On HRCT, areas of CLE have coalesced to
form peripheral bullae. These are marginated by residual septa. Because of its peripheral
location, this may be termed paraseptal emphysema.
PLE typically involves the lower lungs, with relative sparing of the upper
lobes, especially in nonsmokers. Alpha-1-antitrypsin deficiency is the most
common cause of PLE, but PLE also occurs with intravenous injection of
crushed methylphenidate (Ritalin) tablets, Swyer-James syndrome, old age, and
rarely from cigarette smoking (45).
Paraseptal Emphysema
Paraseptal (distal acinar) emphysema results in the presence of subpleural
lucencies, which often share very thin walls visible on HRCT; these walls may
correspond to interlobular septa. Paraseptal emphysema can be seen as an
isolated abnormality but is often associated with CLE (Figs. 6-1 and 6-22 to 624). Paraseptal emphysema affects the most distal parts of the acinus, the
alveolar sacs and ducts, and spares the respiratory bronchioles. It occurs most
commonly in the upper lobes, in a subpleural location, but it can also involve the
posterior lower lobes (45). Areas of emphysema may enlarge, resulting in
subpleural bullae.
FIGURE 6-23 A–C: Centrilobular and paraseptal emphysema. A: Centrilobular and
paraseptal emphysema are most extensive in the upper lobes. Paraseptal emphysema is visible
peripherally and along the mediastinal pleural surface. Individual emphysematous lesions 1 cm or
more in diameter are termed bullae. B and C: Both centrilobular and paraseptal emphysema are
less extensive at the lung bases. Although paraseptal emphysema mimics the appearance of
emphysema, it is unassociated with findings of fibrosis, and emphysema often predominates in
the lower lobes.
FIGURE 6-24 HRCT in a patient with paraseptal and CLE. The larger areas of subpleural
emphysema (arrows) are most appropriately termed bullae.
Irregular Airspace Enlargement
Irregular airspace enlargement, previously known as irregular or cicatricial
emphysema, can be seen in association with fibrosis, as in patients with silicosis
and progressive massive fibrosis or sarcoidosis (45,52,53).
Bullae and Bullous Emphysema
Bullous emphysema does not represent a specific histologic entity but represents
emphysema characterized primarily by large bullae (Figs. 6-1 and 6-25) (54). It
is often associated with centrilobular and paraseptal emphysema.
FIGURE 6-25 HRCT in a patient with paraseptal and CLE associated with large bullae. Small
lucencies lacking walls in the central lung (white arrows) represent CLE. Subpleural lucencies
(black arrow) reflect associated paraseptal emphysema. Large bullae are also subpleural in
location.
A bulla has been defined as a sharply demarcated area of emphysema
measuring 1 cm or more in diameter and possessing a thin epithelialized wall
that is usually no thicker than 1 mm (Figs. 6-25 and 6-26) (2–4). Although it is
not always possible to distinguish a bulla from a lung cyst, bullae are uncommon
as isolated findings, except in the lung apices, and are usually associated with
evidence of extensive centrilobular or paraseptal emphysema. Subpleural bullae
are often associated with paraseptal emphysema. When emphysema is associated
with predominant bullae, it may be termed bullous emphysema (54).
FIGURE 6-26 HRCT at three levels in a patient with combined honeycombing and
centrilobular and paraseptal emphysema. A: In the upper lobes, clear-cut areas of CLE (white
arrows) can be seen, with subpleural bullae due to paraseptal emphysema (black arrows). B: At a
lower level, findings of both emphysema and fibrosis are visible. Areas of paraseptal emphysema
are visible anteriorly (black arrows), whereas honeycombing and traction bronchiectasis are
visible in the posterior lung (white arrows). Paraseptal emphysema occurs in a single layer,
whereas honeycomb cysts may occur in multiple layers. C: Near the lung bases, findings of
honeycombing and fibrosis predominate.
On HRCT, bullae show a thin but distinct wall. Bullae can range up to 20 cm
in diameter but are usually between 2 and 8 cm in diameter. They can be seen in
a subpleural location or within the lung parenchyma, but subpleural bullae are
more frequent.
In patients with bullous emphysema, bullae are often asymmetric, with one
lung being involved to a greater degree (54). Idiopathic giant bullous
emphysema is a chronic, progressive condition usually affecting young male
smokers, characterized by large emphysematous bullae, most common in the
upper lobes, and occupying at least one-third of a hemithorax (55). Very large
bullae may mimic pneumothorax, and asymmetric lung involvement is typical.
Normal lung parenchyma is often displaced centrally and toward the lung bases,
resulting in significant atelectasis.
The term bleb is used pathologically to refer to a gas-containing space within
the visceral pleura or subpleural lung, no larger than 1 cm (2,4).
Radiographically, this term is sometimes used to describe a focal thin-walled
lucency contiguous with the pleura, usually at the lung apex. However, the
distinction between bleb and bulla based on size is of little practical significance
and is seldom justified. The term bulla is preferred (2,4).
Differentiation of Paraseptal Emphysema and
Honeycombing
The appearance of paraseptal emphysema may mimic that of honeycombing in
some cases, although a careful consideration of anatomical findings usually
allows them to be distinguished (45). In patients with paraseptal emphysema,
areas of lung destruction are typically marginated by thin linear opacities
extending to the pleural surface. These linear opacities often correspond to
interlobular septa, sometimes thickened by minimal fibrosis (Figs. 6-23 and 624). Areas of paraseptal emphysema usually occur in a single layer at the pleural
surface, predominate in the upper lobes, and may be associated with CLE or
other findings of emphysema such as large subpleural bullae, but are typically
unassociated with significant fibrosis. Honeycomb cysts are usually smaller, may
occur in several layers in the subpleural lung, tend to predominate at the lung
bases, and are associated with disruption of lobular architecture and other
findings of fibrosis, such as irregular reticulation and traction bronchiectasis. In
occasional patients, emphysema and honeycombing coexist. In such cases,
emphysema usually predominates in the upper lobes and central or subpleural
lung, whereas honeycombing predominates at the bases and in the subpleural
lung regions (Fig. 6-26). The HRCT appearance, however, may be confusing.
Differentiation of Centrilobular Emphysema and Lung
Cysts
In many patients with CLE, the focal areas of lucency that characterize this
condition lack visible walls, whereas lung cysts have walls recognizable on
HRCT. However, in some patients with CLE, areas of lung destruction show
very thin walls on HRCT, mimicking the appearance of lung cysts. These walls
likely reflect the presence of minimal lung fibrosis or compressed adjacent lung
parenchyma and are usually less well defined than those seen in patients with
cystic lung disease. Also, lung cysts often appear larger than areas of CLE,
which usually range from several millimeters to 1 cm. In patients with CLE,
lucencies can often be seen involving only one part of an otherwise normal-
appearing secondary lobule; this appearance is diagnostic.
CT Quantitation of Emphysema
Quantitation of emphysema and determining its distribution can be valuable in
determining treatment in patients with chronic obstructive pulmonary disease
(COPD). A number of studies have used CT to determine the COPD phenotype,
i.e., the relative proportions of emphysema and airways disease present in a
given patient (51,56–58).
The extent of emphysema may be estimated using a simple semiquantitative
scoring system, and this technique generally shows good correlation (r = 0.7–
0.9) with the pathologic extent of emphysema and good interobserver agreement
(51).
CT techniques employed for quantitation of emphysema include the density
mask technique, in which the percentage of lung pixels or voxels (i.e., pixel or
voxel index) with an attenuation less than a specific threshold is calculated.
Using thick slices (i.e., 10 mm), an attenuation of less than –910 HU has been
shown to best correlate with the extent of emphysema (47). With thin slices (i.e.,
1 mm), attenuation less than –950 HU best correlates with emphysema
morphology (56–60).
Another approach to emphysema quantitation involves obtaining a frequency
distribution (histogram) of pixel density measurements for the entire lung, and
determining the threshold value, in HU, below which there is a predetermined
percentage of voxels (61). Generally, percentile values between 5% and 15%
have been used for this determination, and 15% is most frequently employed
(57,58,61,62).
PNEUMATOCELE
Pneumatocele is defined as a thin-walled gas-filled space within the lung,
usually occurring in association with acute pneumonia, trauma, or hydrocarbon
aspiration, and is often transient (2,4). It is believed to arise from a combination
of lung necrosis or laceration and bronchiolar obstruction. Pneumatocele has an
appearance similar to lung cyst or bulla on HRCT and cannot be distinguished
on the basis of HRCT findings. The association of such an abnormality with
acute pneumonia, particularly resulting from Pneumocystis jirovecii or
Staphylococcus, would suggest the presence of a pneumatocele, but a spectrum
of cystic abnormalities can be seen in such patients (Figs. 6-27 and 6-28)
(63–65). Usually the cysts persist after resolution of the acute infection.
FIGURE 6-27 Two patients with P. jirovecii pneumonia. A: HRCT shows ground-glass opacity
typical of acute P. jirovecii infection and focal lung cysts likely representing pneumatoceles. B: In
this patient, some ground-glass opacity is visible in the right lung, but cystic spaces on the left
largely reflect a prior P. jirovecii pneumonia.
FIGURE 6-28 HRCT at two levels in an AIDS patient with recurrent P. jirovecii pneumonia
associated with pneumatoceles and pneumothorax. A: Patchy areas of ground-glass opacity are
associated with a number of small cystic spaces representing pneumatoceles. A moderate
pneumothorax is present on the right, and a small pneumothorax is visible on the left. B: At a
lower level, one of the cystic lesions (arrow) in the right lung is visible protruding into the air-filled
pleural space. The rupture of such a lesion likely accounts for the pneumothorax.
CAVITARY NODULES
A cavity is an air-filled space, seen as a lucency within an area of pulmonary
consolidation, mass or nodule. A cavity is usually produced by the expulsion or
drainage of an area of necrosis (2). A thin-walled air-filled space should not
generally be referred to as a “cavity” unless it is known that cavitation, i.e.,
necrosis and expulsion of necrotic material, has occurred.
Cavitary nodules usually have thicker and more irregular walls than lung
cysts, but there is some overlap between these appearances (Figs. 6-8, 6-29, and
6-30). In patients with diffuse lung diseases, cavitary nodules have been reported
in LCH (Fig. 6-8) (21,22), tuberculosis (66), fungal infections, and sarcoidosis
(67), but they can also be seen in patients with such disorders as rheumatoid lung
disease, septic embolism, pneumonia, metastatic tumor, tracheobronchial
papillomatosis (Fig. 6-30), benign metastasizing leiomyoma, and granulomatosis
with polyangiitis (Wegener granulomatosis). Some metastases may have very
thin walls.
FIGURE 6-29 Cavitary nodules in a patient who has AIDS with a fungal pneumonia. Nodules
appear both solid and cavitary. The cavitated nodule in the right upper lobe is thick walled.
FIGURE 6-30 A–C: Cavitary nodules or cysts in a patient with tracheobronchial
papillomatosis. Thin-walled cystic lesions are visible, with a predominance in the right lung.
Associated nodules may be seen within cysts (A, arrow) or within lung parenchyma (C, arrow).
BRONCHIECTASIS
Bronchiectasis is generally defined as localized, irreversible bronchial dilatation,
often associated with thickening of the bronchial wall (2,3,68). Generally
speaking, a bronchus is considered to be dilated if the bronchoarterial ratio (its
internal diameter divided by the diameter of its accompanying artery) exceeds
one (Fig. 6-31). However, this appearance is sometimes seen in normal subjects
living at altitude or in elderly patients (see Chapter 2) (69,70). Also, a bronchus
may normally appear larger than the adjacent artery if the scan traverses an
undivided bronchus near its branch point, and its accompanying artery has
already branched. In this situation, two artery branches may be seen to lie
adjacent to the “dilated” bronchus (Figs. 6-31 and 6-32). The presence of
bronchial wall thickening in addition to an increase in bronchial diameter can be
helpful in diagnosing true bronchiectasis. Also, fluid, mucus, or pus may fill
bronchi in patients with bronchiectasis, resulting in bronchial impaction.
FIGURE 6-31 Bronchiectasis and pseudobronchiectasis. Bronchiectasis is considered to be
present if the internal diameter of a bronchus is greater than that of its accompanying artery (i.e.,
the signet ring sign) (large white arrow). In the left lower lobe, a bronchus appears to be dilated
because its adjacent artery has divided into two branches (small white arrows). In the left upper
lobe (black arrow), a cardiac pulsation or “doubling” artifact results in the appearance of
bronchiectasis.
FIGURE 6-32 Bronchiectasis. A: Dilated bronchi in the anterior lung are seen extending to
the pleural surface. Bronchi are not normally visible in the peripheral 1 cm of lung. The dilated
bronchi appear largely cylindrical (large arrow). The signet ring sign (small arrow) is visible
posteriorly. Note that bronchial walls are thickened. B: Cylindrical bronchiectasis in another
patient is associated with the signet ring sign (large arrow). A smaller bronchus is thick walled and
is contiguous with a tree-in-bud in the more peripheral lung (small arrows). C: At a lower level in
the patient shown in B, mucous plugging of dilated bronchi in the lower lobes (arrows) has a
nodular appearance. D: Bronchiectasis (arrows) in a lung specimen. (Courtesy of Martha
Warnock, MD.)
Although bronchiectasis usually results from chronic infection, airway
obstruction by tumor, stricture, impacted material, or inherited abnormalities can
also play a significant role. The HRCT diagnosis of bronchiectasis is described
in detail in Chapter 20.
Types of Bronchiectasis
Bronchiectasis is usually classified morphologically, in relation to its appearance
on CT or pathology, as cylindrical, varicose, or cystic (saccular) (Fig. 6-1).
Generally, this classification correlates with the degree of bronchial abnormality
and a reduction in bronchial divisions, but other factors are generally more
important in predicting abnormalities in lung function and symptoms (1). In
patients with bronchiectasis, the extent of bronchiectasis, the presence of
bronchial wall thickening, and associated small airway abnormalities, such as
mosaic perfusion, are associated with exacerbation frequency, symptoms such as
sputum volume, and airflow obstruction on PFTs (71). Using multivariate
analysis, bronchial wall thickening was found to be a significant determinant of
airflow obstruction, whereas small airway abnormalities were associated with
sputum volume (71).
Cylindrical Bronchiectasis
Cylindrical bronchiectasis, the mildest form of this abnormality, is characterized
on HRCT by the presence of thick-walled bronchi that extend into the lung
periphery and fail to show normal tapering. On HRCT, bronchi are not normally
visible in the peripheral 1 cm of lung, but in patients with bronchiectasis, with
bronchial wall thickening, peribronchial fibrosis, and dilatation of the bronchial
lumen, bronchi can often be seen in the lung periphery (Figs. 6-1, 6-32, and 633) (72,73). Depending on their orientation relative to the scan plane, dilated
bronchi can simulate tram tracks or can show the signet ring sign, in which the
dilated, thick-walled bronchus and its accompanying pulmonary artery branch
are visible adjacent to each other (74). Ectatic bronchi containing fluid or mucus
appear as tubular opacities. Cylindrical bronchiectasis is often associated with
chronic airway infection.
FIGURE 6-33 Morphologic types of bronchiectasis. A: Cylindrical bronchiectasis in a patient
with cystic fibrosis. Bronchi in the right upper lobe (arrow) are roughly cylindrical in shape and
show a lack of tapering. B: Varicose bronchiectasis (arrow) in a patient with allergic
bronchopulmonary aspergillosis. The bronchus is quite irregular in contour. C: Cystic
bronchiectasis involving the right middle lobe. The focal distribution allows distinction of this entity
from cystic lung disease, such as in LAM.
In patients with acute infection, inflammatory lung disease, or focal
atelectasis, transient bronchial dilatation may be seen, mimicking the appearance
of cylindrical bronchiectasis. With resolution of the acute pulmonary
abnormality, such bronchi may return to normal in appearance. This occurrence
has been described as “reversible bronchiectasis,” an oxymoron. One should be
cautious in making the diagnosis of cylindrical bronchiectasis, when an acute or
subacute lung abnormality is present.
Varicose Bronchiectasis
Varicose bronchiectasis is similar in appearance to cylindrical bronchiectasis;
however, with varicose bronchiectasis, the bronchial walls are more irregular and
can assume a beaded appearance (Figs. 6-1, 6-33, and 6-34). The term string of
pearls has been used to describe varicose bronchiectasis. Varicose bronchiectasis
is common in cystic fibrosis and allergic bronchopulmonary aspergillosis.
FIGURE 6-34 Bronchiectasis in a patient with cystic fibrosis. A: In the upper lung, multiple
dilated thick-walled bronchi are present. The signet ring sign is visible (arrow). B: Irregular or
varicose bronchiectasis is visible in the anterior right lung (large white arrow). Mucous plugging of
bronchi is also visible (small white arrows), as is tree-in-bud (black arrows). C: Multiple dilated
bronchi with examples of the signet ring sign are also visible at the lung bases.
Cystic Bronchiectasis
Cystic bronchiectasis most often appears as a group or cluster of thin-walled airfilled cysts, but cysts can also be fluid filled, giving the appearance of a bunch of
grapes. Cystic bronchiectasis is often patchy in distribution, and may be lobar,
allowing it to be distinguished from a diffuse cystic lung disease such as LAM
(Figs. 6-1 and 6-34). Air-fluid levels may be present in the dependent portions of
the cystic, dilated bronchi. In a patient with multiple lung cysts, air-fluid levels
suggest bronchiectasis; they are not usually seen in patients with a diffuse cystic
lung disease such as LAM or LCH. Cystic bronchiectasis often reflects an early
childhood infection.
Traction Bronchiectasis
In patients with lung fibrosis and distortion of lung architecture, traction
bronchiectasis is commonly present (Figs. 3-27, 3-28, 3-30, and 6-35). In this
condition, traction by fibrous tissue on the walls of bronchi results in irregular
bronchial dilatation, or bronchiectasis, which is typically varicose in appearance
(2,6,75). Traction bronchiectasis usually involves the segmental and
subsegmental bronchi and can also affect small peripheral bronchi or
bronchioles. Dilatation of intralobular bronchioles because of surrounding
fibrosis is termed traction bronchiolectasis. In patients with honeycombing,
bronchiolar dilatation contributes to the cystic appearance seen on HRCT (7).
Traction bronchiectasis does not reflect airways disease and is unassociated with
symptoms of airways disease (e.g., sputum production) or typical pulmonary
function abnormalities (e.g., airway obstruction).
FIGURE 6-35 Traction bronchiectasis in a patient with idiopathic pulmonary fibrosis. Dilated
bronchi in association with reticular opacities are visible in the lung bases.
The increased transpulmonary pressure and elastic recoil associated with
advanced pulmonary fibrosis, along with local distortion of airways by fibrotic
tissue, contribute to the varicose dilatation of airways in traction bronchiectasis.
Because of peribronchial interstitial thickening, bronchial walls can appear to
measure up to several millimeters in thickness. Traction bronchiectasis is usually
most marked in areas of lung that show the most severe fibrosis. It is commonly
seen in association with honeycombing, as is bronchiolectasis. Mucoid
impaction or air-fluid levels are characteristically absent.
ALGORITHMIC APPROACH TO THE DIAGNOSIS OF
CYSTIC AIRSPACES
The differential diagnosis of abnormalities associated with cystic airspaces
includes honeycombing, emphysema, lung cysts, pneumatoceles, and
bronchiectasis. Air-filled cystic spaces first may be classified as subpleural or
intraparenchymal for the purposes of differential diagnosis (Fig. 6-36). Air-filled
cystic spaces in the subpleural regions may represent paraseptal emphysema or
honeycombing. Both have distinct walls. Paraseptal emphysema is usually
distinguishable from honeycombing because the cystic spaces occur in a single
layer, whereas honeycomb cysts usually occur in multiple layers. Areas of
paraseptal emphysema can also be larger (bullae) than typical honeycomb cysts.
Paraseptal emphysema tends to have upper lobe predominance and may be
associated with CLE, whereas honeycombing usually has lower lobe
predominance and is associated with findings of fibrosis.
FIGURE 6-36 Algorithmic approach to cystic airspaces in the subpleural lung.
Intraparenchymal cystic airspaces (i.e., those not occurring primarily at the
pleural surface) can represent CLE, lung cysts, dilated bronchi, or
pneumatoceles (Fig. 6-37). In patients with CLE, areas of lucency do not usually
have recognizable walls, have an upper lobe distribution in most patients, are
relatively small (less than 1 cm in diameter), have a spotty distribution, and may
sometimes be seen surrounding a centrilobular artery. Cystic bronchiectasis may
result in clustered or scattered thin-walled cystic airspaces. The correct diagnosis
may be suggested if air-fluid levels or other findings of bronchiectasis are
visible. The term lung cyst is used to describe a thin-walled, well-defined, and
well-circumscribed air-containing lesion. Although there are a number of causes
of cystic lung disease, the algorithm in Fig. 6-37 reviews only the diseases most
frequently seen; the appearances of other causes are listed in Table 6-1.
FIGURE 6-37 Algorithmic approach to intraparenchymal cystic airspaces.
LCH and LAM result in multiple lung cysts (21–27). The cysts have a thin but
easily discernible wall, ranging up to a few millimeters in thickness. Associated
findings of fibrosis are usually absent or much less conspicuous than they are in
patients with honeycombing. In these diseases, the cysts are usually interspersed
within areas of normal-appearing lung. In patients with LCH, the cysts can have
bizarre shapes, typically have upper lobe predominance, and may occur in men.
LAM is associated with rounder and more uniformly shaped cysts, is diffusely
distributed from apex to base, and exclusively occurs in women. Cysts are
sometimes seen in patients with LIP associated with Sjögren syndrome, AIDS,
or other systemic diseases; cystic airspaces in LIP have thin walls, measure 1 to
30 mm in diameter, and are typically less numerous than those in LCH and LAM
(15,28,76). They may be associated with vessels, and cysts in amyloidosis or
light-chain disease, also associated with Sjögren syndrome, may have a similar
appearance. Cysts representing pneumatoceles can be seen in patients with
infection, particularly P. jirovecii pneumonia; pneumatoceles are often scattered
and patchy in distribution and limited in number, and findings of pneumonia or a
history of pneumonia may be present. Scattered cysts are also seen in association
with lung disease in patients with HP and DIP. Birt-Hogg-Dube syndrome is
associated with large subpleural cysts, renal tumor, and skin lesions.
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7
HRCT Findings: Decreased Lung Attenuation
IMPORTANT TOPICS
MOSAIC PERFUSION
THE MOSAIC ATTENUATION PATTERN: DIFFERENTIATION OF MOSAIC PERFUSION FROM
GROUND-GLASS OPACITY
MIXED DISEASE AND THE HEADCHEESE SIGN
AIR TRAPPING ON EXPIRATORY HRCT
Abbreviations Used in This Chapter
COPD
chronic obstructive pulmonary disease
CPTE
chronic pulmonary thromboembolism
DIP
desquamative interstitial pneumonia
DLCO
diffusing capacity
FEF
forced expiratory flow
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity
GGO
ground-glass opacity
HU
Hounsfield units
LIP
lymphoid interstitial pneumonia
PFT
pulmonary function test
PH
pulmonary hypertension
PI
pixel index
RB-ILD
respiratory bronchiolitis-interstitial lung disease
In this chapter, we will discuss causes, patterns, and diseases associated with
decreased lung attenuation, not due to lung destruction or cystic airspaces, which
were reviewed in Chapter 6. These include mosaic perfusion, the mosaic
attenuation pattern, the headcheese sign, and air trapping on expiratory scans.
MOSAIC PERFUSION
Lung density and attenuation are partially determined by the volume of blood
present within pulmonary vessels. Thus, regional differences in lung perfusion in
patients with airways disease or pulmonary vascular disease can result in
inhomogeneous lung opacity on high-resolution computed tomography (HRCT)
(1–5). Because this is often patchy or “mosaic” in distribution, with different
regions of lung being of differing attenuation, it has been termed mosaic
perfusion (6) or mosaic oligemia (7), although the former term is most
appropriate (8). This can result from airways or vascular disease.
Areas of relatively decreased lung opacity seen on HRCT can be of varying
sizes and sometimes appear to correspond to lobules, segments, lobes, or an
entire lung (Figs. 7-1 to 7-5). In almost all cases, mosaic perfusion is seen in
association with diseases causing regional decreases in lung perfusion. However,
differences in attenuation between normal and abnormal lung regions
recognizable on HRCT are accentuated by compensatory increased perfusion of
normal or relatively normal lung areas.
FIGURE 7-1 A and B: Mosaic perfusion in two patients with cystic fibrosis. In each patient,
vessels appear larger in relatively dense lung regions, a finding of great value in making the
diagnosis of mosaic perfusion. The relatively dense lung regions are normally perfused or
overperfused because of shunting of blood away from the abnormal areas. Also note that
abnormal airways (i.e., bronchiectasis, bronchial wall thickening, tree-in-bud) are visible in
relatively lucent lung regions. These areas are poorly ventilated and poorly perfused.
FIGURE 7-2 HRCT in a patient with bronchiolitis obliterans related to rheumatoid arthritis.
Bronchiectasis is visible, along with patchy lung attenuation, a finding that reflects mosaic
perfusion. Note that the pulmonary vessels in the lucent-appearing peripheral left lung (black
arrows) are smaller than vessels in the denser medial left lung (white arrows).
FIGURE 7-3 HRCT in a 9-year-old boy with postinfectious bronchiolitis obliterans. Patchy
areas of mosaic perfusion are visible, with decreased vascular size within the lucent regions.
Some lucent regions are lobular; this is typical of an airway abnormality.
FIGURE 7-4 A and B: HRCT in a bone marrow transplant recipient with bronchiolitis
obliterans. Patchy areas of mosaic perfusion are visible, associated with findings of
bronchiectasis. In patients with bronchiolitis obliterans, bronchiectasis is commonly visible.
FIGURE 7-5 Mosaic perfusion with patchy lung attenuation in two patients with pulmonary
embolism. A: Multidetector-row HRCT in a patient with extensive acute pulmonary embolism;
patchy mosaic perfusion is visible. Vessels appear smaller in the lucent lung regions. B and C: In
a patient with chronic pulmonary embolism, vessels appear smaller in the large low-attenuation
regions in the peripheral lung. Large lucent regions are typical of CPTE.
Mosaic perfusion is most frequent in patients with airways diseases that result
in focal air trapping or poor ventilation of lung parenchyma (Figs. 7-1 to 7-4)
(1–3); in these patients, areas of poorly ventilated lung are poorly perfused
because of reflex vasoconstriction or because of a permanent reduction in the
pulmonary capillary bed. In our experience, this finding has been most common
in patients with bronchiolitis obliterans (constrictive bronchiolitis) (Figs. 7-2 to
7-4) or other diseases associated with small airways obstruction such as cystic
fibrosis, infections, bronchiectasis, and cellular bronchiolitis, but it can also be
seen as a result of large bronchial obstruction (9–11). Mosaic perfusion also
occurs in association with pulmonary vascular obstruction such as that caused by
chronic pulmonary embolism (Fig. 7-5) (7,12,13).
Regardless of its cause, when mosaic perfusion is present, pulmonary vessels
in the areas of decreased opacity usually appear smaller than vessels in relatively
dense areas of lung (3,13) (Figs. 7-1 to 7-5). This discrepancy reflects
differences in regional blood flow and can be quite helpful in distinguishing
mosaic perfusion from patchy ground-glass opacity (GGO), which can have a
similar 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 airways disease, Im et al. (14) observed
smaller vessels in areas of low attenuation in 93.8% of cases. It must be pointed
out, however, that decreased vessel size may be subtle and difficult to observe in
some patients with mosaic perfusion as the cause of inhomogeneous lung
attenuation. In a blinded study by Arakawa et al. (15) of patients with
inhomogeneous lung opacity of various causes, only 68% of patients with
airways or vascular disease were believed to show small vessels in areas of low
attenuation. In patients with inhomogeneous lung attenuation, if a confident
diagnosis of mosaic perfusion or patchy ground-glass opacity cannot be made,
the abnormal appearance may be referred to using the less specific term mosaic
attenuation pattern (4), described in what follows.
Decreased lung attenuation, when diffuse, can reflect panlobular emphysema
or diffuse airways disease with air trapping (1,2). This distinction can be very
difficult to make.
Mosaic Perfusion Due to Airways Disease
In patients with mosaic perfusion resulting from airways disease, abnormally
dilated or thick-walled airways (i.e., bronchiectasis) may be visible in the
relatively lucent lung regions, thus suggesting the correct diagnosis (3,5,11,15).
In one study (16), abnormal airways were seen in 70% of patients with airways
disease and mosaic lung attenuation (Figs. 7-1, 7-2, and 7-4). Mosaic perfusion
can be seen in a variety of airways diseases, including bronchiectasis, cystic
fibrosis, hypersensitivity pneumonitis, and constrictive bronchiolitis. In patients
with mosaic perfusion secondary to airways disease, lobular areas of low
attenuation are common (Fig. 7-3); these are much less frequent in patients with
vascular obstruction. Air trapping on expiratory scans, described later in this
chapter, is often helpful in confirming the diagnosis.
Mosaic Perfusion Due to Vascular Disease
Heterogeneous lung attenuation is common in patients with acute or chronic
pulmonary thromboembolism (CPTE), and decreased vessel size in relatively
lucent regions is often visible (Fig. 7-5B,C) (17,18). In a study of pulmonary
parenchymal abnormalities in 75 patients with CPTE, 58 patients (77.3%)
showed mosaic perfusion with normal or dilated arteries in areas of
hyperattenuation (13); areas of relatively increased attenuation averaged –727
Hounsfield units (HU), whereas areas of decreased attenuation averaged –868
HU. In another study of patients with pulmonary hypertension (PH) due to
CPTE, PH of other causes, and a variety of other pulmonary diseases, HRCT
was believed to show mosaic perfusion in all patients with CPTE (19).
Considerably more variation in vessel size in different lung regions was also
visible in the patients with CPTE. Overall, HRCT had sensitivities of 94% to
100% and specificities of 96% to 98% in diagnosing CPTE (19).
Mosaic perfusion is less frequent in patients with acute pulmonary embolism
(Fig. 7-5A) (20,21). For example, Arakawa et al. (22) reported mosaic perfusion
in 47% of patients with pulmonary embolism, most of whom had acute
pulmonary embolism; in most of these patients, the mosaic perfusion was likely
related to bronchoconstriction and air trapping. Mosaic perfusion may also be
seen in patients with large-vessel vasculitis resulting in pulmonary artery
stenosis. These include Takayasu arteritis and giant cell arteritis (23).
The frequency with which mosaic perfusion is seen on CT in patients with
various causes of PH has been studied by Sherrick et al. (24). Of 23 patients
with PH caused by vascular disease, 17 patients (74%) had mosaic perfusion; 12
of these had chronic pulmonary embolism. Of 21 patients with PH associated
with lung disease, 1 patient (5%) had mosaic perfusion. Among 17 patients with
PH caused by cardiac disease, 2 patients (12%) had mosaic perfusion (24).
In patients with vascular disease as a cause of mosaic perfusion, areas of low
attenuation are usually larger than lobules, representing segments, lobes, or
larger nonanatomic lung regions (e.g., the peripheral lung) (Fig. 7-5). In patients
with mosaic perfusion occurring in association with CPTE, enlargement of the
main pulmonary arteries may be visible because of PH (see Chapter 22).
THE MOSAIC ATTENUATION PATTERN: DIFFERENTIATION
OF MOSAIC PERFUSION FROM GROUND-GLASS OPACITY
The presence of inhomogeneous lung attenuation on HRCT is a common
finding; in one study, inhomogeneous lung opacity was the predominant HRCT
abnormality in 19% of scans reviewed (15). This appearance can be a diagnostic
dilemma, resulting from several possible causes. These include (a) ground-glass
opacity, (b) mosaic perfusion resulting from airways obstruction and reflex
vasoconstriction, (c) mosaic perfusion resulting from vascular obstruction, or (d)
a combination of these (i.e., mixed disease). If the cause of the inhomogeneous
lung opacity is not readily apparent, it may be described using the terms mosaic
pattern or mosaic attenuation pattern (4,25). However, most cases of
inhomogeneous opacity can be correctly classified as one of these four
possibilities based on HRCT findings (15,16).
On inspiratory scans, it is often possible to distinguish between ground-glass
opacity, mosaic perfusion caused by airways disease, and mosaic perfusion
caused by vascular disease (Fig. 7-6). In two studies (15,16), an accurate
distinction was possible in more than 80% of cases based on HRCT findings.
The use of expiratory scanning, described in the next section, is of further value
in making this distinction.
FIGURE 7-6 Algorithmic approach to inhomogeneous lung opacity. CL, centrilobular; PE,
pulmonary embolism; PA, pulmonary artery.
The most important HRCT finding in determining the presence of mosaic
perfusion is reduced vessel size in lucent lung regions. If reduced vessel size is
visible in lucent regions, a confident diagnosis of mosaic perfusion can usually
be made. Also, in patients with mosaic perfusion, some lung regions may appear
too lucent to be normal, but this is somewhat subjective and based on experience
with the window settings used for scan viewing.
In patients with mosaic perfusion resulting from airways disease, abnormally
dilated or thick-walled airways (i.e., bronchiectasis) may be visible in the
relatively lucent lung regions (Figs. 7-1 to 7-3), suggesting the proper diagnosis;
this is visible in approximately 70% of cases and can be very helpful in the
diagnosis (10,26–29). Furthermore, lobular areas of lucency are common in
patients with airways disease (Fig. 7-3). In a study by Im et al. (14) of 48
consecutive patients with lobular areas of low attenuation seen on HRCT, 46
(95%) had symptoms related to respiratory disease, such as productive cough (n
= 25) and hemoptysis (n = 18). Only two patients with this appearance, one with
CPTE and one with Takayasu arteritis combined with bronchiectasis, had
pulmonary vascular disease.
In patients with vascular obstruction (e.g., CPTE) as a cause of mosaic
perfusion, dilatation of central pulmonary arteries may be present as a result of
PH, lobular areas of lucency are typically absent, and larger areas of low
attenuation are usually visible (Fig. 7-5B,C).
Ground-glass opacity may be accurately diagnosed as the cause of
inhomogeneous lung opacity if it is associated with other findings of infiltrative
disease such as consolidation, reticular opacities (i.e., the crazy-paving pattern),
or nodules (see Chapter 5). Also, a pattern in which the areas of higher
attenuation are centrilobular almost always represents ground-glass opacity with
a centrilobular distribution. This pattern is not seen with mosaic perfusion
resulting from airways disease; it is very uncommonly the result of vascular
disease with mosaic perfusion.
Ground-glass opacity may also result in very ill-defined and poorly
marginated areas of increased opacity, lacking the sharply marginated and
geographic appearance sometimes seen in patients with mosaic perfusion.
Ground-glass opacity can often be diagnosed simply because the lung looks too
dense, although this is quite subjective and depends on using consistent window
settings and being familiar with the appearance of normal lung parenchyma.
MIXED DISEASE AND THE HEADCHEESE SIGN
In occasional patients with the mosaic attenuation pattern, inspiratory scans
show a patchy pattern of variable lung attenuation, representing the combination
of ground-glass opacity (or consolidation) and reduced lung attenuation as a
result of mosaic perfusion. This combination of mixed attenuation, including the
presence of mosaic perfusion, often gives the lung a geographic appearance and
has been termed the headcheese sign because of its resemblance to the
variegated appearance of a sausage made from the chopped parts of the head of a
hog or other animal (Figs. 7-7 to 7-9) (30,31). If you can be sure that both
ground-glass opacity or consolidation and mosaic perfusion are visible (rather
than one or the other), the headcheese sign is present. Air trapping is commonly
visible on expiratory scans when the headcheese sign is seen (Fig. 7-9).
FIGURE 7-7 A–D: Headcheese and the headcheese sign. A and B: A slice of headcheese
shown in color and black and white has a variegated appearance, consisting of chunks of different
meats from the head of a hog. In the black-and-white image, some areas appear dark, some
appear light, and some are gray. C and D: Mycoplasma pneumonia with the headcheese sign.
Inspiratory images show inhomogeneous lung attenuation consisting of ground-glass opacity and
multiple lobular areas of lucency due to mosaic perfusion, secondary to bronchiolitis. Note small
or invisible vessels in lucent regions. Air trapping was present on expiratory scans.
FIGURE 7-8 The headcheese sign. A: In a patient with hypersensitivity pneumonitis, lobular
areas of lucency (red arrows) reflect mosaic perfusion associated with cellular bronchiolitis and
bronchiolar obstruction. Patchy areas of ground-glass opacity and ground-glass opacity
centrilobular nodules are visible. B: Ground-glass opacity and lobular mosaic perfusion in a
patient with DIP.
FIGURE 7-9 The headcheese sign and air trapping in hypersensitivity pneumonitis. A:
Lobular areas of lucency reflect mosaic perfusion associated with cellular bronchiolitis and
bronchiolar obstruction. Diffuse ground-glass opacity is present, with some centrilobular nodules
visible. B: On a postexpiratory scan, air trapping is seen within the lucent lobules. Lung showing
ground-glass opacity increases in attenuation.
The headcheese sign is often indicative of mixed infiltrative and obstructive
disease, usually associated with bronchiolitis (30,31). In patients with this
appearance, the presence of ground-glass opacity or consolidation is caused by
lung infiltration, whereas the presence of mosaic perfusion with decreased vessel
size is usually caused by small airway obstruction.
The most common causes of this pattern (Table 7-1) are hypersensitivity
pneumonitis (Figs. 7-8A and 7-9), sarcoidosis, atypical (viral or mycoplasma)
infections with associated bronchiolitis (Fig. 7-7), desquamative interstitial
pneumonia (DIP) (Fig. 7-8B) or respiratory bronchiolitis-interstitial lung disease
(RB-ILD) associated with ground-glass opacity and bronchiolar obstruction, and
sometimes lymphoid interstitial pneumonia (LIP) with follicular bronchiolitis;
occasionally, pulmonary edema may result in this pattern. Each of these diseases
results in an infiltrative abnormality and may be associated with airway
obstruction. This combination may also be seen in patients with two
abnormalities, an infiltrative process coexisting with an airways disease, such as
asthma.
TABLE 7-1 Differential Diagnosis of Mixed Disease (the
Headcheese Sign)
Diagnosis
Comments
Hypersensitivity pneumonitis
Atypical pneumonia
Sarcoidosis
DIP and RB-ILD
LIP
Pulmonary edema
HP the most common cause; lobular MP and air trapping with
patchy or centrilobular GGO; MP and air trapping also seen
with fibrotic disease
Patchy GGO or consolidation with MP and air trapping; viral
and mycoplasma infections most typical
MP and air trapping commonly seen; GGO uncommon
Air trapping in a few percent of patients, associated with GGO
and cysts
Patchy ground-glass may be seen with LIP; follicular
bronchiolitis may result in MP or air trapping
An uncommon manifestation; air trapping may reflect a
coexistent airway abnormality or “cardiac asthma”
AIR TRAPPING ON EXPIRATORY HRCT
Obtaining HRCT scans at selected levels after expiration may be useful in (a) the
diagnosis of air trapping in patients with obstructive lung disease, including
chronic obstructive pulmonary disease (COPD) (15,28,29,32–34), (b) the
diagnosis of airways disease unassociated with distinct morphologic
abnormalities on inspiratory images (35), (c) distinguishing mosaic perfusion
from ground-glass opacity (15,16), and (d) allowing the diagnosis of mixed
infiltrative and obstructive diseases (Fig. 7-9) (15,36,37).
Diagnosis of Air Trapping
Expiratory HRCT scans have proved useful in the evaluation of patients with a
variety of lung diseases characterized by obstruction of airflow (10,11). Air
trapping visible using dynamic expiratory or postexpiratory HRCT techniques
has been recognized in patients with emphysema (27,38,39), COPD (32–34),
asthma (40–44), cystic fibrosis (45), bronchiolitis obliterans and bronchiolitis
obliterans syndrome (2,5,27,35,46–55), the cystic lung diseases associated with
Langerhans histiocytosis and tuberous sclerosis (56), bronchiectasis (27,57),
airways disease related to AIDS (58), and small airways disease associated with
thalassemia (59). Expiratory HRCT has also proved valuable in demonstrating
the presence of bronchiolitis in patients with primarily infiltrative diseases such
as hypersensitivity pneumonitis (37,60–62), sarcoidosis (36,63), and pneumonia.
Air trapping may also be seen in patients with acute pulmonary embolism or
CPTE; Arakawa et al. (22) reported this finding in 60% of patients with
pulmonary embolism, presumably due to bronchoconstriction.
It must be understood that limited air trapping can be seen in normal subjects,
particularly in the superior segments of the lower lobes, in scattered secondary
lobules, and in dependent lung regions. Abnormal air trapping differs from this
in extent. Expiratory CT techniques and normal findings are described in
Chapters 1 and 2.
Lung Attenuation Abnormalities in the Diagnosis of Air Trapping
In normal subjects, lung increases significantly in attenuation during expiration
(Figs. 2-30 to 2-32; Fig. 7-10). In the presence of airway obstruction and air
trapping, the lung remains lucent on expiration and shows little change in a
cross-sectional area. Areas of air trapping are seen as relatively low in
attenuation on expiratory scans.
FIGURE 7-10 Normal postexpiratory HRCT. Inspiratory image (A) shows homogeneous lung
attenuation. B: After expiration, there has been a significant reduction in lung volume associated
with an increase in lung attenuation. Lung attenuation remains homogeneous. Note flattening of
the posterior tracheal membrane.
On expiratory HRCT, the diagnosis of air trapping is easiest to make when the
abnormality is patchy in distribution, and normal lung regions can be contrasted
with abnormal, lucent lung regions (Figs. 7-11 to 7-15) (3,11). Areas of air
trapping can be patchy and nonanatomical; can correspond to individual
secondary pulmonary lobules, segments, and lobes; or may involve an entire
lung (26,64). Air trapping in a lobe or lung is usually associated with large
airway or generalized small airway abnormalities, whereas lobular or segmental
air trapping is associated with diseases that produce small airway abnormalities
(26). Pulmonary vessels within the low-attenuation areas of air trapping often
appear small relative to vessels in the more opaque normal lung regions (26).
FIGURE 7-11 Inspiratory (A) and expiratory (B) HRCT in a patient with postinfectious
bronchiolitis obliterans. A: On inspiration, the lungs appear heterogeneous in attenuation due to
mosaic perfusion. B: On expiration, marked inhomogeneity in lung attenuation is noted, with
multifocal air trapping. Many regions of air trapping appear to be lobular.
FIGURE 7-12 Mosaic perfusion and air trapping in a patient with chronic airway infection and
bronchiolitis. A: Inspiratory HRCT shows large regions of mosaic perfusion in the upper lobes. B:
Image from a low-dose dynamic expiratory HRCT shows air trapping in the regions that appeared
lucent on the inspiratory scan. Note bowing of the posterior tracheal membrane due to expiration.
FIGURE 7-13 Expiratory air trapping in a patient with bronchiolitis obliterans. A: Inspiratory
scan is normal. B: Postexpiratory scan shows patchy lung attenuation with the relatively lucent
regions representing regions of air trapping. Normally ventilated areas increase significantly in
attenuation on expiration.
FIGURE 7-14 Postexpiratory air trapping in a patient with asthma. A: An inspiratory scan is
normal. B: Routine postexpiratory scan obtained during suspended respiration after a forced
exhalation scan shows patchy air trapping.
FIGURE 7-15 Postexpiratory air trapping in a patient with bronchiolitis obliterans related to
smoke inhalation. A: An inspiratory scan is normal. B: A low-dose dynamic expiratory scan shows
patchy air trapping. Note anterior bowing of the posterior tracheal membrane, a good indication of
forceful exhalation.
In patients with airways disease or emphysema who have a diffuse
abnormality, expiratory heterogeneity in lung attenuation may not be visible, but
air trapping can be detected by measuring the degree of lung attenuation change
occurring with expiration (10,26–29,54). Areas of air trapping show significantly
less attenuation increase than seen in normal lung on expiratory scans (50). The
normal mean attenuation difference between full inspiration and expiration
usually ranges from 80 to 300 HU. On dynamic scans, a lung attenuation change
of less than 70 or 80 HU between full inspiration and full exhalation may be
regarded as abnormal (Fig. 7-16). On simple postexpiratory scans, a lung
attenuation change of less than 70 HU sometimes may be seen in normals. Lung
attenuation change is most simply measured using small (1–2 cm) regions of
interest on both inspiratory and expiratory scans (28). Measuring the change in
overall lung attenuation from inspiration to expiration may be used in patients
with diffuse air trapping (28) but is clearly less sensitive in patients with patchy
disease. In a study by Berger et al. (65), the difference between mean lung
attenuation on inspiration and expiration was significantly larger in nonsmokers
(128 HU) than in ex-smokers (77 HU) or current smokers (67 HU).
FIGURE 7-16 Dynamic expiratory HRCT in a patient with cystic fibrosis obtained using an
electron-beam scanner. A: Six dynamic images from a sequence of 10, through the right upper
lobe region, shown sequentially in a clockwise fashion from the upper left to lower left. On
inspiration (top middle), lung opacity appears homogeneous. On expiration (lower left corner), a
part of the anterior segment shows a normal increase in opacity, whereas the remainder of the
upper lobe remains lucent. B: Time-attenuation curve measured in a lucent region of the upper
lobe shows little change in attenuation during expiration.
A second method is to compare equivalent areas in each lung on expiratory
scans. In healthy subjects, the mean difference in attenuation change between
symmetric regions of the right and left lungs during exhalation was measured as
36 ± 14 HU (66). From this, a right-left difference in attenuation increase during
exhalation exceeding 78 HU (more than three standard deviations greater than
the mean) can be considered abnormal. This method is especially useful when
air trapping is unilateral.
Occasionally, lung attenuation decreases during expiration in regions of air
trapping; a decrease of attenuation by as much as –258 HU has been reported
during dynamic expiration (27). Although there is no definite explanation for
this phenomenon, several suggestions have been made (27). The most likely is
that during exhalation, lung units trapping air compress small pulmonary vessels,
squeezing blood out of the lung and decreasing lung perfusion. Another possible
explanation is so-called pendelluft, in which air may pass from a normally
ventilated lung unit to a partially obstructed lung unit during rapid expiration,
resulting in an increased gas volume (26).
Although measurement of lung attenuation can be used to diagnose air
trapping, except in patients with diffuse air trapping (e.g., COPD, emphysema,
large bronchial obstruction), the extent of air trapping rather than overall lung
attenuation better predicts pulmonary function test (PFT) findings of obstruction
(26,27).
Air-Trapping Score in the Diagnosis of Air Trapping
The extent of air trapping present on expiratory scans can be measured using a
semiquantitative scoring system, which estimates the percentage of lung that
appears abnormal on each scan (5,27–29,43,57,59,66–68). Such systems have
the advantage of being simple, quick, and easy to perform at the time of image
interpretation. Furthermore, in one study (67), a simple 5-point scoring system
was found to be associated with better interobserver agreement than a more
detailed scoring system.
Because the distribution of areas of air trapping can be heterogeneous,
Bankier et al. (69) attempted to determine the number of expiratory slices
necessary to accurately assess air trapping in patients with suspected
bronchiolitis obliterans. Overall, the extent of air trapping increased from the
upper to lower lung regions, with significant differences between regions (p <
0.001). It was found that expiratory imaging at fewer than three levels could
show a result not representative of the overall extent of air trapping (69),
although results varied in individual patients.
In the scoring system proposed by Webb et al. (66) and Stern et al. (27),
estimates of air trapping were made at three levels scanned using expiratory
technique (at the aortic arch, carina, and 5 cm below the carina). At each level
and for each lung, a 5-point scale is used to estimate the extent of air trapping
visible subjectively: 0 = no air trapping; 1 = 1% to 25% of cross-sectional area
of lung affected; 2 = 26% to 50% of affected lung; 3 = 51% to 75% of affected
lung; 4 = 76% to 100% of affected lung. The air-trapping score is the sum of
these numbers for the three levels studied and ranges from 0 to 24. In several
studies using this method, significant differences were found in the extent of air
trapping in normal patients and those with airway obstruction, and significant
correlations were found between the extent of air trapping and PFT measures of
airway obstruction (15,27,28).
Other methods of visually scoring the extent of air trapping on expiratory
scans have been used and validated (29,57). Lucidarme et al. (29) and Lee et al.
(68) used a grid superimposed on the expiratory HRCT image and counted the
number of squares containing lucent lung and the number encompassing the
entire lung. The air-trapping score represented the ratio of air-trapping squares to
the total number of squares overlying the lung and approximated the crosssectional percent of abnormal lung. Excellent interobserver agreement was
achieved using this method (29).
In patients studied using postexpiratory HRCT, correlations between the airtrapping score and various PFT findings of obstruction range from
approximately r = –0.4 to r = –0.6 (15,28,59,68); correlations are generally best
when normal and abnormal patients are grouped together and when patients with
emphysema are included among those with airway obstruction (28). Thus, in a
study by Chen et al. (28), considering only patients with obstructive disease, airtrapping score correlated significantly with forced expiratory volume in 1 second
(FEV1) (r = –0.78), FEV1/forced vital capacity (FVC) (r = –0.64), FVC (r = –
0.61), and forced expiratory flow (FEF) at 25% to 75% of vital capacity (r = –
0.65); when both normal and abnormal patients were considered together,
correlations were higher, with r values measuring –0.89, –0.74, –0.77, and –
0.81, respectively.
In a study by Lucidarme et al. (29) of 74 patients with suspected chronic
airways disease, expiratory air trapping was seen in 18 of 35 (51%) patients with
severe airway obstruction (FEV1/FVC < 80%), in 21 of 29 (72%) patients with
predominantly small airway obstruction (abnormal flow-volume curve and
FEV1/FVC < 80%), and in 4 of 10 (40%) patients with normal PFT results. Airtrapping scores were 27%, 12%, and 8% for these groups, respectively, with
significant negative correlations with FEV1 (r = –0.45), FEV1/FVC (r = –0.31),
and FEF at 25% of vital capacity (r = –0.57). Lee et al. (68) studied 47
asymptomatic subjects using PFTs and expiratory HRCT; in all, PFTs were
considered to be normal. In this study, the air-trapping grade correlated with
FEV1/FVC (r = –0.44). In a study of 70 patients with chronic purulent sputum
production (57), the air-trapping score defined at a lobular level significantly
correlated with values of FEV1 and FEV1/FVC. In a study of 33 patients
developing bronchiolitis obliterans syndrome after hematopoietic stem cell
transplantation, postexpiratory air trapping was the principal finding seen on CT,
and its severity correlated with PFTs. In this study, HRCT scans were visually
ranked for degree of air trapping and also scored for findings of bronchial wall
thickening, bronchiectasis, and centrilobular opacities (5). The degree of air
trapping on expiratory HRCT correlated significantly with FEV1 (r = –0.52; p =
0.002), FEV1/FVC (r = –0.57; p < 0.001), residual volume (r = –0.62; p <
0.001), and carbon monoxide diffusion capacity (p = 0.023). Bronchial wall
thickening occurred in 73%, predominantly in lower lobes (p = 0.007), but was
mild. Bronchiectasis occurred in 42.4% and centrilobular opacities in 39.4%.
Lung Area Changes in the Diagnosis of Air Trapping
Decreased reduction in lung area with expiration correlate with the presence of
air trapping and lung volume change, but area change measurements are less
easily obtained during the clinical interpretation of expiratory HRCT.
Robinson and Kreel (70) showed that a significant correlation exists between
changes in cross-sectional lung area measured using CT and lung volume (r =
0.569). The percentage decrease in lung cross-sectional area that occurred during
exhalation also correlates with the attenuation increase (66,70). In a study using
dynamic ultrafast HRCT (66), a significant correlation between cross-sectional
lung area and lung attenuation was found for each of three lung regions
evaluated (upper lung: r = 0.51, p = 0.03; mid-lung: r = 0.58, p = 0.01; lower
lung: r = 0.51, p = 0.05).
Usually, areas of air trapping show little or no area and volume change during
exhalation and can help identify areas of air trapping. In one study of nine cases
of Swyer-James syndrome (2), expiratory CT scans in areas of abnormal lung
showed no significant lung volume change, and mediastinal shift toward the
normal lung was also seen.
In a study by Lucidarme et al. (29) of 74 patients with suspected chronic
airways disease and 10 normal subjects, an area reduction score was measured,
representing the reduction in cross-sectional lung area from inspiration to
expiration. Area reduction scores were 18%, 30%, and 35%, respectively, for
groups of patients with severe airway obstruction (FEV1/FVC < 80%),
predominantly small airways obstruction (abnormal flow-volume curve and
FEV1/FVC = 80%), and normal PFT results. In the normal subjects, the area
reduction score was 43%. Area reduction score correlated significantly with all
PFT indexes (r = 0.35–0.66) except total lung capacity.
Air Trapping in Normals
Air trapping can be seen in normal subjects, although its extent is limited. Air
trapping in one or more secondary pulmonary lobules is not uncommon. Also,
focal areas of relative lucency can be seen in normal subjects on expiratory scans
in the superior segments of the lower lobes, in the lingula or middle lobe, and in
dependent lung at the lung bases (26,66,68,71–73). Tanaka et al. (71) found a
frequency of air trapping of 64% in asymptomatic patients with normal
pulmonary function. In a study by Chen et al. (28), focal areas of air trapping,
including the superior segments of the lower lobes, were visible in 61% of
patients having normal PFTs. In a study by Lee et al. (68), air trapping was seen
in 52% of 82 asymptomatic subjects with normal PFTs.
The frequency of air trapping increased with age (p < 0.05) in a study (68) of
82 asymptomatic subjects with normal PFTs, being seen in 23% of patients aged
21 to 30 years, 41% of those aged 31 to 40 years, 50% of those aged 41 to 50
years, 65% of those aged 51 to 60 years, and 76% of those older than 61 years.
In another study, discounting the superior segments and air trapping involving
less than two contiguous or five noncontiguous pulmonary lobules, air trapping
was not seen on expiratory scans in 10 healthy nonsmokers, although it was
visible in 40% of patients with suspected chronic airways disease who had
normal PFTs (29).
Mastora et al. (72) assessed inspiratory and postexpiratory HRCT in 250
volunteers, including 144 smokers, 47 ex-smokers, and 59 nonsmokers. Air
trapping was seen in 62% of the subjects. Lobular air trapping (fewer than three
adjacent lobules) was seen in 47%, without significant differences among
smokers, ex-smokers, and nonsmokers. Segmental (from three adjacent lobules
to a segment) air trapping (seen in 14%) and lobar (larger than a segment) air
trapping (seen in 1%) were more frequent among smokers and ex-smokers (p <
0.001). Air trapping was limited to less than 25% of lung area in 72.5% of
subjects with air trapping. In a similar study of 70 young men (mean age 36.1
years) with normal spirometry, most of whom were nonsmokers, Mets et al. (74)
found air trapping on volumetric postexpiratory HRCT in 56 (80%), and in 55,
air trapping was lobular. The median number of involved lobules was 2, but 14
subjects showed more than 3 lobules, and 5 had more than 5 lobules with air
trapping. Three patients showed segmental air trapping. There was no difference
in the frequency of lobular air trapping and smoking history.
Tanaka et al. (71) studied 50 subjects with normal pulmonary function,
including 26 nonsmokers and 24 smokers (14 current and 10 ex-smokers). All 50
subjects underwent thin-section CT at which images were obtained during deep
inspiration and end expiration at three levels. Air trapping was visually classified
into four degrees (none, lobular, mosaic, or extensive), and the extent of air
trapping was also calculated. The mean increase in lung attenuation in the three
levels at expiration was 111.9 HU ± 46.3 (SD). The overall frequency of air
trapping was 64%. Lobular (one or two adjacent lobules), mosaic (three or more
regions of lobular air trapping), and extensive (larger than three adjacent lobules
and subsegmental, segmental, or lobar in distribution) air trapping were seen in
10 (20%), 14 (28%), and 8 (16%) patients, respectively. There was no significant
difference in the visual grade and extent of air trapping among the nonsmokers,
smokers, and ex-smokers (71). The extent of air trapping relative to crosssectional lung area averaged 5.6 ± 6.4% in nonsmokers (range, 0%–20.4%) and
5.9 ± 4.2% and 6.6 ± 4.5% (range, 0%–13.8%) in smokers and ex-smokers,
respectively.
In their study of 10 young normal subjects, Webb et al. (66) found that,
although air trapping was present in 4 patients, the air-trapping score never
exceeded a total of 2 (i.e., 25%) at any one level. In subsequent experience with
patients having normal PFT, an air-trapping score of up to 6/24 (i.e., 25%) has
been found when the superior segments are included in analysis (28). In a study
by Lucidarme et al. (29) of 10 normal nonsmokers, excluding the superior
segments of the lower lobes and isolated pulmonary lobules, no air trapping was
visible. In a study by Lee et al. (68), an air-trapping score equivalent to less than
5% of lung was seen in 32% of asymptomatic patients, and an air-trapping score
of between 5% and 25% was seen in an additional 20%. In this study, although
all patients were considered normal, an air trapping extent between 5% and 25%
was more frequent in smokers (33%) than nonsmokers (14%) (68).
Segmental and lobar air trapping are highly suggestive of small airways
disease. In a study by Mastora et al. (72), these patterns of air trapping were
observed with a significantly higher frequency among smokers and ex-smokers,
as compared with nonsmokers, and in subjects who had inspiratory HRCT
features of smoker’s lung. Also, a higher frequency of segmental air trapping
was observed in the subgroup of heavy smokers, as compared with mild
smokers, and the pattern of lobar air trapping was found exclusively in heavy
smokers (72).
Air Trapping in Patients with Normal Inspiratory Scans
In some patients, inhomogeneous lung attenuation is visible on expiratory scans
in the presence of normal inspiratory scans, indicating the presence of
obstructive disease (Figs. 7-13 to 7-15). In one study (35), HRCT scans of 273
consecutive patients with suspected diffuse lung disease were reviewed. Fortyfive patients showed air trapping on expiratory HRCT scans. Of these 45
patients, inspiratory HRCT scans showed abnormal findings in 36
(bronchiectasis, bronchiolitis obliterans, asthma, chronic bronchitis, and cystic
fibrosis). In the remaining 9 patients, inspiratory HRCT showed normal findings;
conditions in these 9 patients included bronchiolitis obliterans (constrictive
bronchiolitis) and its many causes (n = 5), asthma (n = 3), and chronic bronchitis
(n = 1). Results of PFTs in patients with air trapping and normal findings on
inspiratory scans were intermediate, falling between those of patients with
normal findings on inspiratory and expiratory HRCT scans and those of patients
with air trapping and abnormal findings on inspiratory scans. This appearance
can also be seen in patients with hypersensitivity pneumonitis.
Use of Expiratory Scans in the Assessment of Mosaic
Attenuation
As indicated previously, the presence of inhomogeneous lung attenuation on
inspiratory scans is a common finding (15). This appearance may result from
ground-glass opacity, mosaic perfusion resulting from airways obstruction and
reflex vasoconstriction, mosaic perfusion resulting from vascular obstruction, or
a combination of these.
Expiratory HRCT scans may be useful in the diagnosis of mosaic attenuation
and can usually allow the differentiation of mosaic perfusion resulting from
airways obstruction from other abnormalities when the inspiratory scans are
inconclusive. In patients with ground-glass opacity, expiratory HRCT typically
shows a proportional increase in attenuation in areas of both increased and
decreased opacity (Fig. 7-17). In patients with mosaic perfusion resulting from
airways disease, attenuation differences are accentuated on expiration (Fig. 718); relatively dense areas increase in attenuation, whereas lower-attenuation
regions remain lucent (i.e., air trapping is present) (3,26,56,66).
FIGURE 7-17 Inspiratory and postexpiratory HRCT in a patient with pulmonary hemorrhage
and ground-glass opacity. A: Patchy differences in lung opacity are visible on the inspiratory scan.
This appearance mimics mosaic perfusion. B: On a postexpiratory scan, proportional increases in
lung opacity are seen throughout the lungs. Lung attenuation increased by 150 to 200 HU on the
expiratory scan in all lung regions.
FIGURE 7-18 Inspiratory and postexpiratory HRCT in a patient with bronchiolitis obliterans.
A: Inspiratory scan shows subtle differences in opacity in different lung regions, representing
mosaic perfusion. B: Postexpiratory HRCT shows a marked accentuation in attenuation
inhomogeneities due to air trapping. Regions of lucency increased in attenuation by approximately
50 HU on expiration. Although some areas of air trapping appear patchy and nonanatomical
(asterisk), others appear subsegmental or lobular (arrows).
In a study by Arakawa et al. (15) of patients showing inhomogeneous opacity
as their predominant HRCT abnormality, the accuracy of HRCT in correctly
diagnosing the type of disease present increased from 81% to 89% in patients
with ground-glass opacity and from 84% to 100% in diagnosing airways disease
when expiratory scans were included in the analysis (15). Some patients who
appear to show ground-glass opacity on inspiratory scans but show air trapping
on expiratory scans thus may be correctly diagnosed as having obstructive
disease (Fig. 7-19).
FIGURE 7-19 Expiratory HRCT in the diagnosis of inhomogeneous lung opacity.
In patients with mosaic perfusion resulting from vascular disease, expiratory
HRCT findings often mimic those seen in patients with ground-glass opacity;
both low-attenuation and high-attenuation regions increase in attenuation on
expiration (Fig. 7-20).
FIGURE 7-20 Mosaic perfusion and expiratory HRCT findings in a patient with chronic
pulmonary embolism. A and B: On HRCT, some lung regions show increased attenuation and
size of vessels, indicating mosaic perfusion. C and D: Dynamic expiratory images at the same
levels as A and B show a proportional increase in lung attenuation in both dense and lucent lung
regions.
In patients with mosaic perfusion due to vascular disease, air trapping is not
usually seen. However, in a study of patients with inhomogeneous lung
attenuation of various causes (16), air trapping was believed to be present on
expiratory scans in some patients with vascular disease when scans were viewed
blindly. Furthermore, air trapping has been reported in some patients with acute
pulmonary embolism, likely due to bronchoconstriction (22). Arakawa et al. (22)
studied 29 patients with suspected pulmonary embolism using CT angiography
and expiratory HRCT. In 15 patients with pulmonary embolism, mosaic
perfusion was identified in 7 patients (46.7%), and air trapping was identified in
9 patients (60%). Of 32 areas of mosaic perfusion identified, 23 (71.9%) showed
air trapping on expiratory scans. Of 68 areas with air trapping on expiratory
scans, 23 areas (33.8%) showed mosaic perfusion on inspiratory scans, and 44
areas (64.7%) had clots in the arteries leading to them.
Expiratory Scans in the Diagnosis of Mixed Disease
In patients with mixed infiltrative and airways disease, inspiratory scans may
show a patchy pattern of variable lung attenuation, representing the combination
of ground-glass opacity (or consolidation), normal lung, and reduced lung
attenuation as a result of mosaic perfusion. This combination of mixed densities
has been termed the headcheese sign (Figs. 7-7 to 7-9) (30) and is most typical
of hypersensitivity pneumonitis, sarcoidosis, DIP or respiratory bronchiolitis,
atypical infections with associated bronchiolitis, and occasionally LIP.
In some patients with mixed infiltrative and obstructive diseases, ground-glass
opacity may be seen on the inspiratory scans without clear-cut findings of
mosaic perfusion. However, in such cases, the presence of air trapping on
expiratory images may allow the correct diagnosis of mixed infiltrative and
obstructive disease (15). The combination of ground-glass opacity or
consolidation on inspiratory scans and air trapping on expiratory scans should
also be considered indicative of a mixed abnormality (Figs. 7-9 and 7-21) (15).
FIGURE 7-21 Hypersensitivity pneumonitis with the headcheese sign. A: An inspiratory scan
shows inhomogeneous lung attenuation consisting of ground-glass opacity and lobular areas of
lucency (arrows) due to mosaic perfusion. B: Expiratory scan shows air trapping in the lucent
regions (arrows). These areas show little or no change in attenuation on the expiratory scans.
In a study by Chung et al. (30), 14 of 400 consecutive patients having HRCT
with routine expiratory images showed findings of infiltrative lung disease on
inspiratory scans and significant air trapping on expiratory scans. These 14
patients included 6 with hypersensitivity pneumonitis, 5 with sarcoidosis, 2 with
atypical infections, and 1 with pulmonary edema. Ten patients showed groundglass opacity on inspiratory scans, whereas four patients with sarcoidosis
showed nodules. Mosaic perfusion was seen in 10 patients. PFTs demonstrated a
mixed pattern in five patients, an obstructive pattern in four patients, and a
restrictive pattern in three patients. FEV1/FVC correlated significantly with the
extent of air-trapping score (r = 0.58, p = 0.05). The extent of infiltrative
abnormalities correlated significantly with FVC (r = –0.77, p = 0.003) and
diffusing capacity (DLCO) (r = –0.75, p = 0.01).
Air trapping in association with ground-glass opacity is a common HRCT
finding in both the subacute and chronic stages of hypersensitivity pneumonitis
(37). In a series of 22 patients with hypersensitivity pneumonitis, HRCT scans
with a limited number of expiratory images were correlated with PFTs (37).
Areas of decreased attenuation, mosaic perfusion, and air trapping were seen in
19 patients and were the most frequent findings. In addition, the extent of
decreased attenuation correlated well with severity of functional index of air
trapping, as indicated by increased residual volume (r = 0.58, p < 0.01).
In patients with sarcoidosis, HRCT commonly shows findings of mosaic
perfusion and air trapping in addition to findings of infiltrative disease (36,63).
Hansell et al. (36) attempted to determine the relationship between the
obstructive defects of pulmonary sarcoidosis and HRCT patterns of disease in 45
patients. The most prevalent CT patterns were decreased lung attenuation on
expiratory scans (n = 40), a reticular pattern (n = 37), and a nodular pattern (n =
36). A reticular pattern was the main determinant of functional impairment,
particularly airflow obstruction, as shown by inverse relationships with FEV1
and FEV1/FVC, among others. Decreased attenuation on expiratory scans was
also significantly related to measures of airway obstruction, although
correlations were weaker. Terasaki et al. (75) found air trapping in 98% of 45
patients with sarcoidosis. Although the authors found a significant correlation
between FVC and the extent of air trapping, not surprisingly, they found that the
patient’s smoking history (half of their patients were smokers) was also
important in determining pulmonary function.
Air trapping has also been reported in patients with silicosis (76). In a study
by Arakawa et al. (76), 33 of 34 patients with silicosis showed air trapping on
postexpiratory scans. The extent of air trapping correlated with FEV1/FVC (r = –
0.632, p < 0.001).
Quantitative Assessment of Air Trapping
In patients with suspected air trapping, precise quantitative techniques have
primarily been used to assess the relative proportions of emphysema and airways
disease in patients with COPD, and to determine the COPD phenotype
(emphysema-predominant, airway-predominant, or mixed) (32–34). To date,
these techniques are largely confined to the research setting, and a number of
technical, methodological, and physiologic variables will need to be considered
and overcome before quantitation of air trapping is practical in routine clinical
practice (77–81). A detailed review and comparison of the various quantitative
techniques employed, and the results obtained, are beyond the scope of this
chapter. Nonetheless, several techniques are described briefly in what follows.
Each of these can show significant correlations with measures of air trapping in
patients with COPD (34). These methods include:
a. the density mask technique, in which the percentage of lung pixels or voxels
(pixel or voxel index) with an attenuation less than a specific threshold (–
850, –856, –900, –910, and –950 HU have been used in different studies)
are calculated on expiratory HRCT (32,82);
b. determining the percentage of lung pixels between –850 HU and –910 or –
950 HU on expiratory HRCT (pixels with an attenuation less than –910 or –
950 HU are considered to represent emphysema and excluded) (34);
c. measuring the change in relative lung volume with attenuation values from
–860 HU to –950 HU on paired inspiratory and expiratory scans (82,83);
and
d. calculating the expiration-to-inspiration ratio of mean lung density
(34,74,84).
The density mask (pixel index [PI]) technique has been most widely used
(Fig. 7-22) (38,40,85). Although the inspiratory PI has wide normal range, with
some normals showing pixels with an attenuation of less than 950 H (see
Chapter 2) (74,86,87), the expiratory PI is relatively constant. The normal PI at
full inspiration ranges from 0.6 to as much as 58.0 when the threshold is –900
HU (88), although the mean value ranges from 10 to 25, depending on the level
scanned and on the CT scan collimation (Fig. 7-22) (40). In a study of 42 healthy
subjects (21 men, 21 women) aged 23 to 71 years, the inspiratory PI measured
using –950 HU ranged from 1.2 to 22.3 (mean, 7.8) (85). At full expiration, with
a threshold value of –900 HU, the normal range of PI is rather small with a mean
of less than 1.04 (SD, 1.3) (40). Thus, in normal subjects, the area of lung having
an attenuation of less than –900 HU at full expiration can generally be regarded
as less than a few percent (Figs. 7-22 and 7-23). Others have used an attenuation
value of less than –850 or –856 HU on expiration to indicate air trapping or
emphysema, and found a mean PI value of 5.12 (SD, 7.98), a median PI value of
3.22, and an upper limit of normal of 17.2, in a study of 70 young men (mean
age 36.1 years) with normal spirometry, most of whom were nonsmokers (74).
FIGURE 7-22 PI measured in a patient with bilateral lung transplantation and normal lung
function. An expiratory scan (A) and scan with pixels measuring less than –900 HU (highlighted)
(B) are shown. The low-attenuation pixels shown in B represent 0.6% of lung area (PI, 0.6). This
is normal. (From Arakawa H, Webb WR. Expiratory HRCT scan. Radiol Clin North Am
1998;36:189, with permission.)
FIGURE 7-23 Inspiratory and postexpiratory images in a patient with left lung transplantation
for panlobular emphysema. A: Inspiratory HRCT shows extensive right-sided emphysema. B: On
a postexpiratory HRCT, measured using a region of interest, there was little or no attenuation
increase in the right lung. As compared to the inspiratory image, patchy air trapping on the left is
visible as inhomogeneous opacity. This finding suggests small airway obstruction and is
consistent with constrictive bronchiolitis. This was confirmed on transbronchoscopic biopsy. C:
Pixels having a value of less than –900 HU in the postexpiratory image have been highlighted.
The PI for the emphysematous right lung measures 72 and is markedly abnormal. The PI for the
left lung measures 0.7 and is within normal limits. (From Arakawa H, Webb WR. Expiratory HRCT
scan. Radiol Clin North Am 1998;36:189, with permission.)
The expiratory PI can be used to quantitatively assess the area of lowattenuation lung in patients with air trapping or emphysema (Fig. 7-23). For
example, in one study (38), 64 patients underwent both inspiratory and
expiratory CT correlated with pulmonary physiology. There were 28 patients
with an inspiratory PI of more than 40, and 14 of these had an expiratory PI of
more than 15. This group showed markedly abnormal PFT values suggestive of
emphysema, whereas other patients showed preserved lung function. Also, an
expiratory PI of more than 15 accurately reflected and quantitated the degree of
emphysema estimated by various PFTs.
The expiratory PI has also been used to quantitatively discriminate asthmatic
patients from normal subjects. In one study of both asthmatic and normal
subjects (40), both inspiratory and expiratory PI were obtained at two levels (at
the transverse aorta and just superior to the diaphragm) and compared with PFTs.
Using a slice thickness of 10 mm and 1.5 mm, the expiratory PI at a level
immediately superior to the diaphragm was significantly higher in asthmatic
subjects (4.45 and 10.03 for the two thicknesses, respectively) than in normal
subjects (0.16 and 1.04, respectively) and provided the best separation between
the groups (40).
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SECTION
III
High-Resolution CT Diagnosis of Diffuse Lung Disease
In this section, we will review high-resolution computed tomography (HRCT)
findings and its utility in various lung diseases and disease categories commonly
imaged using this technique. The last chapter provides a glossary of HRCT terms
for reference.
8
The Idiopathic Interstitial Pneumonias, Part I: Usual
Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis and Nonspecific
Interstitial Pneumonia
IMPORTANT TOPICS
IDIOPATHIC INTERSTITIAL PNEUMONIAS
USUAL INTERSTITIAL PNEUMONIA AND IDIOPATHIC PULMONARY FIBROSIS
NONSPECIFIC INTERSTITIAL PNEUMONIA
Abbreviations Used in This Chapter
AIP
acute interstitial pneumonia
ALAT
Latin American Thoracic Association
ATS
American Thoracic Society
BOOP
bronchiolitis obliterans organizing pneumonia
COP
cryptogenic organizing pneumonia
DAD
diffuse alveolar damage
DIP
desquamative interstitial pneumonia
DLCO
carbon monoxide diffusing capacity
ERS
European Respiratory Society
FVC
forced vital capacity
IIP
idiopathic interstitial pneumonia
IPF
idiopathic pulmonary fibrosis
JRS
Japanese Respiratory Society
LIP
lymphoid interstitial pneumonia
NSIP
nonspecific interstitial pneumonia
OP
organizing pneumonia
PCP
Pneumocystis jirovecii pneumonia
PPFE
pleuroparenchymal fibroelastosis
RB-ILD
respiratory bronchiolitis-interstitial lung disease
TLC
total lung capacity
UIP
usual interstitial pneumonia
IDIOPATHIC INTERSTITIAL PNEUMONIAS
The idiopathic interstitial pneumonias (IIPs) are a group of diffuse parenchymal
lung diseases of unknown etiology with varying degrees of inflammation and
fibrosis (1). Several classifications for the IIPs have been proposed. The most
widely accepted scheme is the 2002 American Thoracic Society/European
Respiratory Society (ATS/ERS) consensus classification (1) with a supplement
update published in 2013 (2). The recent update of the classification separates
the IIPs into four groups: chronic fibrosing IIPs (idiopathic pulmonary fibrosis
[IPF] and idiopathic nonspecific interstitial pneumonia [NSIP]), acute or
subacute IIPs (acute interstitial pneumonia [AIP] and cryptogenic organizing
pneumonia [COP]), smoking-related IIPs (respiratory bronchiolitis-interstitial
lung disease [RB-ILD] and desquamative interstitial pneumonia [DIP]), and rare
IIPs (idiopathic lymphoid interstitial pneumonia [LIP] and idiopathic
pleuroparenchymal fibroelastosis [PPFE]) (Table 8-1) (2). The recent update
recognized one new IIP, idiopathic PPFE, as a specific rare entity characterized
by predominantly upper lobe pleural and adjacent parenchymal fibrosis, the
latter being associated with elastosis of alveolar walls (2,3). The ATS/ERS
classification emphasizes the need for dynamic interactions between clinicians,
radiologists, and pathologists to arrive at a final clinico-radiologic-pathologic
diagnosis (1,2). Therefore, although the histopathologic patterns provide the
basis for the ATS/ERS classification, the gold standard is no longer the histology
but rather a multidisciplinary approach (1,2). For example, usual interstitial
pneumonia (UIP) is, as the name implies, the most common of the interstitial
pneumonias, accounting for 50% to 60% of cases (4). UIP is a type of lung
reaction pattern to injury. It may occur secondary to exposure to dusts (e.g.,
asbestos), drugs (e.g., bleomycin), or be seen in hypersensitivity pneumonitis or
in association with collagen-vascular diseases (1). When, after careful clinical
evaluation, no etiology is found, it is classified as an IIP, and in this context, it is
considered synonymous with IPF (1,5). In this book, we use UIP only to refer to
the histologic abnormality, and we use IPF to describe the disease that so
commonly results in this histologic finding.
TABLE 8-1 Clinical and Pathologic Features of the Idiopathic
Interstitial Pneumonias
NSIP is a form of chronic interstitial pneumonia characterized by relatively
uniform expansion of the alveolar septa by interstitial inflammation and/or
fibrosis (1,6,7). It accounts for 14% to 35% of biopsies performed for interstitial
pneumonia (8). Although NSIP may be idiopathic, many cases are related to
collagen-vascular disease, drug reaction, or hypersensitivity pneumonitis (1,6,9).
The diagnosis of idiopathic NSIP can only be made when all known potential
causes of this reaction pattern have been excluded clinically.
In this chapter, we focus on the two most common IIPs: IPF and NSIP. The
remaining IIPs are discussed in Chapter 9.
USUAL INTERSTITIAL PNEUMONIA AND IDIOPATHIC
PULMONARY FIBROSIS
In 2011, an official ATS/ERS/JRS/ALAT statement defined IPF as a chronic,
progressive fibrosing interstitial pneumonia of unknown cause, occurring
primarily in older adults, limited to the lungs, and associated with the
histopathologic and/or radiologic pattern of UIP (5). IPF is more common in
smokers and ex-smokers than in lifelong nonsmokers, and more common in men
than in women (5). IPF usually occurs in adults older than 55 years (median age
of diagnosis, 66 years) (10) and is rare in patients less than 50 years old (5).
Patients who have IPF typically present with chronic exertional dyspnea, cough,
bibasilar inspiratory crackles, and finger clubbing (5). Pulmonary function tests
show a restrictive pattern with reduced lung volumes and impairment in gas
exchange (11). IPF has a poor prognosis, with a median survival of 2.5 to 3.5
years after the time of diagnosis (1,10).
The pathogenesis of IPF is unknown. The current evidence suggests that it
likely involves several components, including repetitive microinjuries to
susceptible lung, leading to fragmentation of type I alveolar cells and disruption
of the basement membrane, release of factors responsible for the migration of
fibroblasts, and exaggerated production of extracellular matrix by the
fibroblastic foci, resulting in the destruction of the lung parenchyma (10,12). The
previous theory that the earliest histologic abnormality was alveolitis and that
this inflammatory process led to progressive fibrosis (13–15) is no longer
accepted. Occasionally IPF occurs in family kindreds as well as in twins,
suggesting a possible genetic predisposition (16).
UIP is characterized histologically by a patchy heterogeneous appearance in
which areas of fibrosis and honeycomb change alternate with areas of lessaffected or normal parenchyma, a heterogeneity that is best seen at low-power
magnification (5,17). Inflammation is usually mild (5,17). Another characteristic
histologic feature is the presence of fibroblastic foci (i.e., aggregates of
proliferating fibroblasts and myofibroblasts that represent microscopic zones of
acute lung injury set against a backdrop of chronic fibrosis) (Fig. 8-1) (8,17).
The histologic abnormalities therefore reflect different stages in the evolution of
fibrosis, a combination of old and active lesions; this is termed temporal
heterogeneity and is characteristic of UIP (1,5,8). The fibrosis and
honeycombing usually involve mainly the subpleural, paraseptal, and basal lung
regions (Fig. 8-2) (5,18). The histopathologic diagnosis of UIP requires the
presence of all of the following four criteria: evidence of marked fibrosis and
architectural distortion ± honeycombing in a predominantly subpleural and
paraseptal distribution; presence of patchy involvement of lung parenchyma by
fibrosis; presence of fibroblast foci; and absence of features suggestive of an
alternate diagnosis (5).
FIGURE 8-1 Usual interstitial pneumonia. Low-magnification photomicrograph of lung
specimen shows variegated distribution of abnormalities with peripheral areas of dense fibrosis
(asterisk). Fibroblastic foci (arrows) can be seen at the leading edge of the fibrosis. Fibroblastic
foci consist of fibroblasts and myofibroblasts and are seen in all patients with UIP. (Courtesy of Dr.
John English, Department of Pathology, Vancouver General Hospital, Vancouver, British
Columbia, Canada.)
FIGURE 8-2 Usual interstitial pneumonia. A sagittal slice of the right lung shows severe
fibrosis and honeycomb change in the basal aspects of the lower and middle lobes. Less marked
disease can be seen in the subpleural region of the upper and lower lobes. (From Müller NL,
Fraser RS, Lee KS, et al. Diseases of the lung: radiologic and pathological correlations.
Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)
The international official ATS/ERS/JRS/ALAT statement on IPF published in
2011 (5) established that a diagnosis of UIP can often be made on highresolution computed tomography (HRCT), obviating lung biopsy. In patients
with characteristic UIP findings on HRCT or lung biopsy, the diagnosis of IPF
requires exclusion of other known causes of interstitial lung disease such as
domestic and occupational environmental exposures, connective tissue disease,
and drug toxicity (5).
The most common radiographic finding in IPF, described in approximately
80% of patients who have biopsy-proven disease, consists of bilateral irregular
linear opacities causing a reticular pattern (19–21). Although these opacities may
be diffuse throughout both lungs, in 60% to 80% of cases they involve
predominantly the lower lung zones (22,23). As fibrosis develops, a fine
reticular pattern appears that may be diffuse but is often first seen and more
severe in the lower lung zones. As fibrosis progresses, the reticular pattern
becomes coarser, and there is progressive loss of lung volume. In the end stage,
there is extensive honeycombing. It is well known, however, that the
radiographic appearance of IPF is nonspecific and the chest radiograph
correlates poorly with the histologic findings and with the anatomic distribution
and severity of disease (4). Furthermore, in about 10% of patients with IPF, the
chest radiograph is normal (24,25).
High-Resolution Computed Tomography Findings
On HRCT, IPF is characterized by intralobular interstitial thickening that
corresponds to areas of irregular fibrosis (Figs. 8-3 and 8-4) and reflects the
typical pathologic features of UIP (Table 8-2) (26–28). The intralobular
interstitial thickening results in a reticular pattern (Figs. 8-5 and 8-6) (29,30). In
70% to 95% of patients, the reticulation involves mainly the subpleural regions
and lower lung zones (30–32). Dilated and distorted centrilobular bronchioles
(i.e., traction bronchiolectasis) are frequently visible within the areas of
reticulation (Figs. 8-3 and 8-4) (1,27,33). In areas of severe fibrosis, the
segmental and subsegmental bronchi become dilated and tortuous, a finding
referred to as traction bronchiectasis (Fig. 8-7) (34). Thickening of the
intralobular interstitium also results in the presence of irregular interfaces
between the lung and pulmonary vessels, bronchi, and pleural surfaces (Fig. 8-8)
(27). Subpleural lines can also be seen, usually indicating fibrosis (Fig. 8-5).
FIGURE 8-3 Reticular opacities in an 83-year-old man with mild IPF. HRCT at the level of the
lower trachea demonstrates bilateral intralobular linear opacities, resulting in a reticular pattern in
the subpleural lung regions. Also noted are irregular septal thickening (red arrows) and traction
bronchiolectasis (blue arrow). Irregular interfaces are present along the mediastinal surfaces.
FIGURE 8-4 Reticular opacities in a 74-year-old man with IPF. HRCT at the level of lung
bases demonstrates irregular reticular opacities bilaterally in the subpleural lung regions. In
several areas, irregular septal thickening (small arrows) and traction bronchiolectasis (curved
arrow) are visible. Irregular interfaces are present along the mediastinal and costal lung surfaces.
Also noted is mild subpleural honeycombing.
FIGURE 8-5 Reticular opacities in a patient with IPF. Scans at two levels (A and B) show a
peripheral predominance of abnormalities indicative of fibrosis, including irregular interlobular
septal thickening (black arrows) and subpleural lines (white arrows). However, the predominant
pattern is that of intralobular interstitial thickening with areas of honeycombing.
TABLE 8-2 HRCT Findings in Idiopathic Pulmonary Fibrosis
Findings of fibrosis (i.e., honeycombing,b traction bronchiectasis and bronchiolectasis,
intralobular interstitial thickening,b irregular interlobular septal thickening,b irregular
interfaces)a
Ground-glass opacity (usually in areas showing fibrosis)a
Peripheral and subpleural predominance of abnormalitiesa,b
Lower lung zone and posterior predominancea,b
aMost common finding(s).
bFinding(s) most helpful in differential diagnosis.
Honeycombing is common and is critical for making a definitive diagnosis on
HRCT (5). In many cases of IPF, findings of honeycombing predominate
(26,29). In such cases, there is gross distortion of lung architecture, and
individual lobules are no longer visible (Figs. 8-9 to 8-11). Honeycomb cysts
usually range from 3 to 10 mm in diameter, but they can be as large as 2.5 cm
(Figs. 8-9 to 8-11) (5,26,29). They typically appear to share walls on HRCT and
usually occur in several layers in the subpleural lung. Honeycomb cysts have
been reported on HRCT in 24% to 91% of patients who have IPF (27,30,35) and
the frequency of this finding varies with the severity or stage of the disease.
Findings of honeycombing and fibrosis are most often symmetric, but
asymmetry may be present and may occasionally be quite marked (36).
FIGURE 8-6 A–C: Prone HRCT in a 71-year-old man with IPF and progressive shortness of
breath. Abnormalities predominate in the posterior, subpleural lower lobes and are characterized
by intralobular interstitial thickening (B, arrows) and interlobular septal thickening (C, arrow).
Although ground-glass opacity is superimposed on the abnormal reticulation, this was found to
represent end-stage fibrosis on biopsy.
FIGURE 8-7 Traction bronchiectasis and bronchiolectasis in a 75-year-old man with IPF.
HRCT demonstrates peripheral reticulation mainly in the dorsal regions of the lower lobes. The
bronchi within the areas of reticulation are dilated and distorted (traction bronchiectasis) (arrows).
Dilated bronchioles (traction bronchiolectasis) are present (curved arrows) a few millimeters away
from the pleura. Also noted are a few honeycomb cysts (arrowheads) adjacent to the pleura.
Ground-glass opacities are present, but only in areas with reticulation, traction bronchiectasis, and
bronchiolectasis, and are therefore most consistent with microscopic fibrosis below the resolution
of CT.
FIGURE 8-8 Irregular interfaces in a 73-year-old woman with mild IPF. HRCT shows small
intralobular linear opacities resulting in irregular pleural interfaces (arrowheads). Also noted is
mild irregular thickening of the interlobular septa (arrows).
FIGURE 8-9 Honeycombing in IPF. Typical honeycomb cysts are present mainly in the
subpleural lung regions. Also noted is traction bronchiectasis (arrows).
FIGURE 8-10 Honeycombing in IPF. A–C: HRCT at three levels in a 54-year-old man with
IPF. Abnormalities include intralobular interstitial thickening and traction bronchiectasis (A, white
arrows). Honeycombing characterized by subpleural cystic lucencies is also present (black
arrows). At the lung bases (C), some overlap between the appearances of honeycombing and
traction bronchiolectasis is visible.
FIGURE 8-11 Extensive honeycombing in end-stage IPF. A: HRCT at the level of the right
upper lobe bronchus in a 73-year-old man shows bilateral reticulation and honeycombing, mainly
in the peripheral lung regions. B: HRCT at the level of the lung bases demonstrates diffuse
reticulation and honeycombing in the left lower lobe, and subpleural reticulation and
honeycombing in the right lower lobe.
Interlobular septal thickening is sometimes seen on HRCT in patients who
have IPF, but it is a less conspicuous finding than intralobular interstitial
thickening or honeycombing (Figs. 8-3 to 8-6). In patients who have
honeycombing, findings of septal thickening are usually visible only in less
abnormal lung regions. When visible, septal thickening is characteristically
irregular in contour (Figs. 8-3 to 8-6) (29,37), and septa marginating pulmonary
lobules can appear irregular in shape or distorted. Abnormal prominence of the
centrilobular vessel, which normally appears as a dot-or Y-shaped branching
opacity in the lobular core, is often present in patients who show septal
thickening, but is not a conspicuous finding in most (29). In addition, the
centrilobular bronchiole, which is not normally seen, is sometimes visible
because of a combination of dilatation (i.e., traction bronchiolectasis), thickening
of the peribronchiolar interstitium, and increased opacity of surrounding lung
(Figs. 8-4 and 8-7) (29).
Ground-glass opacity is commonly seen on HRCT but is usually less
extensive than the reticulation (5,31). It may indicate the presence of active
inflammation, but, in patients with IPF it more commonly reflects the presence
of fibrosis below the resolution of HRCT (Fig. 8-12) (38), or areas of
honeycombing filled with secretions (39). Ground-glass opacity should be
considered to represent an active process only when there are no associated
HRCT findings of fibrosis. Findings of fibrosis in association with ground-glass
opacity include intralobular interstitial thickening, honeycombing, and traction
bronchiectasis and bronchiolectasis (Figs. 8-5, 8-6, and 8-12) (38). Ground-glass
opacities distinct from areas of fibrosis are present in approximately 25% of
patients with IPF and are typically less extensive than the reticulation (30).
FIGURE 8-12 Ground-glass opacities in a 55-year-old man with IPF. HRCT shows peripheral
reticulation, traction bronchiectasis and bronchiolectasis, and extensive ground-glass opacities.
Some of the areas of ground-glass opacity are associated with reticulation (straight arrows) and
therefore probably reflect the presence of microscopic fibrosis. However, some of the areas of
ground-glass opacity are not associated with findings of fibrosis (curved arrows) and therefore are
most consistent with active inflammation.
Another hallmark of IPF on HRCT is its patchy distribution (Figs. 8-13 and 814). Areas of mild and severe fibrosis and normal lung are often present in the
same patient, in the same lung, and in the same lobe. Also, and most important
diagnostically, findings of IPF often predominate in the peripheral and
subpleural regions (Figs. 8-3 to 8-14) and in the lung bases (Figs. 8-10, 8-11, and
8-14) (5,26). Concentric subpleural honeycombing is characteristic of IPF (Figs.
8-9 to 8-11 and 8-14). This subpleural predominance is evident on HRCT in 80%
to 95% of patients (26,27,40). In approximately 70% of patients, the fibrosis is
most severe in the lower lung zones; in approximately 20%, all zones are
involved to a similar degree; and in approximately 10%, mainly the middle or
upper lung zones are involved (40,41).
FIGURE 8-13 A 73-year-old man with IPF. HRCT through the lung bases shows a patchy
distribution of abnormalities, with mild honeycombing in the right lower lobe and extensive
honeycombing and marked loss of lung volume in the left lower lobe.
FIGURE 8-14 Characteristic patchy, peripheral, and basal distribution of IPF in a 59-year-old
man. A: HRCT at the level of the upper lobes demonstrates patchy subpleural reticulation and
mild honeycombing. Some of the subpleural regions are normal. B: HRCT at the level of the
bronchus intermedius shows more extensive subpleural reticulation and honeycombing. C: HRCT
at the level of the lung bases demonstrates extensive bilateral reticulation and honeycombing. D:
Coronal reformation better demonstrates the patchy distribution of the fibrosis and the
predominant subpleural and basal involvement.
A confident diagnosis of IPF on HRCT requires clinical exclusion of known
causes of UIP and the presence of all of the following four criteria: reticular
pattern, honeycombing, subpleural and basal predominance, and absence of
atypical features (5). Findings considered atypical for IPF include upper or midlung predominance, peribronchovascular predominance, consolidation, extensive
ground-glass opacities, profuse micronodules, discrete cysts (multiple, bilateral,
away from areas of honeycombing), and diffuse mosaic attenuation/air trapping
(bilateral, in three or more lobes) (5). These criteria and the utility of HRCT in
the diagnosis of UIP and IPF are reviewed in Chapter 3 (see Tables 3-5 and 3-6).
Other findings described in patients with IPF include emphysema, seen in
approximately 30% of patients, areas of decreased attenuation and vascularity in
4% to 43%, small areas of consolidation in 3%, and a few centrilobular nodules
in 2% to 15% (30,42,43). Patients with upper lobe emphysema and lower lobe
UIP are considered to have combined pulmonary fibrosis and emphysema
(10,44). The prognosis of combined IPF and emphysema is controversial, having
been reported to be similar or better than that of IPF alone (45,46) or worse than
that of patients with IPF who do not have emphysema (10,44). Occasionally, fine
linear or small nodular foci of calcification are seen within areas of fibrosis as a
result of ossification (Fig. 8-15) (47,48). Kim et al. (48) found disseminated
dendriform pulmonary ossification on HRCT in 5 of 75 patients (6.7%) with IPF,
but in none of 44 patients with NSIP.
FIGURE 8-15 Pulmonary ossification in a 74-year-old-man with IPF. A: HRCT at the level of
the right hemidiaphragm shows bilateral subpleural reticulation. B: HRCT image photographed
using soft-tissue windows at same level as A shows bilateral small calcified nodules within areas
of reticulation consistent with pulmonary ossification.
Patients with IPF have an increased risk of lung cancer and tuberculosis;
patients who are receiving corticosteroids are at an increased risk of
opportunistic infection particularly Pneumocystis jirovecii (49). A large
longitudinal study in the UK found an approximate five-fold increase in the
incidence of lung cancer in patients with IPF compared with the general
population (50). The majority of lung cancers in IPF present as well-defined
nodules or masses that may be located within areas of fibrosis and
honeycombing or away from them (Fig. 8-16) (51–53). Patients with IPF have
an increased prevalence of pulmonary tuberculosis and the radiologic
manifestations of tuberculosis in these patients are frequently atypical (49,54). In
one study (54) of nine patients with IPF and active tuberculosis, HRCT
demonstrated peripheral nodules or mass-like lesions in six (67%) and segmental
or lobar consolidation with and without cavitation in three (33%). Typical
patterns of active tuberculosis, including patchy multifocal consolidation, treein-bud pattern, and centrilobular nodules, were uncommon (54).
FIGURE 8-16 Lung cancer in IPF. HRCT demonstrates extensive bilateral peripheral
honeycombing and a right lower lobe nodule, which was shown on core needle biopsy to be an
adenocarcinoma.
Mediastinal lymph node enlargement is evident on CT in approximately 70%
of patients with IPF (55–57). The lymphadenopathy usually involves only one or
two nodal stations, and the nodes usually measure less than 15 mm in short-axis
diameter (56,57). The likelihood of lymphadenopathy increases with the extent
of parenchymal involvement and decreases in the presence of recent steroid
treatment. In a study by Franquet et al. (58), the prevalence of enlarged nodes
was 14% in patients who had recently received oral steroids, and 71% in patients
who had not taken steroids for at least 6 months.
Follow-up studies have shown only minor changes in the HRCT appearance
of IPF in the first 6 months following diagnosis (59), but progressive increase in
the extent of reticulation and honeycombing 1 year or more after diagnosis (Figs.
8-17 and 8-18) (60–62). This progression usually occurs over several months or
years and is associated with a gradual decline in pulmonary function. However,
every year approximately 5% to 10% of patients with IPF develop acute
respiratory worsening (5,63). This may be secondary to pneumonia, pulmonary
embolism, pneumothorax, or cardiac failure (5,63). When a cause cannot be
identified, the term acute exacerbation of IPF is used (5,64,65). An increased
risk of acute exacerbation is present after surgery, particularly lung surgery, with
an incidence ranging from 2% to 7% (66). The histologic findings of acute
exacerbation of IPF consist of diffuse alveolar damage (DAD) or, less
commonly, prominent organizing pneumonia (OP) superimposed on the UIP
pattern (Fig. 8-19) (5,67,68). The HRCT manifestations consist of extensive
bilateral ground-glass opacities and/or consolidation superimposed on
reticulation and honeycombing (Figs. 8-19 and 8-20) (67,69,70). The groundglass opacities and consolidation may be diffuse, multifocal, or peripheral
(67,69). The consolidation tends to involve mainly the dorsal half of the lung.
FIGURE 8-17 IPF with progression over 3 years. A: HRCT at presentation demonstrates mild
reticular pattern involving mainly the subpleural lung regions. Also noted is minimal traction
bronchiectasis. B: HRCT 3 years later demonstrates more extensive reticular changes, traction
bronchiectases, and mild subpleural honeycombing.
FIGURE 8-18 Progression of IPF. A: The initial HRCT shows subpleural reticulation. B: Five
months later, despite treatment, there has been progression of pulmonary fibrosis with intralobular
interstitial thickening, traction bronchiectasis, and more extensive lung involvement. The presence
of ground-glass opacity superimposed on reticulation may represent fibrosis or DAD secondary to
acute exacerbation.
FIGURE 8-19 A–C: A 56-year-old woman with acute exacerbation of IPF. A: HRCT shows
multifocal ground-glass opacities superimposed on fine peripheral reticular pattern. Minimal
traction bronchiolectasis is seen bilaterally in the upper lobes (straight arrows). B: Low-power
view demonstrates irregular peripheral fibrosis with fibroblastic focus (straight arrow)
characteristic of UIP. Insert shows high-power view of fibroblastic foci. C: High-power view of
different area shows DAD and hyaline membranes (arrowheads). (From Silva CIS, Müller NL,
Fujimoto K, et al. Acute exacerbation of chronic interstitial pneumonia: high-resolution computed
tomography and pathologic findings. J Thorac Imaging 2007;22:221–229, with permission.)
FIGURE 8-20 Acute exacerbation of IPF. A: HRCT shows irregular linear opacities, small foci
of ground-glass attenuation, and honeycombing in a patchy distribution predominantly in the
subpleural lung regions. B: HRCT performed when the patient presented with acute exacerbation
of clinical symptoms and rapid development of severe hypoxemia demonstrates extensive
bilateral areas of ground-glass attenuation. Also noted is slight progression of the honeycombing.
Patients with acute exacerbation have a poor prognosis with mortality
exceeding 60% (10,65). It was initially reported that patients with peripheral
ground-glass opacities on HRCT had a better prognosis than patients with
multifocal or diffuse opacities (67). This, however, was not confirmed in
subsequent studies (69–71). In a recent study of 60 patients with acute
exacerbation of IPF, Fujimoto et al. (70) demonstrated that the strongest
predictor of outcome is the extent of abnormalities on HRCT, including groundglass attenuation and/or consolidation with or without traction bronchiectasis or
bronchiolectasis and areas of honeycombing. The main differential diagnosis of
acute exacerbation on HRCT in patients with known IPF and acute clinical
deterioration is opportunistic infection, particularly P. jirovecii pneumonia
(PCP). In the context of IPF, the HRCT findings of PCP may be
indistinguishable from those of acute exacerbation (49).
Utility of High-Resolution Computed Tomography
Several studies have shown that CT and HRCT are superior to the chest
radiograph in the assessment of patients who have IPF. For example,
honeycombing is seen in up to 90% of CT studies, as compared to 30% of cases
on radiographs (35). HRCT findings have been shown to correlate with
symptoms and pulmonary function abnormalities in patients who have IPF.
Staples et al. (35) compared CT with clinical, functional, and radiologic findings
in 23 patients who had IPF. The CT scans provided a better estimate of the
pattern, distribution, and extent of pulmonary fibrosis and showed more
extensive honeycombing than did radiographs. In this study, there was also good
correlation between the extent of fibrosis on CT, and the severity of dyspnea (r =
0.64, p < 0.001). In one study of 39 untreated patients with IPF, global extent of
disease on HRCT correlated best with carbon monoxide diffusing capacity
(DLCO) and forced vital capacity (FVC) (72). In the same study, changes over
time in the total extent of the disease on HRCT also correlated with interval
decrease in DLCO and vital capacity (72). Lynch et al. (30) showed that the
presence and extent of honeycombing and the overall extent of fibrosis on
HRCT had a strong inverse correlation with the percent-predicted DLCO. The
FVC was significantly inversely associated only with the overall extent of
fibrosis score (30).
Several groups of investigators have shown that the extent of fibrosis and
honeycombing on HRCT are predictive of poor prognosis in IPF (73–75).
Flaherty et al. (76) demonstrated that among patients with IPF, a HRCT showing
characteristic features of IPF, namely, honeycombing, was associated with worse
survival than a HRCT showing findings more suggestive of NSIP (no
honeycombing) (median survival, 2.08 years vs. 5.76 years) and worse than
patients with a histologic diagnosis of NSIP (median survival > 9 years) (76).
Jeong et al. (73) found that patients who have IPF and minimal or no
honeycombing (i.e., honeycombing involving less than 5% of the parenchyma)
on HRCT had a mortality rate similar to those with NSIP, and significantly lower
than those with UIP and honeycombing. Sumikawa et al. (75) assessed the
prognostic value of HRCT findings in 98 patients with a histologic diagnosis of
UIP and a clinical diagnosis of IPF. On multivariate analysis, only extent of
fibrosis and extent of traction bronchiectasis were significant predictors of
mortality. Shin et al. (74) assessed the utility of clinical, HRCT, and
histopathologic findings in predicting the prognosis in 79 patients with UIP and
29 with fibrotic NSIP. The 5-year survival rate was 46% for patients with UIP
and 76% in fibrotic NSIP. On multivariate analysis, a high fibrotic score (extent
of reticulation plus honeycombing) and an initial low DLCO were identified as
associated with increased death risk. Overall, these various studies demonstrate
that the prognosis of IPF is worse than that of NSIP and that the prognosis in IPF
is influenced by the extent and severity of fibrosis.
The vast majority of the studies correlating extent of fibrosis on HRCT with
pulmonary function tests and with prognosis in patients with IPF have been
based on semiquantitative scores of the visual extent of lung fibrosis on CT. This
visual assessment is associated with intra-and interobserver variability and
typically limited to research studies. Objective quantitative evaluation would
have the potential of eliminating this variability and providing predictive
information at the time of the scan, which would be helpful to the clinicians for
determining treatment options (77). Best et al. (78) correlated measurements of
skewness, kurtosis, and mean lung attenuation, i.e., computer derived values that
describe the shape of HRCT frequency histograms with pulmonary function tests
in 144 patients with IPF. They found that kurtosis showed the greatest degree of
correlation with physiologic abnormality (r = 0.53, p < 0.01) and that kurtosis
alone provided predictions of pulmonary function that were virtually as good as
those from all histogram features combined (78). In a subsequent study, Best et
al. (77) assessed the value of baseline quantitative CT indexes, visual CT scores,
and pulmonary function tests as predictors of mortality in 167 patients with IPF.
At univariate analysis, baseline variables predictive of death included skewness,
kurtosis, visual extent of fibrosis, and total lung capacity (TLC). At multivariate
analysis, only visual extent of fibrosis and FVC were predictors of short-term
mortality (77). In 95 patients who had both baseline and serial CT scans over 12
months, skewness, kurtosis, mean lung attenuation, and visual extent of fibrosis
showed change indicating disease progression. The authors concluded that
evaluation of quantitative CT measures can show disease progression in patients
with IPF (77).
Although surgical lung biopsy was until recently considered the gold standard
for evaluating patients who have IPF, it has limitations. Most important, it is
invasive and usually assesses only a small part of the lung. Thus, the region
sampled may not be representative of the lung as a whole, and the presence of
inflammation may be missed. Furthermore, different lobes may show different
pathology. For example, in one review of the surgical lung biopsy specimens
obtained from two or more lobes in 109 patients with a clinical syndrome of IPF
and a histologic pattern of either UIP or NSIP, 51 patients had a histologic UIP
pattern in all lobes (concordant UIP), 33 patients had NSIP in all lobes sampled,
and 28 (26%) had both NSIP and UIP (i.e., discordant UIP) (79). In another
review of the multiple surgical lung biopsy specimens obtained in 64 patients
with suspected IPF, 39% had concordant UIP, 48% had concordant NSIP, and
13% had both UIP and NSIP (discordant UIP) (80). Only by correlating the CT
with the pathologic findings can an overall evaluation of the pattern and extent
of lung disease be adequately assessed.
CT is also helpful in determining the optimal site for lung biopsy, if this
procedure is considered necessary. At the time of surgical lung biopsy, the
surgeon must attempt to obtain diagnostic tissue by avoiding areas of extensive
honeycombing (19). This can be difficult in cases of IPF because the most severe
honeycombing is typically subpleural in location. An important role for CT in
the assessment of patients who have IPF is to help the surgeon choose the best
area for biopsy. Areas of honeycombing can be avoided, and less abnormal
areas, or areas of ground-glass opacity, can be sought (81).
Accuracy in Diagnosis
HRCT findings have been shown to be highly accurate in making a diagnosis of
UIP and IPF (40,82–86). Mathieson et al. (40) compared the accuracy of CT
with that of chest radiography in the prediction of specific diagnoses in 34
patients who had IPF and 84 patients who had other chronic interstitial diseases.
The radiographs and CT scans were assessed independently by three observers
without knowledge of clinical or pathologic data. A confident diagnosis of IPF
was made on CT scan in 73% of patients; this diagnosis was correct 95% of the
time. By comparison, a confident diagnosis was made in only 30% of chest
radiographs (the diagnosis being correct in 87% of cases) (40). Tung et al. (82)
reviewed the HRCT findings in 86 patients with diffuse lung diseases (including
41 with IPF) and found that a confident first-choice diagnosis on CT had a
sensitivity of 60% and a specificity of 98% for IPF. Swensen et al. (87) reviewed
the CT findings in 85 patients (including 18 who had IPF and who underwent
biopsy). A confident diagnosis of IPF on HRCT in this study had a sensitivity of
60% and a specificity of 93%. In a study of 134 patients with diffuse lung
disease, including 24 with IPF by Nishimura et al. (88), the HRCT diagnosis of
IPF had a sensitivity of 77% and a specificity of 93%. Recently Aaløkken et al.
(86) assessed the accuracy of HRCT and histologic findings in the diagnosis of
UIP in the context of IPF in a retrospective study of 91 patients with clinically
suspected interstitial lung disease. All underwent surgical lung biopsy and
HRCT. On the basis of a multidisciplinary approach, 41 patients had a final
diagnosis of UIP (IPF). The sensitivity, specificity, and positive predictive value
of the CT diagnosis of UIP were 63%, 96%, and 96%, respectively. The
sensitivity, specificity, and positive predictive value of the histologic diagnosis
of UIP were 73%, 74%, and 83%, respectively.
The diagnostic accuracy based on the HRCT findings increases with severity
of disease. Primack et al. (83) reviewed the HRCT scans of 61 consecutive
patients who had end-stage lung disease (defined by the presence of
honeycombing, extensive cystic changes, or conglomerate fibrosis). A correct
first-choice diagnosis of IPF was made in 23 of the 26 cases (88%); when the
observers were confident in their first-choice diagnosis of IPF (based on the
presence of predominantly subpleural and lower lung zone honeycombing), they
were correct in 100% of cases. The diagnosis of IPF in these patients was
established by biopsy specimens taken from relatively uninvolved areas or
before the development of end-stage disease (83).
The majority of studies were based on retrospective analysis of patients who
had HRCT and clinical or histologic diagnosis of various interstitial lung
diseases. The high specificity of a confident HRCT diagnosis was confirmed in
two prospective studies, both of which only included patients with biopsyproven diagnosis and used histologic features as gold standard (84,85). Raghu et
al. (85) assessed the accuracy of a clinical diagnosis of IPF and interstitial lung
diseases other than IPF in 59 patients who were referred for evaluation of newonset interstitial lung disease. A specific clinical diagnosis was independently
made by a clinician who was an expert in interstitial lung diseases after a
thorough clinical assessment that included evaluation of the HRCT findings. The
chest radiographs and CT scans were separately reviewed by the thoracic
radiologist, who made a radiologic diagnosis independently. The sensitivity and
specificity of the IPF diagnosis by the clinical expert were 62% and 97%,
respectively. The sensitivity and specificity of the radiologic first-choice
diagnosis of IPF were 78% and 90%, respectively (85). Hunninghake et al. (84)
performed a prospective multicenter investigation of 91 patients, including 54
patients with biopsy-proven IPF. The sensitivity of HRCT for a confident
diagnosis of IPF by experienced chest radiologists was 48%, and the specificity
and positive predictive values were 95% and 96%, respectively (84). Based on
these various studies, it is now well accepted that in the appropriate clinical
setting the presence of characteristic HRCT findings allows confident
noninvasive diagnosis of IPF obviating lung biopsy (1,5,10).
As mentioned previously, a confident HRCT diagnosis of IPF requires (a)
clinical exclusion of known causes of UIP, (b) presence of both a reticular
pattern and honeycombing, (c) predominately subpleural and basal distribution,
and (d) absence of atypical features (5). The latter include upper-or mid-lung
predominance, peribronchovascular predominance, consolidation, extensive
ground-glass opacities, profuse micronodules, discrete cysts (multiple, bilateral,
away from areas of honeycombing), and diffuse mosaic attenuation/air trapping
(bilateral, in three or more lobes) (5). If only the first, third, and fourth criteria
are present, namely if honeycombing is absent, the findings can only be
interpreted as “possible IPF” (5). The strongest predictors of IPF on HRCT are
lower lung honeycombing (odds ratio, 5.36) and upper lung reticulation (odds
ratio, 6.28) (32). Although basal and peripheral honeycombing is a strong
predictor of IPF, there is considerable interobserver disagreement in the
diagnosis of honeycombing (30,89). Confident diagnosis of honeycombing
requires presence of clustered cystic airspaces measuring 2 mm to 1 cm in
diameter that have well-defined thick walls and are located adjacent to the
pleura. They must be distinguished from traction bronchiolectasis, which may
have a similar appearance, but is typically located a few millimeters or more
from the pleura.
It should be noted that diagnostic HRCT findings of UIP/IPF are only present
in 50% to 70% of patients (5,84). In the remaining patients surgical biopsy is
required for a definitive diagnosis. When the histologic findings are
characteristic of UIP and the HRCT findings are consistent with this diagnosis,
the final diagnosis is UIP. However, when the histologic findings are not specific
for UIP or when the HRCT and histologic patterns are discordant, close clinical,
radiologic, and histopathologic correlations with multidisciplinary discussion
among experienced experts is required for an accurate diagnosis (5,90). It is
important to note that in the correct clinical setting a diagnosis of IPF is not
excluded by HRCT findings more suggestive of an alternate diagnosis. In a study
by Sverzellati et al. (91), the HRCT scans in 34 of 55 (62%) biopsy-proven IPF
cases were interpreted by at least two of three observers as low-grade probability
(< 30%) for IPF. In these atypical IPF cases, the most common HRCT diagnoses
were NSIP, chronic HP, and sarcoidosis (91).
NONSPECIFIC INTERSTITIAL PNEUMONIA
NSIP is a chronic interstitial lung disease characterized by homogeneous
expansion of the alveolar walls by varying amounts of interstitial inflammation
and fibrosis (6,7). It accounts for 14% to 35% biopsies performed for chronic
interstitial pneumonia (8). NSIP may be idiopathic but more commonly occurs as
a manifestation of collagen-vascular disease, hypersensitivity pneumonitis, druginduced lung disease, and slowly healing DAD (8,9,92). The histologic hallmark
of NSIP is its relative temporal and geographic homogeneity, the findings
appearing to represent the same stage in the evolution of the disease, as distinct
from the heterogeneity seen in UIP (Fig. 8-21; Table 8-1) (6,8,17). The
histologic findings may range from an inflammatory process with minimal
fibrosis (i.e., cellular NSIP) to predominant fibrosis (i.e., fibrotic NSIP). In
cellular NSIP, the alveolar septa are thickened by infiltrates of lymphocytes and
plasma cells, while in fibrotic NSIP the thickening is due to uniform fibrosis of
the same age, with varying amounts of cellular inflammation (6,8). Fibrotic
NSIP is much more common than cellular NSIP and the extent of interstitial
fibrosis is variable (6,79). The fibrosis may involve the alveolar septa,
peribronchiolar interstitium, interlobular septa, and visceral pleura (8).
Honeycombing is uncommon at presentation. It was not seen on surgical lung
biopsy specimens in any of 67 patients with definite or probable NSIP confirmed
by a panel of expert pathologists (6). It should be noted that although NSIP has
well-defined histologic features, lung biopsy specimens in these patients
commonly also show other features particularly foci of OP, bronchiolocentricity,
foci of DIP, and fibroblastic foci (6). Therefore there is considerable
interobserver variability between pathologists in the diagnosis of NSIP and often
difficulty in confidently distinguishing NSIP from other interstitial lung diseases
such as OP, HP, DIP, and UIP (6). A definitive diagnosis therefore requires a
multidisciplinary approach and careful clinico-radiologic-pathologic review (6).
FIGURE 8-21 Nonspecific interstitial pneumonia. Low-magnification photomicrograph shows
diffuse thickening of the alveolar septa by inflammatory cells. Note the temporal and geographic
homogeneity of the findings as distinct from the variegated appearance of UIP. (Courtesy of Dr.
John English, Department of Pathology, Vancouver General Hospital, Vancouver, British
Columbia, Canada.)
The presence of fibrosis in NSIP is associated with a worse prognosis (1).
Patients with an exclusively inflammatory component (i.e., cellular NSIP) have
an excellent prognosis with few reported deaths, while the reported median
survival of patients with fibrotic NSIP ranges from approximately 6 to 14 years
(4). The prognosis of NSIP, whether cellular or fibrotic, is therefore considerably
better than the prognosis of IPF (median survival, 2.5–3.5 years) (1,10).
NSIP has been described in patients ranging from 9 to 78 years of age, but the
median age of onset of symptoms in most studies is 40 to 50 years, which is
more than 10 years younger than patients with IPF (1,92). It is more common in
women than in men and in nonsmokers as compared to smokers or ex-smokers
(1,92). The respiratory symptoms, similar to those of IPF, usually consist of
dyspnea on exertion and dry cough (1,92).
The radiographic findings consist mainly of ground-glass opacities or
consolidation involving predominantly the lower lung zones (93). Other
manifestations include a reticular pattern or a combination of interstitial and
airspace patterns (7,93). In approximately 10% to 15% of cases, the chest
radiograph is normal (93,94).
High-Resolution Computed Tomography Findings
The typical HRCT manifestations of NSIP consist of ground-glass opacities,
irregular linear (reticular) opacities, and traction bronchiectasis in a
predominantly lower lung zone distribution (Figs. 8-22 to 8-24; Table 8-3)
(9,31,95). In virtually all studies, ground-glass opacities were reported in 76% to
100% of patients and were most commonly the predominant finding (31,95–97).
Importantly however, ground-glass opacities were only seen in 44% of patients
in a large multicenter review by a panel of experts (6). Reticular opacities have
been reported in 50% to 100% of patients (31,95,96). The different prevalences
of ground-glass opacities and reticulation in the various studies may reflect the
different prevalence of cellular and fibrotic NSIP or the timing of the CT. Silva
et al. (98) demonstrated a significant reduction in the extent of ground-glass
opacities and an increase in the extent of reticulation in 23 patients with NSIP
who had a follow-up CT 3 or more years after initial diagnosis. Most patients
with reticulation and some with only ground-glass opacities also have traction
bronchiectasis and bronchiolectasis (Figs. 8-23 to 8-25). Honeycombing has
been reported in 0% to 44% of patients (9,95,96,98). The broad range in the
prevalence of honeycombing probably reflects the difficulty in distinguishing
NSIP from UIP and the timing of the CT. In the large multicenter study
mentioned above that found reticulation to be the predominant finding in most
cases, the prevalence of honeycombing was 5% (6). Silva et al. demonstrated
that the prevalence of honeycombing in NSIP increases in patients who have
follow-up HRCT 3 or more years after initial presentation (98). When present,
honeycombing tends to be mild, involving less than 5% of the parenchyma (Fig.
8-26). Areas of consolidation and centrilobular nodules have been reported in a
small percentage of patients in several studies (6,95,96) but were not seen in one
other large study (31). The abnormalities in NSIP may be diffuse, but in 60% to
90% of cases involve mainly the lower lung zones (Fig. 8-27) (31,95,96). The
lower lobe predominance is particularly evident in patients with fibrotic NSIP
where it is typically associated with volume loss (6,9,95). Upper lobe
predominance is uncommon in NSIP and should suggest another diagnosis such
as sarcoidosis or chronic HP (9). A peripheral predominance is less common
than a lower lobe predominance, being seen in 38% to 74% of cases (31,95–97).
Furthermore, Silva et al. (43,98) demonstrated that a characteristic feature of
NSIP is relative sparing of the immediate subpleural lung in the dorsal regions of
the lower lobes (Figs. 8-23, 8-25, and 8-26). This relative subpleural sparing can
be helpful in distinguishing fibrotic NSIP from UIP because UIP is typically
most severe in the subpleural regions (43). The prevalence of relative subpleural
sparing in NSIP in various studies has ranged from 20% to 64% of patients
(6,43,98).
FIGURE 8-22 NSIP in a 48-year-old woman. HRCT demonstrates extensive bilateral groundglass opacities. The findings are consistent with cellular NSIP.
FIGURE 8-23 NSIP in a 74-year-old man. HRCT shows diffuse bilateral ground-glass
opacities with relative sparing of the lung immediately adjacent to the pleura (relative subpleural
sparing, arrows). Also noted are mild reticulation and traction bronchiectasis. The findings are
consistent with mixed cellular and fibrotic NSIP.
FIGURE 8-24 A–C: NSIP in a 60-year-old man who had dyspnea. HRCT findings consist of
ground-glass opacity associated with some irregular reticulation. The lung involvement is diffuse
and patchy, with no definite peripheral or basal predominance. The findings are consistent with
mixed cellular and fibrotic NSIP.
FIGURE 8-25 A–C: NSIP in a 34-year-old man. HRCT images show extensive bilateral
intralobular interstitial thickening and traction bronchiectasis. Ground-glass opacities are present
only in areas of reticulation. Note relative subpleural sparing of the dorsal regions of the lower
lobes, a characteristic feature of NSIP. The findings are consistent with fibrotic NSIP.
FIGURE 8-26 Honeycombing in NSIP. A: HRCT at the level of the upper lobes in a 60-yearold woman with NSIP demonstrates extensive bilateral ground-glass opacities, mild reticulation,
traction bronchiectasis (curved arrows), traction bronchiolectasis (arrowheads), and a few
subpleural honeycomb cysts (straight arrows). B: HRCT at the level of the inferior pulmonary
veins demonstrates more severe reticulation and traction bronchiectasis. A few subpleural
honeycomb cysts are seen (arrows). Note relative sparing of the lung immediately adjacent to the
pleura (relative subpleural sparing) in the dorsal regions of the lower lobes, a characteristic
feature seen in up to 65% of patients with fibrotic NSIP.
TABLE 8-3 HRCT Findings in Nonspecific Interstitial Pneumonia
Ground-glass opacitya
Findings of fibrosis (i.e., traction bronchiectasis and bronchiolectasis, intralobular interstitial
thickening, irregular interlobular septal thickening, irregular interfaces) common but milda
Honeycombing uncommon and mildb
Lower lung zone predominance of ground-glass opacity and reticulationa,b
Basal and peripheral predominance of ground-glass opacity and reticulationa,b
Relative subpleural sparing in the dorsal regions of the lower lobesa,b
aMost common finding(s).
bFinding(s) most helpful in differential diagnosis.
Patients with NSIP and only ground-glass opacities on HRCT are likely to
have cellular (inflammatory) NSIP (Fig. 8-22) (9,99). This pattern, however, is
seen in a small percentage of cases. The vast majority of patients with groundglass opacities also have reticulation and/or traction bronchiectasis and may have
cellular or, more commonly, fibrotic NSIP (Figs. 8-23 to 8-26) (31,42,100).
Several studies have shown that although patients with fibrotic NSIP tend to
have greater extent of reticulation, reticulation is also frequently present in
patients with cellular NSIP (31,42,100). Furthermore, these studies showed no
appreciable difference in the extent of ground-glass opacities between patients
with cellular and fibrotic NSIP (31,42,100). In summary, the HRCT findings of
cellular and fibrotic NSIP frequently overlap, and there is no reliable way to
differentiate between the two subtypes (9).
Serial CT scans in patients with NSIP have shown that patients with
predominant ground-glass opacities on the initial CT are more likely to improve
with treatment and have a better long-term prognosis than patients with
predominant fibrosis (Figs. 8-28 and 8-29). In one study of 13 patients with
biopsy-proven NSIP, the initial CT scans showed ground-glass opacities and, to a
lesser extent, reticulation (101). On follow-up HRCT, there was a significant
reduction in the extent of ground-glass opacities and an improvement in FVC
that correlated with the extent of reduction in ground-glass opacities on CT
(101). Screaton et al. (102) performed serial CT scans in 38 patients with
histologically proven NSIP, including 4 with cellular NSIP, 13 with mixed
cellular and fibrotic NSIP, and 21 with fibrotic NSIP. The predominant initial CT
pattern was interpreted as inflammatory (ground-glass opacities and
consolidation) in 6 (16%) patients and fibrotic (reticulation) in 32 (84%)
patients. The predominant pattern on the initial HRCT was significantly
associated with change in extent of parenchymal abnormality on follow-up CT.
At a mean follow-up of approximately 1 year, all patients with an inflammatory
predominant pattern on the initial CT improved, whereas of the 32 patients with
a fibrotic predominant pattern, 7 (22%) improved, 6 (19%) deteriorated, and 19
(59%) remained stable. Surprisingly, there was no significant association
between the histologic findings and the likelihood of improvement on follow-up
CT (102). Hozumi et al. (103) assessed the prognostic significance of the HRCT
findings in 59 patients with biopsy-proven NSIP (25 idiopathic NSIP, 34
collagen-vascular disease-associated NSIP). Extent of ground-glass opacities
without traction bronchiectasis or bronchiolectasis and extent of airspace
consolidation were associated with favorable outcome, whereas extent of
reticular opacities was associated with worse prognosis (103).
FIGURE 8-27 Basal predominance of NSIP in a 52-year-old woman. A: HRCT at the level of
the right upper lobe bronchus shows patchy bilateral ground-glass opacities. B: HRCT at the level
of the lung bases shows extensive bilateral ground-glass opacities, mild reticulation, and traction
bronchiectasis. C: Coronal reformation better demonstrates the basal and peripheral
predominance of the findings.
FIGURE 8-28 NSIP improved with treatment. A: HRCT shows patchy bilateral ground-glass
opacities and mild reticulation, mainly in a peripheral distribution. B: HRCT 7 months later shows
almost complete resolution of the ground-glass opacities and mild residual peripheral reticulation.
FIGURE 8-29 NSIP: progression of fibrosis over 4 years. A: HRCT in a 60-year-old woman
with NSIP shows extensive bilateral ground-glass opacities. Also noted are mild reticulation and
traction bronchiectasis consistent with fibrosis. B: HRCT 4 years later at the same level as A
shows progression of the fibrosis with marked increase in the extent of reticulation and traction
bronchiectasis. Note relative subpleural sparing in the dorsal regions.
The majority of patients with NSIP who show progression of fibrosis on
follow-up maintain a CT pattern most suggestive of NSIP (Fig. 8-29); however, a
significant minority progress to a UIP pattern (Fig. 8-30) (98,104). Silva et al.
(98) reviewed the HRCT findings of 48 patients with biopsy-proven NSIP (n =
23) or IPF (n = 25) who had HRCT at initial diagnosis and 34 to 155 months
later. Follow-up CT in patients with NSIP showed marked decrease in the extent
of ground-glass opacities, increase in reticulation, and a greater likelihood of
peripheral distribution (all p < 0.05). At presentation, the CT findings were
interpreted by two independent radiologists as suggestive of NSIP in 18 of 23
patients with NSIP and indeterminate or suggestive of IPF in 5. In 5 of the 18
(28%) patients with initial findings suggestive of NSIP, the follow-up CT scans
were interpreted as more suggestive of IPF. There were no CT features at
presentation that allowed distinction of patients with NSIP that maintained a
NSIP pattern at follow-up from those that progressed to an IPF pattern (98). Kim
et al. (104) did a retrospective review of changes in HRCT in 61 patients with
fibrotic NSIP who had follow-up HRCT after at least 1-year interval (median, 38
months). On follow-up HRCT, 22 (36%) were improved, 14 (23%) were stable,
8 (13%) had recurrence after initial improvement, and 17 (28%) progressed
continuously, including 3 patients with conversion to a definite UIP pattern
(104). The lower percentage of patients that progressed to a UIP pattern (5%) in
the study of Kim et al. (104), compared to 28% in the study of Silva et al. (98),
is presumably related to the shorter follow-up period (minimum of 1 year
compared to a minimum of 34 months). Schneider et al. (105) reported the
histologic findings in five patients with proven fibrotic NSIP who had clinical
and radiologic progression and required repeat surgical biopsy or lung
transplantation. Review of the initial histology confirmed the diagnosis of
fibrotic NSIP while the specimens obtained 29 to 115 months later showed
morphologic features of UIP (105). These results indicate that at least some
cases with characteristic HRCT and histologic features of NSIP progress to UIP.
FIGURE 8-30 NSIP with progression to a UIP pattern over 4 years. A: HRCT in a 78-year-old
woman with NSIP shows extensive bilateral ground-glass opacities, mild reticulation, and
extensive traction bronchiectasis consistent with fibrosis. Surgical lung biopsy confirmed the
diagnosis of fibrotic NSIP B: HRCT 4 years later at the same level as A shows patchy subpleural
reticulation and honeycombing. While the HRCT findings at presentation are consistent with
fibrotic NSIP, the pattern and distribution of abnormalities on the follow-up HRCT are
characteristic of UIP.
Similar to patients with IPF, patients with NSIP may develop acute
deterioration with an abrupt worsening of symptoms due to infection, pulmonary
embolism, pneumothorax, or heart failure. Occasionally, however, no
identifiable cause for the acute decline is identified, and these episodes are called
“acute exacerbation” of NSIP (68,69,106). The histologic findings consist of
DAD or, less commonly, OP superimposed on a background of NSIP (Fig. 8-31)
(68,107). The HRCT findings consist of extensive ground-glass opacities and/or
consolidation superimposed on reticulation (Fig. 8-31) (69).
FIGURE 8-31 Fatal acute exacerbation in a 48-year-old woman with biopsy-proven NSIP who
presented with acute shortness of breath. A: HRCT shows diffuse ground-glass opacities and mild
reticulation. B: Low-power view demonstrates area of organizing DAD (straight arrows). C: Lowpower view shows extensive paucicellular alveolar wall fibrosis, characteristic of fibrotic NSIP
(H&E, ×100). (From Silva CIS, Müller NL, Fujimoto K, et al. Acute exacerbation of chronic
interstitial pneumonia: high-resolution computed tomography and pathologic findings. J Thorac
Imaging 2007;22:221–229, with permission.)
Mediastinal lymph node enlargement is evident on CT in approximately 80%
of patients (56,57). The nodal enlargement is usually mild, with lymph nodes
measuring 10 to 15 mm in short-axis diameter and involving only one or two
nodal stations (most commonly the right lower paratracheal or subcarinal
region). The prevalence of mediastinal lymphadenopathy in NSIP is similar to
that in IPF. In one study of 206 patients, mediastinal lymphadenopathy was seen
in 90 of 136 (66%) patients with IPF, 38 of 47 (81%) with NSIP, 5 of 7 (71%)
with RB-ILD or DIP, and 6 of 16 (38%) with COP (also known as idiopathic
bronchiolitis obliterans organizing pneumonia [BOOP]) (57). No significant
difference was found in the prevalence of lymphadenopathy in patients with
predominant ground-glass opacity or predominant reticulation. However, there
was a positive correlation between the extent of disease in patients with NSIP
and the likelihood of lymphadenopathy.
It should be noted that there is considerable overlap between the HRCT
findings of NSIP and those present in other interstitial pneumonias (Table 8-1).
Abnormalities seen on HRCT in patients who have NSIP can mimic those of UIP
(predominantly lower lobe reticulation), HP, RB-ILD/DIP (predominantly
ground-glass opacities), and BOOP (when there is extensive consolidation)
(31,96,108). An ATS-sponsored multidisciplinary workshop on NSIP showed
that this limitation is not restricted to HRCT but also applies to the clinical
assessment and histology (6). The workshop pointed out that NSIP showed the
most overlap clinically, radiologically, and histologically with UIP/IPF, HP,
BOOP, and RB-ILD (6). It also emphasized that when HRCT shows a typical
pattern of UIP (in particular honeycombing), HP, or BOOP, these diagnoses are
favored over idiopathic NSIP, even if a surgical lung biopsy shows histologic
features of NSIP (6). MacDonald et al. (31) compared the HRCT findings of UIP
and NSIP in 53 consecutive patients who had a clinical presentation consistent
with IPF and who underwent lung biopsy. The final diagnosis was IPF in 32
patients and NSIP in 21. HRCT had a sensitivity of 63% and specificity of 70%
for UIP, and a sensitivity of 70% and specificity of 63% for NSIP. The most
helpful finding in distinguishing NSIP from UIP was the greater extent of
ground-glass opacities (odds ratio: 1.04 for each 1% increase in the proportion of
ground-glass opacities) (28). Elliot et al. (97) reviewed the HRCT scans of 47
patients with biopsy-proven IPF (n = 22) and NSIP (n = 25). A confident CT
diagnosis of IPF and NSIP was correct in 88% and 73% of cases, respectively.
The presence of honeycombing as a predominant feature had a specificity of
96%, sensitivity of 41%, and a positive predictive value of 90% for IPF. This
pattern was identified in only a single patient (by both readers) with fibrotic
NSIP. Conversely, predominant ground-glass opacity and/or reticular opacity
with minimal or no honeycombing was identified in 48 of 50 (96%) readings in
patients with NSIP and in 26 of 44 (59%) readings in patients with UIP, giving a
sensitivity of 96% and a specificity of 41% for the diagnosis of NSIP (97).
Sumikawa et al. (42) compared the HRCT findings of various IIPs in 92 patients
with biopsy-proven diagnosis. Two independent observers made the correct
diagnosis in 79% of readings. Multivariate logistic regression analysis showed
that the most useful finding for distinguishing IPF from NSIP was the extent of
honeycombing. The average extent of honeycombing was 4.4% of the
parenchyma in IPF, 0.3% in cellular NSIP, and 0.6% in fibrotic NSIP (42). Akira
et al. (109), in a study that included 54 patients with NSIP and 42 patients with
UIP, demonstrated that the accuracy of HRCT in distinguishing NSIP from UIP
is decreased in patients with concurrent emphysema. Overall, the HRCT
diagnosis of NSIP or UIP was correct in 136 of 192 (71%) readings. In patients
with concurrent emphysema, the diagnosis was correct in 30 of 68 (44%)
readings (109). Silva et al. (43) assessed the accuracy of HRCT in distinguishing
NSIP, IPF, and chronic HP in 66 patients. A confident diagnosis was made in 70
of 132 (53%) readings, and this diagnosis was correct in 66 of 70 (94%)
readings, including 29 of 31 (94%) readings for NSIP. The features that best
differentiated NSIP were relative subpleural sparing, absence of lobular areas
with decreased attenuation, and lack of honeycombing (p < 0.002). The features
that best differentiated IPF were basal predominance of honeycombing, absence
of relative subpleural sparing, and absence centrilobular nodules (p < 0.004).
The features that best differentiated chronic HP were lobular areas with
decreased attenuation and vascularity, centrilobular nodules, and absence of
lower zone predominance of abnormalities (p < 0.008) (43). In summary, these
various studies demonstrate that HRCT allows distinction of NSIP from IPF and
chronic HP in many patients. However, although the presence of predominantly
peripheral and basal honeycombing in the appropriate clinical setting often
allows a confident diagnosis of IPF on HRCT (5), a confident diagnosis of NSIP
requires surgical biopsy and a dynamic multidisciplinary approach with input
from clinicians, radiologists, and pathologists (6). It is important to note that
even a histologic diagnosis of NSIP does not establish a final diagnosis. NSIP is
a common reaction pattern to various drugs, is commonly associated with
collagen-vascular diseases (particularly scleroderma), and can be a histologic
manifestation of hypersensitivity pneumonitis (1,8). These conditions need to be
excluded by careful clinical assessment before making a diagnosis of idiopathic
NSIP.
Utility of High-Resolution Computed Tomography
Although an accurate diagnosis of interstitial pneumonia cannot always be made
using HRCT, the HRCT appearance is often used to determine further
evaluation. In a patient who has suspected IIP, the HRCT finding of patchy or
subpleural ground-glass opacity, with or without reticulation, should suggest a
likely diagnosis of NSIP rather than UIP. Generally, lung biopsy is recommended
in this setting. However, if honeycombing is a predominant feature of disease,
UIP is much more likely than NSIP, and lung biopsy is often avoided.
HRCT may also be valuable in the follow-up of disease. In patients who have
NSIP, areas of ground-glass opacity decrease on follow-up HRCT, and the extent
of decrease correlates significantly with that of functional improvement. In an
early study of 7 patients by Park et al. (93), the most common finding observed
on initial HRCT scans was bilateral ground-glass opacity present alone or with
areas of consolidation in five patients (71%) or irregular lines in two (29%). At
follow-up CT, the initial parenchymal abnormalities had resolved completely in
three patients, improved in another three, and persisted in one. Kim et al. (101)
assessed serial changes on HRCT and PFTs in 13 patients who had NSIP (mean
follow-up period, 11 months). On initial HRCT, all patients had areas of groundglass opacity and irregular linear opacities. The areas of ground-glass opacity
decreased significantly on follow-up CT, whereas areas of irregular linear
opacity decreased slightly. Initial FVC (69%) also improved significantly on
follow-up examination (84%) (p = 0.003).
In a study by Nishiyama et al. (110) of 15 patients who had proven NSIP,
initial HRCT findings included a mixed pattern of ground-glass opacity and
consolidation (n = 11), peribronchovascular interstitial thickening (n = 6),
parenchymal bands (n = 8), intralobular interstitial thickening (n = 12), and
traction bronchiectasis (n = 14). On follow-up HRCT in 14 cases, the
abnormalities had disappeared completely in 3 cases, improved in 9 cases,
persisted in 1 case, and worsened in 1 case. Screaton et al. (102) performed
serial CT scans in 38 patients with histologically proven NSIP, including 4 with
cellular NSIP, 13 with mixed cellular and fibrotic NSIP, and 21 with fibrotic
NSIP. The predominant initial CT pattern was inflammatory (ground-glass
opacities and consolidation) in 6 (16%) patients and fibrotic (reticulation and
honeycombing) in 32 (84%) patients. The predominant pattern on the initial
HRCT was significantly associated with change in extent of parenchymal
abnormality on follow-up CT. At a mean follow-up of approximately 1 year, all
patients with an inflammatory pattern on the initial CT improved, whereas of the
32 patients with a fibrotic pattern 7 (22%) improved, 6 (19%) deteriorated, and
19 (59%) remained stable (102).
Although a definitive diagnosis of NSIP requires surgical biopsy, in clinical
practice surgical biopsy is underused and performed in less than 15% of patients
with chronic interstitial lung disease (111,112). Even if patients undergo lung
biopsy, there is considerable disagreement between pathologists in the diagnosis
of interstitial lung diseases, particularly NSIP (113). Furthermore, as pointed out
by Churg and Müller (114), a histologic diagnosis of NSIP often does not
constitute a final diagnosis because it might reflect hypersensitivity pneumonitis,
collagen-vascular disease, or drug-induced lung disease, and in fact, collagenvascular disease and drug reactions can look like UIP or COP. Moreover, in
many cases, even expert clinicians, pathologists, and radiologists fail to reach a
consensus as to the diagnosis. Churg and Müller (114) therefore proposed an
alternative approach to the IIPs and morphologically and radiologically related
conditions, such as hypersensitivity pneumonitis, interstitial lung disease in
collagen-vascular disease patients, and drug-related interstitial lung disease.
Their approach is based on separating the radiologic or pathologic findings into
three types: (a) purely cellular processes, with or without a component of OP; (b)
processes that show the type of linear fibrosis (fibrosis that follows the original
alveolar walls) without architectural distortion as seen in fibrotic NSIP, some
cases of chronic hypersensitivity pneumonitis, and some drug reactions, with or
without a cellular component; and (c) processes that demonstrate the fibrotic
architectural distortion of UIP, namely, honeycombing (114). Processes that are
purely cellular, including RB-ILD, DIP, cellular NSIP, COP, and subacute
(nonfibrotic) hypersensitivity pneumonitis, usually respond to corticosteroid
therapy. Thus, regardless of the specific diagnosis or label of the disease, if the
process is purely cellular, then it usually responds to treatment. Linear fibrosis
without architectural distortion is associated with a distinctly worse prognosis
than purely cellular lesions. This has been well documented for patients with
NSIP (115) and patients with chronic hypersensitivity pneumonitis and fibrosis
(116). The prognosis for patients with NSIP and linear fibrosis, however, is
better than the prognosis of patients with UIP. Churg and Müller proposed a
similar separation on HRCT (114). Chronic interstitial diseases characterized by
airspace opacification (ground-glass opacities or consolidation) without
reticulation (i.e., without underlying fibrosis) include COP, cellular NSIP, DIP,
and subacute hypersensitivity pneumonitis. These patients usually respond to
therapy and have a good prognosis (62,102,117). Diseases that manifest with
extensive ground-glass opacities and relatively mild reticulation (reticulation
representing <25% of the parenchymal abnormalities), including mixed fibrotic
and cellular NSIP, some cases of DIP, and chronic hypersensitivity pneumonitis,
have a worse prognosis than conditions with purely ground-glass opacities.
However, these patients have a better prognosis than patients with predominant
reticulation, as seen in patients with fibrotic NSIP, chronic hypersensitivity
pneumonitis, and UIP (100,115,117). This classification is practical and helpful,
particularly for cases in which the clinical, histologic, and radiologic features do
not fit neatly into the ATS/ERS classification of IIPs, nor with a diagnosis of
hypersensitivity pneumonitis (114).
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9
The Idiopathic Interstitial Pneumonias, Part II: Cryptogenic
Organizing Pneumonia, Acute Interstitial Pneumonia, Respiratory
Bronchiolitis-Interstitial Lung Disease, Desquamative Interstitial
Pneumonia, Lymphoid Interstitial Pneumonia, and Pleuroparenchymal
Fibroelastosis
IMPORTANT TOPICS
CRYPTOGENIC ORGANIZING PNEUMONIA
ACUTE INTERSTITIAL PNEUMONIA
RESPIRATORY BRONCHIOLITIS AND RESPIRATORY BRONCHIOLITIS-INTERSTITIAL
LUNG DISEASE
DESQUAMATIVE INTERSTITIAL PNEUMONIA
LYMPHOID INTERSTITIAL PNEUMONIA
PLEUROPARENCHYMAL FIBROELASTOSIS
Abbreviations Used in This Chapter
AIP
acute interstitial pneumonia
ATS
American Thoracic Society
BOOP
bronchiolitis obliterans organizing pneumonia
CEP
chronic eosinophilic pneumonia
COP
cryptogenic organizing pneumonia
DAD
diffuse alveolar damage
DIP
desquamative interstitial pneumonia
DLCO
carbon monoxide diffusing capacity
ERS
European Respiratory Society
IIP
idiopathic interstitial pneumonia
LIP
lymphoid interstitial pneumonia
NSIP
nonspecific interstitial pneumonia
OP
organizing pneumonia
PFT
pulmonary function test
PPFE
pleuroparenchymal fibroelastosis
RB
respiratory bronchiolitis
RB-ILD
respiratory bronchiolitis-interstitial lung disease
UIP
usual interstitial pneumonia
The diseases reviewed in this chapter include the subacute and acute idiopathic
interstitial pneumonias (IIPs) (cryptogenic organizing pneumonia [COP] and
acute interstitial pneumonia [AIP]), smoking-related IIPs (respiratory
bronchiolitis-interstitial lung disease [RB-ILD] and desquamative interstitial
pneumonia [DIP]), and rare IIPs (idiopathic lymphoid interstitial pneumonia
[LIP] and idiopathic pleuroparenchymal fibroelastosis [PPFE]) as outlined in the
2013 updated classification of IIPs by the American Thoracic Society/European
Respiratory Society (ATS/ERS) (Table 8-1) (1). The updated classification is a
supplement to the 2002 ATS/ERS consensus classification of IIPs (2). The main
changes in the updated classification regarding the entities discussed in this
chapter are: (a) classification of RB-ILD and DIP as smoking-related IIPs; (b)
recognition of one new IIP, idiopathic PPFE, as a specific rare entity
characterized by predominantly upper lobe pleural and adjacent parenchymal
fibrosis and elastosis of alveolar walls; and (c) creation of a category of rare IIPs
that includes idiopathic LIP and idiopathic PPFE (1). It is important to keep in
mind that the histologic patterns associated with the various IIPs may also be
seen in association with various diseases (e.g., collagen-vascular diseases) or
exposures (e.g., drugs). Furthermore, LIP is usually classified as part of the
spectrum of nonneoplastic pulmonary lymphoproliferative disorders (see
Chapter 11) (3,4) and is usually associated with immune disorders, most
commonly Sjögren syndrome (1,5). However, idiopathic cases do occur, the
clinical and radiologic presentation of LIP enters the differential diagnosis of
diffuse lung disease, and histologically its pattern is that of an interstitial
pneumonia (1,2). It therefore was included in the ATS/ERS international
multidisciplinary consensus classifications of IIPs in 2002 and 2013 (1,2) and is
discussed in this chapter.
CRYPTOGENIC ORGANIZING PNEUMONIA
Organizing pneumonia (OP) is a histologic pattern characterized by the presence
of intraluminal plugs of granulation tissue within alveolar ducts and surrounding
alveoli associated with chronic inflammation of the surrounding lung
parenchyma (Fig. 9-1) (1,2). Granulation tissue polyps may also be present in
the respiratory bronchioles. Therefore, the condition is also known as
bronchiolitis obliterans organizing pneumonia (BOOP) (6,7), although the use of
this term is diminishing with time. OP is a common reaction pattern seen in
association with pulmonary infection, connective tissue diseases, inflammatory
bowel disease, inhalational injury, hypersensitivity pneumonitis, drug toxicity,
malignancy, radiation therapy, and aspiration (2,8,9). Because most cases are
secondary, the 2013 ATS/ERS statement recommends the use of the generic term
“OP” for this reaction pattern, with modifiers as appropriate, for example, OP
associated with polymyositis (1). In some patients, however, no underlying cause
is found, and the condition is termed COP (10) or idiopathic BOOP (6). Because
the clinical, functional, radiologic, and high-resolution computed tomography
(HRCT) findings are primarily the result of an OP, the 2002 and 2013 ATS/ERS
Multidisciplinary Consensus Classification Committees recommended that the
condition be named COP rather than BOOP (1,2).
FIGURE 9-1 COP (idiopathic OP or BOOP): histologic findings. Photomicrograph at low
magnification shows characteristic granulation tissue polyps (arrows) in the alveolar ducts and
adjacent airspaces. Also noted is mild interstitial inflammation. (Courtesy of Dr. John English,
Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.)
Patients who have COP typically present with a 2-to 4-month history of
nonproductive cough (2,8,11). They often have a low-grade fever, malaise, and
shortness of breath (8,12). Pulmonary function tests (PFTs) characteristically
show a restrictive pattern (8,12). The mean age of presentation is approximately
50 to 60 years (8,12). Clinically and functionally, the findings may be similar to
idiopathic pulmonary fibrosis, although the duration of symptoms in patients
who have COP is shorter, systemic symptoms are more common, and finger
clubbing does not occur (2,11,12). The patients usually respond well to
corticosteroid therapy but relapse is common (1,8,12).
The characteristic radiologic features of COP consist of patchy, nonsegmental,
unilateral, or bilateral areas of airspace consolidation (6,10,13,14). In the
majority of patients, the multifocal areas of consolidation change in location
over a matter of weeks (9). In some patients, the consolidation may be peripheral
(13,15). Irregular reticular opacities may be present, but they are seldom a major
feature. Small nodular opacities may be seen as the only finding or, more
commonly, in association with areas of consolidation.
Although the radiographic findings of COP are nonspecific, in the majority of
cases, the presence of areas of consolidation and the paucity or absence of
reticular opacities allow an easy distinction of COP from usual interstitial
pneumonia (UIP) (13,14). The peripheral distribution of consolidation may
mimic chronic eosinophilic pneumonia (CEP). Migration of the areas of
consolidation and spontaneous regression of consolidation are helpful in
narrowing the differential diagnosis to COP, secondary OP, eosinophilic
pneumonia, pulmonary hemorrhage, and pulmonary vasculitis (9).
High-Resolution Computed Tomography Findings
The CT and HRCT findings in patients who have COP have been described by a
number of authors (16–20), and these descriptions are remarkably similar.
Typical HRCT features of this entity include (a) patchy consolidation (seen in
80%–90% of cases), which in 60% to 80% of cases has a subpleural and/or
peribronchial distribution (Figs. 9-2 to 9-6); (b) perilobular pattern seen in 60%
of cases (Fig. 9-7); (c) small, ill-defined nodules (30%–50% of cases) that may
be peribronchial or peribronchiolar (Figs. 9-8 and 9-9); (d) large nodules or
masses (Fig. 9-10); and (e) bronchial wall thickening or dilatation in abnormal
lung regions (Fig. 9-5, Table 9-1). The perilobular pattern is defined as poorly
defined linear opacities that are of greater thickness than those encountered in
thickened interlobular septa and that have an arcade-like or polygonal
appearance (Fig. 9-7) (20). In approximately 20% of patients, OP results in
crescentic or ring-shaped opacities surrounding areas of ground-glass
opacification, a pattern referred to as the atoll sign (21) or reversed halo sign
(Figs. 9-7 and 9-11) (22).
FIGURE 9-2 COP (idiopathic BOOP). A: HRCT through the right lower lung zone in a 64year-old woman shows airspace consolidation mainly in the subpleural regions. Some small
nodules of consolidation are seen to be centrilobular (arrows). B: Mediastinal window settings
better delineate the dense subpleural consolidation.
FIGURE 9-3 COP (idiopathic BOOP). HRCT through the lower lung zones in a 68-year-old
woman shows subpleural and peribronchial distribution of the airspace consolidation. Some areas
of consolidation are nodular.
FIGURE 9-4 COP (idiopathic BOOP) in a 55-year-old man. HRCT shows patchy, bilateral
ground-glass opacities and airspace consolidation mainly in the subpleural regions.
FIGURE 9-5 COP (idiopathic BOOP) in an 81-year-old woman. HRCT demonstrates bilateral
areas of consolidation. The consolidation is predominantly peribronchial in distribution. Note
bronchial dilatation in the areas of consolidation (arrows).
FIGURE 9-6 COP (idiopathic BOOP) in a 31-year-old man. HRCT demonstrates bilateral
peribronchial areas of consolidation. Also noted are small areas of ground-glass opacity and a few
small nodules.
FIGURE 9-7 COP (idiopathic BOOP) with perilobular pattern. A: HRCT image targeted to the
left lung shows poorly defined linear opacities (straight arrows) located in the periphery of
pulmonary lobules. These opacities are of greater thickness than those encountered in thickened
interlobular septa and have an arcade or polygonal appearance (perilobular pattern). In the left
lower lobe, the peripheral ring of consolidation (arrowheads) surrounds an area of ground-glass
opacity (reversed halo sign). B: Coronal reformation in a different patient better demonstrates the
perilobular pattern bilaterally and the reversed halo sign in the right lower lobe (arrowheads).
FIGURE 9-8 COP (idiopathic BOOP). HRCT through the right upper lobe shows ground-glass
opacities, bronchial wall thickening, and small nodules. Many of the nodules are centrilobular.
FIGURE 9-9 Nodular areas of COP (idiopathic BOOP). Ill-defined nodular areas of groundglass opacity and consolidation appear predominantly centrilobular in location.
FIGURE 9-10 A and B: Nodular areas of COP (idiopathic BOOP). Irregular nodular areas of
consolidation are predominantly peribronchial in location.
FIGURE 9-11 COP (idiopathic BOOP) with reversed halo sign. A: Axial HRCT image shows
bilateral ground-glass opacities partially surrounded by a rim of consolidation (arrows), resulting in
the CT reversed halo sign. B: Coronal reformation better demonstrates the extent of the groundglass opacities and the rims of consolidation (arrows).
TABLE 9-1 HRCT Findings in Cryptogenic Organizing Pneumonia
(Idiopathic OP or BOOP)
Patchy bilateral airspace consolidation (80%–90%)a
Ground-glass opacity (60%) or crazy pavinga
Subpleural and/or peribronchovascular distribution (60%–80%)b
Perilobular opacities (60%)b
Combination of first four findingsa,b
Bronchial wall thickening, dilatation in abnormal areasa
Small nodular opacities, often centrilobular
Large nodules
Reversed halo sign (20%)
Focal, mild irregular linear opacities (10%–30%)
Pleural effusion (10%–30%)
Mediastinal lymphadenopathy (20%–40%)
aMost common findings.
bFindings most helpful in differential diagnosis.
Ground-glass opacities are seen in approximately 60% of patients, usually in
association with areas of consolidation (Figs. 9-4, 9-7, and 9-11) (18).
Occasionally, ground-glass opacities may be the predominant or only
manifestation of COP on HRCT (Fig. 9-12). The ground-glass opacities are
usually bilateral and random in distribution. Crazy paving, with a
superimposition of ground-glass opacity and interlobular septal thickening, may
also be seen in patients who have COP (23). COP often involves the lower lung
zones to a greater degree than the upper lung zones.
FIGURE 9-12 COP (idiopathic OP) with predominant ground-glass opacities. HRCT at the
level of the bronchus intermedius shows extensive bilateral ground-glass opacities and dilated
bronchi.
The areas of consolidation in patients with COP reflect the presence of dense
OP and filling of the terminal airspaces with branching granulation tissue buds
(24). Ground-glass opacities have been shown to correlate with the presence of
alveolar septal inflammation, but little granulation tissue, in the terminal
airspaces (24). The perilobular pattern results from accumulation of organizing
exudate in the perilobular alveoli, with or without interlobular septal thickening
at histologic examination (25). The central areas of ground-glass opacification
seen in the reversed halo sign were shown to correspond to alveolar septal
inflammation, whereas the ring-shaped or crescentic periphery corresponds
mainly to OP within alveolar ducts (22). Small nodules are usually centrilobular
in distribution and result from localized zones of OP centered on abnormal
bronchioles (Fig. 9-13) (16).
FIGURE 9-13 Open-lung biopsy specimen from a patient who has COP (idiopathic BOOP)
viewed at low power. In this patient, ill-defined nodular opacities were seen on HRCT. The
pathologic specimen shows that the nodular opacities seen on HRCT are due to small localized
areas of OP (arrows) surrounding areas of abnormal bronchioles.
Müller et al. (16) reviewed the radiographic and CT features of 14 patients
who had biopsy-proven COP. Of the 14 patients, 10 (70%) had patchy unilateral
or bilateral airspace consolidation, and 4 had multiple 1-to 10-mm-diameter
nodules. A predominantly subpleural distribution of the airspace consolidation
was apparent on CT in 6 (60%) patients (Figs. 9-2 to 9-4), whereas this
appearance was seen on radiographs in 2 (20%) patients. In 3 of these patients,
the consolidation was limited almost exclusively to the subpleural and
peribronchial regions, and in 2 other patients, the consolidation was mainly
peribronchial (Figs. 9-5 and 9-6). Areas of ground-glass opacity were also seen
(Figs. 9-8 and 9-12). Subsequent studies by Lee et al. (18), Kim et al. (22), and
Ujita et al. (20), which included a larger number of patients, found consolidation
in 80% to 95% of patients with COP and a predominantly subpleural and
peribronchial distribution in 60% to 80% of cases. Although the consolidation
may be unilateral, it is usually bilateral.
Lee et al. (18) demonstrated that the CT manifestations of COP are influenced
by the patient’s immune status. This study included 32 immunocompetent
patients and 11 immunocompromised patients. Consolidation was seen in 29 of
32 (91%) immunocompetent patients compared to 5 of 11 immunocompromised
patients (45%) (p < 0.01). The consolidation was predominantly subpleural in 7
cases, predominantly peribronchovascular in 10 cases, and both subpleural and
peribronchovascular in 7 cases. Thus, 27 of 43 (63%) cases had a predominantly
subpleural distribution of consolidation, predominantly peribronchovascular
distribution of consolidation, or both. The consolidation had no zonal or
anterior–posterior predominance. Areas of ground-glass opacity were present in
26 of 43 (60%) cases in the study by Lee et al. (18). In all but two cases, the
areas of ground-glass opacity were seen as part of a mixed pattern. The areas of
ground-glass opacity were bilateral and random in distribution. Areas of groundglass opacity were present in 8 of 11 (73%) immunocompromised patients, as
compared to 18 of 32 (56%) immunocompetent patients (p < 0.25).
Nodular opacities measuring 1 to 10 mm in diameter are common and were
seen in 50% of patients studied by Müller et al. (16); these nodules were
typically ill defined (Figs. 9-8 and 9-9). In two patients, these were more
numerous along the bronchovascular bundles. On pathologic examination, the
parenchymal nodules were found to represent localized zones of OP, which were
centered around abnormal bronchioles or within the bronchioles (Fig. 9-13) (16).
Individual abnormal regions were separated from other involved areas by
relatively normal parenchyma. Nodules were also present in 13 of 43 (30%)
cases studied by Lee et al. (18). They were the only finding in 4 cases and were
part of a mixed pattern in 9 cases. They were bilateral in 10 cases and unilateral
in 3. The nodules were smaller than 5 mm in diameter in 5 cases and larger than
5 mm in diameter in 8 cases. Most of the nodules had well-defined, smooth
margins. Nodules were more frequently observed in immunocompromised
patients (6 of 11, 55%) than in immunocompetent patients (7 of 32, 22%) (p <
0.025). Nodules in COP sometimes appear to be predominantly centrilobular
(26). Occasionally, the nodules in COP may be large.
Large nodules or masses may be the predominant HRCT finding in some
patients who have COP (27). Akira et al. (27) reviewed the HRCT scans and
clinical records of 59 consecutive patients who had histologically proven COP;
12 patients had multiple large nodules or masses, 8 mm to 5 cm in diameter, as
the primary manifestation of disease (Fig. 9-10). The number of large nodules
ranged from two to eight per patient. Of 60 lesions in the 12 patients, 53 (88%)
had an irregular margin, 27 (45%) had an air bronchogram, 23 (38%) had a
pleural tail, and 21 (35%) had a spiculated margin. Ancillary findings included
focal thickening of the interlobular septa in 5 of the 12 (42%) patients, pleural
thickening in 4 (33%) patients, and parenchymal bands in 3 (25%) patients. Kim
et al. (22) found nodules (≤3 cm diameter) or masses (>3 cm diameter) in 13 of
31 (42%) patients with COP. The nodules were bilateral in all patients, showed
no zonal predominance in the longitudinal plane, and had a random distribution
in the transverse plane.
Bronchial wall thickening and dilatation may be seen on HRCT in patients
who have extensive consolidation and is usually restricted to these areas (Fig. 95) (16). In a study of 43 patients who had COP (18), bronchial dilatation was
present in association with areas of consolidation in 24 cases and with areas of
ground-glass opacity and nodules in 2 cases each. Follow-up of patients with
COP shows that the bronchial dilatation is usually reversible, resolving
completely along with the parenchymal abnormalities after successful treatment
with corticosteroids.
Irregular linear opacities were seen in 2 of 14 (14%) patients studied by
Müller et al. (16), 3 of 43 (7%) cases studied by Lee et al. (18), and 9 of 31
(29%) patients studied by Kim et al. (22). They are usually associated with
consolidation and located in the subpleural or peribronchial regions of the lower
lung zones. Occasionally, the reticular opacities may be the predominant HRCT
finding (19). Mild honeycombing in the subpleural regions of the lower lung
zones was present in 2 of 43 cases studied by Lee et al. (18). In one study, the
presence of irregular linear opacities (reticulation) on CT was associated with a
worse prognosis. Lee et al. (19) reviewed the HRCT findings of 26 patients with
COP who had radiographic follow-up for a median of 44 weeks after treatment.
Of the 26 patients, 17 had partial or complete resolution of the abnormalities at
follow-up and 9 had persistent or progressive abnormalities. Consolidation was
present on the initial CT scan in 14 of the 17 (82%) patients who improved on
follow-up, but in only 2 of the 9 patients with persistent or progressive disease (p
= 0.009). None of the six patients who had irregular linear opacities as the
predominant pattern on initial HRCT showed complete resolution on follow-up
imaging (p = 0.02). In a more recent study, all four patients who had reticulation
on their initial HRCT had remaining disease on their follow-up CT (mean
follow-up period, 15 months; range, 5–55 months); in three patients the extent of
abnormalities decreased and in one it was unchanged (28). However, the
majority of patients had residual abnormalities on follow-up CT regardless of the
initial CT pattern. Lee et al. (28) reviewed the initial and follow-up CT scans in
22 patients with COP (median follow-up period, 8 months; range, 5–135
months). The two most common patterns of lung abnormality on the initial
HRCT were ground-glass opacification (86% of patients) and consolidation
(77% of patients), distributed along the bronchovascular bundles or subpleural
lungs in 59% of patients. In 6 patients (27%), the abnormalities disappeared
completely; in 15 patients (68%), the disease decreased in extent; and in 1
patient (5%), there was no change in extent on follow-up CT. In 10 of 16 (63%)
patients with residual disease, the CT findings were reminiscent of fibrotic
nonspecific interstitial pneumonia (NSIP). The pattern of abnormality on the
initial CT scans did not constitute a prognosis-determining factor on univariate
or multivariate analysis (28). The authors pointed out that the study only
included 22 of the original 32 patients with biopsy-proven COP and that the lack
of follow-up CT in the remaining 10 patients may have introduced a major bias
into the study because these 10 patients may not have had residual disease (28).
Other findings in patients who have COP include pleural effusions, present in
10% to 30% of cases (16,18,22), and mild right paratracheal or subcarinal
lymphadenopathy, seen in 20% to 40% of cases (22,29). The pleural effusions
are small and may be unilateral or bilateral (18).
Utility of High-Resolution Computed Tomography
The radiographic and CT findings of COP are nonspecific and may be seen in a
variety of infections and neoplastic diseases (30). However, COP can usually be
readily distinguished from other chronic IIPs on HRCT. Johkoh et al. (31)
reviewed the HRCT findings in 129 patients who had various IIPs, including 24
with COP. On average, based on the pattern and distribution of abnormalities on
HRCT, two independent observers made a correct first-choice diagnosis in 79%
of 24 cases of COP, 71% of 35 cases of UIP, 63% of 23 cases of DIP, 65% of 20
cases of AIP, and 9% of 27 cases of NSIP (31).
The predominant subpleural distribution of COP resembles that of CEP.
Arakawa et al. (32) compared the HRCT findings in 38 patients with COP and
43 patients with CEP. Airspace consolidation was the most frequent HRCT
finding in both COP (87%) and CEP (74%), and it had a predominately
peripheral distribution in 66% of patients with COP and 56% of patients with
CEP. A peribronchial distribution of consolidation was seen more frequently in
COP than in CEP (29% vs. 9%). There was no appreciable difference in the
cephalocaudal distribution of the consolidation between COP and CEP. The most
helpful distinguishing feature on CT was the presence of nodules, seen in 32% of
patients with COP and only 5% of patients with CEP. Based on the HRCT
findings, two independent chest radiologists made a correct first choice of COP
or CEP in 67% and 72% of cases, respectively (32). In clinical practice, the
differential diagnosis can be readily made based on clinical history and
laboratory tests. Approximately 50% of patients with CEP have asthma, and the
vast majority has peripheral eosinophilia (33).
CT also provides a better assessment of disease pattern and distribution than
do chest radiographs and is therefore superior to plain film in determining
optimal biopsy site. HRCT is recommended routinely as a guide to optimal
biopsy site in all patients undergoing surgical lung biopsy.
ACUTE INTERSTITIAL PNEUMONIA
AIP is a fulminant disease of unknown etiology that usually occurs in a
previously healthy person and produces histologic findings of diffuse alveolar
damage (DAD) (1,2,34). The key elements for the diagnosis are: (a) acute onset
of respiratory symptoms resulting in severe hypoxia, (b) bilateral pulmonary
opacities on the chest radiograph, (c) histologic documentation of DAD, and (d)
absence of an identifiable etiology or predisposing condition (2,34,35). The
average age at presentation is 50 to 60 years (range, 7–83 years) (2,36). It has no
gender predominance and no association with cigarette smoking. There is often a
prodromal illness associated with symptoms of a viral upper respiratory
infection. The clinical symptoms consist of dry cough and rapidly progressive
severe dyspnea. The majority of patients have symptoms for less than 1 week
before diagnosis, usually develop respiratory failure, and require mechanical
ventilation (36,37). The prognosis is poor, with the majority of studies reporting
a mortality ranging from 50% to 100% (35). The histologic findings are those of
DAD and vary, depending both on the time interval between injury and biopsy
and on the extent and localization of the injury (2,34,38). The acute, exudative
phase shows edema, hyaline membranes, and acute interstitial inflammation. In
the subacute, proliferative (organizing) phase, the fibroblast proliferation mainly
becomes prominent within the interstitium as well as within airspaces. Type II
pneumocyte hyperplasia is also present. In the chronic, fibrotic phase, typically 2
weeks or more after the injury, there is progressive fibrosis with collagen
deposition. Because the presentation is acute and the histologic features are
identical with those of ARDS, AIP has also been referred to as idiopathic ARDS
(38).
The radiographic findings are those of DAD and consist of bilateral airspace
consolidation with air bronchograms (39,40). The consolidation is often initially
patchy but tends to become rapidly confluent and diffuse, although it may have
upper or lower lung zone predominance (39,40). The lung volumes are usually
decreased.
High-Resolution Computed Tomography Findings
In the early stages of AIP, HRCT findings consist primarily of bilateral groundglass opacities that may be patchy or diffuse and of areas of consolidation (Figs.
9-14 and 9-15, Table 9-2) (30,39,41). Focal sparing of lung lobules frequently
results in a geographic appearance (Fig. 9-16) (30,42). Smooth septal thickening
and intralobular lines are frequently seen superimposed on the ground-glass
opacities (“crazy-paving” pattern) (Fig. 9-16) (43). The airspace consolidation
may be patchy or confluent and tends to involve mainly the dependent lung.
Occasionally, it may be predominately peripheral (Fig. 9-15) or central (Fig. 917).
FIGURE 9-14 A–C: AIP in a 70-year-old woman who subsequently died. HRCT findings are
nonspecific, with patchy consolidation and ground-glass opacity predominating in the subpleural
lung regions and at the lung bases.
FIGURE 9-15 An 83-year-old woman who has AIP. HRCT at the level of the bronchus
intermedius demonstrates extensive bilateral consolidation involving the dependent regions of the
lower lobes. Patchy areas of ground-glass opacity are present anteriorly.
FIGURE 9-16 An 80-year-old man who has AIP. HRCT at the level of the main bronchi
demonstrates bilateral ground-glass opacities. Sparing of some of the secondary lobules results in
a geographic appearance. Smooth septal thickening and a few intralobular lines are seen mainly
in the right lung, resulting in a “crazy-paving” pattern.
FIGURE 9-17 AIP in a 47-year-old man. A: HRCT scan shows areas of consolidation having
a peribronchovascular distribution. B: Low-kilovoltage radiograph of inflated and fixed postmortem
lung reveals extensive consolidation. C: Histologic specimen shows dilated alveolar ducts lined by
hyaline membranes and prominent associated interstitial fibrosis (elastica-van Gieson stain, ×25).
(From Akira M. Computed tomography and pathologic findings in fulminant forms of idiopathic
interstitial pneumonia. J Thorac Imaging 1999;14:76–84, with permission.)
TABLE 9-2 HRCT Findings of Acute Interstitial Pneumonia
Extensive bilateral ground-glass opacitiesa
Airspace consolidationa
Architectural distortiona
Combination of first three findingsa
Consolidation predominantly basilar and dependent
aMost common findings.
In a study by Primack et al. (39), bilateral, symmetric areas of ground-glass
opacity were present on HRCT in all nine cases (Fig. 9-16). The areas of groundglass opacity involved all lung zones to a similar extent in seven patients (78%)
and had upper lung zone predominance in the other two patients. In six patients
(67%), the areas of ground-glass opacity had a patchy distribution with focal
areas of sparing, giving a geographic appearance, and three patients had diffuse
involvement. In none of the cases did the areas of ground-glass opacity involve
mainly the central or subpleural lung regions. Bilateral areas of airspace
consolidation were identified on HRCT in six of nine cases (Figs. 9-14, 9-15,
and 9-17) (39), a diffuse distribution in two patients, and upper lung zone
predominance in one patient. A predominantly subpleural distribution of
consolidation was present in two cases, the distribution in the other four cases
being random.
Architectural distortion and traction bronchiectasis may be seen as the disease
evolves and fibrosis develops. In a study by Akira (41), these findings were
observed only on CT scans obtained more than 7 days after the onset of
symptoms. Subpleural honeycombing was seen at HRCT in three of nine
patients reviewed by Primack et al. (Fig. 9-18) (39). The areas of honeycombing
involved less than 10% of the lung parenchyma.
FIGURE 9-18 A 74-year-old man who has AIP. HRCT through the lung bases demonstrates
extensive bilateral areas of ground-glass opacity. Also noted are a reticular pattern and fine
honeycombing involving mainly the subpleural lung regions of the right lower lobe (arrows).
Eight of the nine patients studied by Primack et al. (39) died within 3 months
of presentation. The surviving patient underwent a follow-up HRCT study that
showed only mild residual peripheral reticulation 2 months after the initial
HRCT study. Repeat surgical lung biopsy at the time of the follow-up HRCT
study in this case showed inactive fibrosis.
Johkoh et al. (43) reviewed the HRCT findings in 36 patients who had AIP.
The main abnormalities consisted of extensive ground-glass opacities present in
all patients and areas of consolidation seen in 33 (92%) patients (Table 9-2).
Other common findings included architectural distortion, traction bronchiectasis,
thickening of the bronchovascular bundles, and thickening of the interlobular
septa. The abnormalities involved mainly the lower lung zones in 13 patients
(39%) and the upper lung zones in 5 patients (14%); in the remaining patients,
there was equal involvement of all three lung zones. A predominant dependent
distribution was present in 9 patients (25%) and a peripheral distribution in 3
patients (8%) (43).
Ichikado et al. (42) correlated the HRCT findings with lung pathology in 14
patients who had AIP. Areas of ground-glass opacity and consolidation without
traction bronchiectasis were present in the exudative or early proliferative phase
of AIP. Traction bronchiectasis was seen in the late proliferative and fibrotic
phases of AIP (42). Honeycombing, present in a small percentage of patients
with AIP, correlates with the presence of dense interstitial fibrosis and
restructuring of distal airspaces (39,42).
The HRCT findings can be helpful in predicting likelihood of response to
treatment. Ichikado et al. (44) compared the HRCT findings of AIP between 10
survivors and 21 nonsurvivors. The extent of ground-glass opacity or airspace
consolidation without traction bronchiolectasis or bronchiectasis was greater in
survivors than in nonsurvivors, and the extent of either ground-glass opacity or
airspace consolidation combined with traction bronchiolectasis or bronchiectasis
was greater in nonsurvivors.
Although the HRCT findings of AIP and ARDS reflect the presence of DAD
and therefore overlap, Tomiyama et al. (45) showed that patients with AIP are
more likely to have a symmetric lower lobe distribution of abnormalities and a
greater prevalence of honeycombing (26% of patients vs. 8%).
RESPIRATORY BRONCHIOLITIS AND RESPIRATORY
BRONCHIOLITIS-INTERSTITIAL LUNG DISEASE
Respiratory bronchiolitis (RB), also known as smokers’ bronchiolitis, is a
common incidental histologic finding in cigarette smokers (46–48). RB is
usually unassociated with specific symptoms (47,49). A small percentage of
smokers who have findings of RB are symptomatic and present with clinical
findings mimicking those of interstitial lung disease and are referred to as having
RB-ILD (2,50,51).
RB is characterized histologically by the presence of numerous macrophages
filling respiratory bronchioles and adjacent alveolar ducts and alveoli (Fig. 9-19)
(48,51,52). The macrophages contain periodic acid-Schiff-positive brown
pigment; this pigment represents particulate matter unique to cigarette smoke,
contained within cytoplasmic phagolysosomes. In patients who have
symptomatic RB-ILD, peribronchiolar and alveolar wall inflammation tends to
be more pronounced than in patients who are asymptomatic (50). However, there
are no histologic features that reliably separate RB-ILD from RB (47). RB-ILD
is a clinical-radiologic-pathologic diagnosis defined by the presence of
pulmonary symptoms, abnormal PFTs, abnormal imaging, and a surgical lung
biopsy demonstrating RB (47). RB-ILD typically has a bronchiolocentric
distribution and involves the lung parenchyma in a patchy fashion, with some
areas spared, whereas adjacent lobules may be severely involved. This is distinct
from DIP, in which the findings are diffuse. However, there is commonly
considerable overlap between the findings of RB, RB-ILD, and DIP on multiple
fields in a single specimen. Because RB-ILD and DIP are part of the spectrum of
smoking-related interstitial lung diseases, the distinction in some cases may not
only be difficult but also arbitrary (47,53).
FIGURE 9-19 RB: histologic findings. Photomicrograph shows pigmented (“smokers”)
macrophages within alveolar airspaces adjacent to a respiratory bronchiole (RB) and
accompanying pulmonary artery (PA). The peribronchiolar distribution and the partial filling of the
airspaces account for the poorly defined centrilobular ground-glass opacities seen in some
patients with RB. In many patients, the findings are too mild to be seen on CT. (Courtesy of Dr.
John English, Department of Pathology, Vancouver General Hospital, Vancouver, British
Columbia, Canada.)
Patients who have RB-ILD are typically young—usually in their 30s and 40s
—and complain of chronic cough and progressive shortness of breath, often of 1
or 2 years’ duration. The vast majority of patients are current smokers, with an
average of more than 30 pack-years of cigarette smoking (2,51). Occasionally,
RB-ILD may manifest in ex-smokers or in patients exposed to secondhand
smoke or to fumes (54,55). PFTs most commonly show mild to moderate
impairment in gas transfer (reduction in carbon monoxide diffusing capacity
[DLCO]). Patients with extensive disease may have features of both airway
obstruction and restriction, due to a combination of RB-ILD and centrilobular
emphysema (2).
Chest radiographs can be normal or show airway wall thickening, diffuse
ground-glass opacities, or poorly defined fine reticulonodular opacities that can
be diffuse or have a lower zonal predominance (50,56,57). The prognosis of
patients who have RB-ILD is good; the vast majority of patients improve or
remain stable (57,58). There was only 1 death thought to be related to RB-ILD in
78 patients with follow-up reported in the literature prior to 2010 (59,60).
Smoking cessation usually leads to amelioration of symptoms, improvement in
the PFTs, and a decrease in the ground-glass opacities and centrilobular nodules
on HRCT (61). Patients who continue to smoke may improve clinically, but
those with persistent complaints may benefit from oral corticosteroid therapy.
Despite symptomatic regression, histologic changes may not resolve completely
(54).
Respiratory Bronchiolitis: High-Resolution Computed
Tomography Findings
In the majority of patients who have RB, the histologic abnormalities are too
mild to be detected on HRCT (49,62,63). When present, HRCT findings consist
of poorly defined centrilobular nodules and multifocal ground-glass opacities
(62–64). These findings can be diffuse but tend to involve mainly the upper lung
zones (62,63). Remy-Jardin et al. (62) reviewed the HRCT scans in 39 heavy
smokers (mean smoking index of 41 pack-years) who had the diagnosis of RB
proved at lung resection for solitary nodules. Eleven (28%) had ground-glass
opacities, and four (10%) had poorly defined centrilobular nodules (62).
Correlation with the histologic findings showed that the areas of ground-glass
opacity could be attributed to intra-alveolar macrophages, alveolar wall
thickening by inflammation or fibrosis, or organizing alveolitis (62).
In a study by Heyneman et al. (63), the main abnormalities seen in 16 patients
who had RB were centrilobular nodules present in 12 (75%) patients and
ground-glass opacities seen in 6 (38%) patients (Fig. 9-20). The nodules were
usually poorly defined and measured 3 to 5 mm in diameter. The nodules were
either diffuse throughout the lungs or located predominantly or exclusively in the
middle and upper lung zones. The ground-glass opacities were usually patchy in
distribution and present in all lung zones. Centrilobular emphysema was evident
on HRCT in nine (56%) of the patients who had RB (63).
FIGURE 9-20 Respiratory bronchiolitis. A: HRCT at the level of the aortic arch demonstrates
patchy bilateral ground-glass opacities. Also noted are a few centrilobular nodules and bronchial
wall thickening. B: HRCT at the level of the inferior pulmonary veins demonstrates centrilobular
nodules and branching linear opacities, giving a tree-in-bud appearance. (Courtesy of Dr. Martine
Remy-Jardin, Hôpital Calmette, Universitaire de Lille, Lille, France.)
Respiratory Bronchiolitis-Interstitial Lung Disease: HighResolution Computed Tomography Findings
Not all patients with RB-ILD show abnormalities on HRCT. The most common
HRCT findings consist of (a) centrilobular nodules, (b) ground-glass opacities,
and (c) thickening of bronchial walls (Figs. 9-21 and 9-22, Table 9-3) (56,63,65).
The centrilobular nodules and ground-glass opacities may be diffuse or involve
mainly the upper or lower lung zones. Upper lobe emphysema is commonly
present because of smoking but is usually mild. A small percentage of patients
have a reticular pattern due to fibrosis (56,63,65). The fibrosis in RB-ILD is mild
and tends to involve mainly the lower lung zones (Fig. 9-23).
FIGURE 9-21 Respiratory bronchiolitis-interstitial lung disease. A: HRCT through the upper
lobes shows patchy areas of ground-glass opacity, many of which appear to be centrilobular and
surround small vascular branches. (From Gruden JF, Webb WR. CT findings in a proved case of
respiratory bronchiolitis. AJR Am J Roentgenol 1993;161:44–46, with permission.) B: HRCT at a
lower level also shows small, ill-defined areas of ground-glass opacity. C: Surgical biopsy
specimen shows numerous dark-pigmented macrophages filling alveoli, typical of RB.
FIGURE 9-22 RB-ILD in a 29-year-old female smoker who had 6 months of progressive
dyspnea and cough. Prone HRCT shows patchy areas of ground-glass opacity, some of which
appear nodular.
FIGURE 9-23 RB-ILD in a 60-year-old man who was a heavy smoker. HRCT shows patchy
bilateral ground-glass opacities and mild subpleural reticulation.
TABLE 9-3 HRCT Findings of Respiratory Bronchiolitis-Interstitial
Lung Disease
No visible abnormality
Centrilobular nodular opacitiesa
Patchy ground-glass opacitya
Bronchial wall thickeninga
Upper lobe predominancea,b
Findings of fibrosis usually absent
Associated centrilobular emphysema
aMost common findings.
bFindings most helpful in differential diagnosis.
Holt et al. (65) described the HRCT findings in five patients with RB-ILD.
The findings were variable and ranged from no detectable abnormality to
atelectasis, ground-glass opacities, emphysema, and reticular interstitial opacities
(65). Heyneman et al. (63) reviewed the HRCT findings in eight patients who
had RB-ILD. Of the eight patients, four (50%) had ground-glass opacities and
three (38%) had centrilobular nodules. Only two (25%) showed evidence of
fibrosis, as determined by the presence of intralobular linear opacities and
honeycombing in the lower lobes. Emphysema was evident on HRCT in 50% of
cases (63).
Park et al. (56) correlated HRCT findings with pathologic findings in 21
patients who had RB-ILD. All patients were current or former cigarette smokers.
The most common HRCT findings were bronchial wall thickening (90% of
patients), centrilobular nodules (71%), and ground-glass opacities (67%). The
centrilobular nodules were more profuse in the upper lung zones in eight patients
(53%), the middle or lower lung zones in three patients (20%), and had an even
distribution in four patients (27%). Areas of ground-glass opacity showed no
significant zonal predominance. Other findings included upper lung predominant
centrilobular emphysema (57%) and patchy areas of decreased attenuation
(38%) with lower lung predominance. The extent of centrilobular nodules
correlated with the extent of macrophages in respiratory bronchioles and with
chronic inflammation of respiratory bronchioles, while the extent of groundglass opacity correlated with the amount of macrophage accumulation in the
alveoli and alveolar ducts. At follow-up CT after steroid treatment and smoking
cessation, the extent of bronchial wall thickening, centrilobular nodules, and
ground-glass opacity decreased, but the extent of the areas of decreased
attenuation increased (56).
Nakanishi et al. (61) assessed the HRCT findings in five patients with biopsyproven RB-ILD before and 15 to 62 months after smoking cessation. The main
HRCT findings at presentation in all five patients consisted of centrilobular
ground-glass nodules and areas of ground-glass attenuation that involved all
three lung zones to a similar extent. Other abnormalities included bronchial wall
thickening in five patients, mild emphysema in three, and minimal
predominantly lower lobe fine intralobular linear opacities in three. HRCT
following cessation of smoking showed a decrease in the extent of the
centrilobular nodules and ground-glass opacities but no change in the other CT
findings. The patients also had interval improvement of symptoms and in the
DLCO (61).
DESQUAMATIVE INTERSTITIAL PNEUMONIA
DIP is an uncommon condition, characterized histologically by the presence of
numerous macrophages filling the alveolar airspaces, mild inflammation of the
alveolar walls, and minimal fibrosis (Fig. 9-24) (1,2,66). Approximately 60% to
90% of patients who have DIP are cigarette smokers (58,66,67). DIP may also
occur in association with passive exposure to cigarette smoke, heavy marijuana
smoking, occupational dust exposure (beryllium, copper, fire extinguisher
powder), drug reaction, collagen-vascular disease, leukemia, infection, and
surfactant mutations (2,66,67).
FIGURE 9-24 DIP: histologic findings. Photomicrograph shows homogeneous diffuse filling of
alveolar airspaces with macrophages and mild interstitial inflammation. (Courtesy of Dr. John
English, Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia,
Canada.)
In some patients who have DIP, the macrophage accumulation may have a
peribronchiolar predominance similar to that seen in RB-ILD, the only
distinction being the presence of more diffuse involvement of the airspaces in
DIP (53,57). However, there is a continuum of the extent of airspace macrophage
accumulation between RB-ILD and DIP, sometimes making it difficult to
distinguish between these two entities. Therefore, it is likely that RB-ILD and
DIP are highly related conditions, representing different degrees of small airway
and parenchymal reaction to cigarette smoke (53,63). However, the HRCT
manifestations, response to therapy, and, most importantly, the prognosis differ
(1). DIP results in a 6% to 30% mortality compared to an approximately 1%
mortality in patients with RB-ILD (60,66). Therefore RB-ILD and DIP were
classified as two separate smoking-related IIPs in the 2013 ATS/ERS
classification (1). DIP is quite rare, probably accounting for less than 3% of
interstitial lung disease (68). Many cases previously called DIP have been
reclassified as RB-ILD (68).
DIP occurs most commonly in patients between 35 and 55 years of age (mean
and median age approximately 45 years) (58,69). The clinical symptoms usually
consist of slowly progressive exertional dyspnea and dry cough (2,70). The most
common finding on chest radiographs in patients who have DIP is the presence
of ground-glass opacities in the lower lung zones (70,71). However, in 3% to
22% of patients who have biopsy-proven DIP, the chest radiograph has been
reported as being normal (70,71).
High-Resolution Computed Tomography Findings
On HRCT, the predominant abnormality in patients who have DIP is the
presence of areas of ground-glass opacity (63,69) (Figs. 9-25 to 9-27, Table 9-4).
This is not surprising, considering that the predominant histologic findings in
patients who have DIP are filling of the alveolar airspaces with macrophages,
relative preservation of the underlying pulmonary anatomy, and minimal
fibrosis. A subpleural and basal predominance is often present, and although
reticular opacities may be associated with the ground-glass opacity,
honeycombing is uncommon. Because of its association with smoking,
centrilobular emphysema may also be present. Air-filled cysts may be visible
within areas of ground-glass opacity. Focal regions of lucency are sometimes
seen, perhaps representing areas of mosaic perfusion related to bronchiolitis and
airway obstruction.
FIGURE 9-25 A 39-year-old man who has DIP. A: HRCT at the level of the superior
segmental bronchi shows areas of ground-glass opacity in a predominantly subpleural
distribution. B: HRCT obtained at the same level as in A with the patient in the prone position
shows that the ground-glass opacity is not secondary to dependent atelectasis. (From Hartman
TE, Primack SL, Swensen SJ, et al. Desquamative interstitial pneumonia: thin-section CT findings
in 22 patients. Radiology 1993;187:787–790, with permission.)
FIGURE 9-26 A 45-year-old patient who has DIP. HRCT at the level of the tracheal carina
demonstrates bilateral areas of ground-glass opacity. The ground-glass opacity is most marked in
the subpleural lung regions.
FIGURE 9-27 A 71-year-old man who has DIP. A: HRCT at the level of the inferior pulmonary
veins demonstrates bilateral areas of ground-glass opacity involving mainly the subpleural lung
regions. B: HRCT through the lung bases demonstrates more extensive bilateral involvement.
There is mild reticulation.
TABLE 9-4 HRCT Findings in Desquamative Interstitial Pneumonia
Bilateral, patchy ground-glass opacitya
Subpleural and basal predominancea
Superimposition of first two findingsb
Reticular opacities
Honeycombing (uncommon)
Associated centrilobular emphysema
aMost common findings.
bFindings most helpful in differential diagnosis.
Hartman et al. (69) reviewed the HRCT scans in 22 patients who had biopsyproven DIP. The predominant abnormality in this group was the presence of
areas of ground-glass opacity. The areas of ground-glass opacity were seen
mainly in the lower lung zones in 16 patients (73%), the middle lung zones in 3
patients (14%), and the upper lung zones in 3 patients (14%). The areas of
ground-glass opacity had a predominantly peripheral distribution in 13 patients
(59%), a patchy distribution in 5 patients (23%), and a diffuse distribution in 4
patients (18%) (Figs. 9-25 to 9-27). Irregular linear opacities were seen in 13 of
22 (59%) patients. These were more marked in the lower lung zones in 11
patients, middle lung zones in 1 patient, and upper lung zones in 1 patient. In 11
of the 13 patients with irregular linear opacities, there was associated
architectural distortion, indicating the presence of fibrosis. Honeycombing was
identified in seven patients. The honeycombing was present only in the lower
lung zones, was peripheral, and involved less than 10% of the lung bases (69).
Heyneman et al. (63) reviewed the HRCT findings in 16 patients who had RB,
8 patients who had RB-ILD, and 6 patients who had DIP. The predominant
abnormalities in patients who had RB consisted of poorly defined centrilobular
nodules seen in 75% of patients and ground-glass opacities seen in 38% of
patients. The main findings in patients who had RB-ILD were ground-glass
opacities seen in 50% of patients, centrilobular nodules in 38%, and mild fibrosis
present in 25%. All patients who had DIP had extensive ground-glass opacities,
and 63% showed evidence of mild fibrosis. All patients who had RB and RBILD, and 85% of patients who had DIP, had a smoking history. The authors
concluded that the considerable overlap between the HRCT findings of RB, RBILD, and DIP is consistent with the concept that these entities are part of the
spectrum of the same disease process, representing different degrees of severity
of reaction to cigarette smoke (63).
Sumikawa et al. (72) reviewed the HRCT scans of 92 patients with various
IIPs, including 26 with DIP or RB-ILD. The mains findings in patients with DIP
and RB-ILD were bilateral ground-glass opacities (average extent 27% of the
lung parenchyma), poorly defined centrilobular nodules (average extent 9%),
and mild reticulation (average extent 7%). Other common findings included
traction bronchiectasis, cysts, and emphysema (72).
Johkoh et al. (31) assessed the accuracy of HRCT in distinguishing various
IIPs in 129 patients, including 23 with DIP. On average, two independent
observers made a correct first-choice diagnosis in 63% of cases of DIP. The most
common findings in patients with DIP were ground-glass opacities (100%),
intralobular reticular opacities (78%), and poorly defined centrilobular nodules
(44%). The abnormalities had lower lung zone predominance in 83% of patients
and a peripheral distribution in 43% (31).
Follow-up of patients with DIP frequently shows improvement of the findings
with treatment. In a study by Hartman et al. (73) of 11 patients with DIP, the
initial CT scans showed ground-glass attenuation in all 11 cases, irregular linear
opacities in 5, and mild honeycombing in 1. Follow-up HRCT scans performed
after a median interval of 10 months showed a decrease or resolution of the
ground-glass opacities in 6 patients, no interval change in 3, and slight
progression of the fibrosis in 2 patients (Fig. 9-28) (73).
FIGURE 9-28 DIP: improvement with treatment. A: HRCT at the level of the distal trachea
shows bilateral peripheral ground-glass opacities. B: HRCT 6 months later, following treatment
with corticosteroids, shows marked improvement.
Akira et al. (74) performed serial HRCT scans in eight patients with DIP
(average follow-up, 3 years). Common findings on the initial CT scans included
ground-glass opacities, linear areas of opacity, and small cysts. Surgical biopsy
samples from patients with DIP with cystic lesions showed dilated alveolar ducts
and bronchioles and/or pulmonary cysts, as well as numerous macrophage-filled
airspaces and mild fibrosis, but no typical honeycomb cysts. Follow-up CT scans
showed a decrease in the extent of ground-glass opacity in all patients after
treatment with corticosteroids; however, in three cases, the ground-glass
opacities increased again on low-dose corticosteroids. In five of six patients who
had small cysts on the initial CT scan, these improved or remained unchanged on
follow-up; in one patient, they increased (74).
LYMPHOID INTERSTITIAL PNEUMONIA
LIP is an uncommon condition characterized histologically by a diffuse
interstitial lymphoid infiltrate consisting mainly of polyclonal lymphocytes with
varying numbers of plasma cells (Fig. 9-29) (2,3,75). LIP is usually considered
as part of a spectrum of pulmonary lymphoproliferative disorders that range in
severity from benign airway-centered cellular aggregates (lymphoid hyperplasia)
to malignant lymphomas (2,3,75). However, LIP can occasionally occur as an
idiopathic inflammatory and nonneoplastic process (2,75,76). Furthermore, the
clinical, radiologic manifestations often resemble those of other interstitial
pneumonias, and the histologic pattern is that of an interstitial pneumonia that
can mimic NSIP (1,2). Indeed, many of the cases previously interpreted as LIP
would now be considered examples of cellular NSIP (1,75,76). Therefore, it was
included in the ATS/ERS international multidisciplinary consensus classification
of IIPs in 2002 (2) and 2013 (1). Although the majority of patients with LIP
initially respond to corticosteroids, approximately 33% to 50% of patients die
within 5 years of diagnosis (3,4).
FIGURE 9-29 Lymphoid interstitial pneumonia: pathologic findings. Histologic specimen
shows diffuse lymphocytic infiltration of the pulmonary interstitium. (Courtesy Dr. W. D. Travis,
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.)
LIP usually occurs in association with other conditions, most commonly
Sjögren syndrome, autoimmune disorders, dysproteinemia, and AIDS (2,5,76). It
may also occur in association with allogeneic bone marrow transplantation,
common variable immunodeficiency, and drug reaction (4). Idiopathic LIP is
rare (75).
Except for patients who have AIDS, in which affected patients are most often
children, the majority of patients who have LIP are adults. The average age of
presentation is 50 to 60 years; women are affected twice as commonly as men
(3,76). The onset is typically insidious over several years (2). The main clinical
symptoms are cough and slowly progressive dyspnea (2,75). The radiographic
findings consist of a reticular or reticulonodular pattern involving mainly the
lower lung zones (77–79). Less common abnormalities include a nodular pattern,
ground-glass opacities, and airspace consolidation.
High-Resolution Computed Tomography Findings
The predominant abnormalities on HRCT consist of extensive bilateral groundglass opacities and poorly defined centrilobular nodules (Figs. 9-30 and 9-31,
Table 9-5); other common findings include subpleural nodules, thickening of the
bronchovascular bundles ([Figs. 9-32 and 9-33], cystic airspaces Fig. 9-34), and
patchy ground-glass opacity (Fig. 9-35; Figs. 11-26 to 11-28) (80–82). In some
patients, the appearance of LIP may closely mimic that of lymphangitic spread
of carcinoma (Fig. 9-33).
FIGURE 9-30 Lymphoid interstitial pneumonia in a 75-year-old man who has AIDS. HRCT
demonstrates extensive bilateral areas of ground-glass opacity and small poorly defined nodules,
some of which appear centrilobular.
FIGURE 9-31 Lymphoid interstitial pneumonia in a 38-year-old woman who has AIDS. Illdefined centrilobular nodules are visible diffusely.
FIGURE 9-32 Lymphoid interstitial pneumonia in an 11-year-old boy who has AIDS. A:
Extensive peribronchovascular nodules are visible. B: At a lower level, small nodules are visible in
relation to the pleural surfaces and major fissure (arrows), and a large nodule is also present.
FIGURE 9-33 Lymphoid interstitial pneumonia in a 44-year-old woman who has AIDS and
fever. A: Small well-defined nodules are visible at the pleural surfaces (arrows). B: Nodular
thickening of interlobular septa is also visible (arrow), typical of a perilymphatic distribution of
disease. C: Nodular thickening of interlobular septa is also visible near the lung base. This
appearance mimics that of lymphangitic spread of carcinoma.
FIGURE 9-34 Lymphoid interstitial pneumonia. HRCT demonstrates patchy ground-glass
opacities and cystic spaces in both upper lobes.
FIGURE 9-35 A 26-year-old woman who has Lymphoid interstitial pneumonia. HRCT
demonstrates patchy bilateral ground-glass opacities and a few poorly defined centrilobular and
subpleural nodules, best seen in the right lower lobe.
TABLE 9-5 HRCT Findings in Lymphoid Interstitial Pneumonia
Ground-glass opacitya
Poorly defined centrilobular nodulesa
Subpleural nodulesa
Interlobular septal thickeninga
Thickening of peribronchovascular interstitiuma
Cystic airspacesa,b
Lymph node enlargementa
aMost common findings.
bFindings most helpful in differential diagnosis.
Johkoh et al. (80) reviewed the HRCT findings in 22 patients who had LIP.
All patients had areas of ground-glass opacity and poorly defined centrilobular
nodules. Small subpleural nodules were seen in 19 (86%) patients, thickening of
the peribronchovascular interstitium in 19 (86%), mild interlobular septal
thickening in 18 (82%), and cystic airspaces in 15 (68%) (Figs. 9-30 to 9-35)
(70). The cystic airspaces had thin walls, measured 1 to 30 mm in diameter, and
involved less than 10% of the lung parenchyma (Fig. 9-36). Less common
manifestations seen on HRCT include nodules 1 to 2 cm in diameter, airspace
consolidation, bronchiectasis, and, occasionally, honeycombing (80,83).
Although lymph node enlargement is seldom evident on the chest radiograph,
mediastinal lymphadenopathy was present on CT in 15 of the 22 (68%) patients
reported on by Johkoh et al. (80).
FIGURE 9-36 A 63-year-old woman who has Lymphoid interstitial pneumonia. HRCT
demonstrates several thin-walled cysts of various sizes, patchy bilateral ground-glass opacities,
and mild subpleural reticulation.
Occasionally, lung cysts may be extensive and be the predominant finding of
LIP. Silva et al. (84) reported the findings in one patient who had idiopathic LIP
and diffuse lung cysts measuring 0.5 to 10 cm in diameter and who underwent
unilateral lung transplant (Fig. 9-37). The cysts in the native lung remained
unchanged on follow-up HRCT 4 years later.
FIGURE 9-37 LIP in a 64-year-old man who underwent lung transplant. A: HRCT at the level
of the upper lobes shows multiple thin-walled cysts of various sizes and mild centrilobular
emphysema (curved arrows). Also noted is focal ground-glass opacity in the right upper lobe
(straight arrows). B: HRCT at the level of the lower lobes demonstrates more numerous and
larger cysts with minimal intervening lung parenchyma. C: Low-power view shows extensive
infiltration of the interstitium by mature and transformed small lymphocytes and plasma cells. Also
noted is infiltration around ectatic bronchioles (arrow) (H&E, ×4). D: Photomicrograph of different
area demonstrates ectatic small peripheral bronchus (asterisks) leading into large cyst (H&E, ×2).
(From Silva CI, Flint JD, Levy RD, et al. Diffuse lung cysts in lymphoid interstitial pneumonia: highresolution CT and pathologic findings. J Thorac Imaging 2006;21:241–244, with permission.)
Correlation of HRCT with pathologic findings has demonstrated that the
centrilobular nodules in LIP are due to peribronchiolar infiltration with
lymphocytes and plasma cells, whereas the ground-glass opacities reflect a
diffuse interstitial infiltration. The cystic airspaces have been postulated to be
due to partial airway obstruction by the peribronchiolar cellular infiltration (81).
In one patient who underwent lung transplant, the lung explant showed several
markedly ectatic bronchioles and small peripheral bronchi that directly
communicated with the large cystic spaces (Fig. 9-37). The cysts were identified
within the lung parenchyma mostly in areas with lymphocytic infiltration.
Nodules occasionally seen in association with the cysts in patients with LIP may
represent amyloid deposits; they may calcify (Fig. 9-38) (83).
FIGURE 9-38 Lymphoid interstitial pneumonia (LIP) and amyloid. A: HRCT image at the level
of inferior pulmonary veins demonstrates multiple cysts and a few irregular nodules. Note
subpleural distribution (along the fissures) of some cysts. B: CT image photographed at softtissue windows shows that some of the nodules are calcified. The patient was a 40-year-old man
with Sjögren syndrome and LIP. Biopsy of one of the nodules showed amyloid. (Courtesy of Dr.
Neil Colman, McGill University Health Centre, Montreal General Hospital, Montreal, Quebec,
Canada.)
HRCT findings helpful in distinguishing LIP from lymphoma include the
presence of cysts and the lack of pleural effusion. Honda et al. (85) compared
the HRCT findings of LIP to those in patients who had malignant lymphoma.
Cysts were more common in patients who had LIP (82%) than in patients who
had malignant lymphoma (2%), whereas airspace consolidation and large
nodules (11–30 mm in diameter) were more common in patients who had
malignant lymphoma (66% and 41%, respectively) than in patients who had LIP
(18% and 6%, respectively) (p < 0.001). Pleural effusions (25%) were seen only
in patients who had malignant lymphoma.
Follow-up in patients with LIP usually shows improvement. Johkoh et al. (86)
performed serial HRCT scans 4 to 82 months (median, 13 months) apart in 14
patients with LIP. The findings on the initial CT scan consisted of ground-glass
opacities (100%), thickening of interlobular septa (93%), centrilobular nodules
(86%), cystic airspaces (71%), and airspace consolidation (29%). On follow-up
CT, nine patients improved, one showed no change, and four showed increased
extent of disease. With the exception of cysts, the parenchymal opacities were
reversible. On follow-up CT, new cysts were seen in three patients; these
developed mainly in areas with centrilobular nodules on initial CT.
Honeycombing was seen on follow-up CT in four patients; in three patients, it
developed in areas of airspace consolidation, and in one patient, it developed in
an area with ground-glass attenuation on initial CT (86).
PLEUROPARENCHYMAL FIBROELASTOSIS
PPFE is a recently described rare condition characterized radiologically by upper
lobe predominance and histologically by elastotic fibrosis of the pleura and
adjacent parenchyma (1,87,88). The majority of cases are idiopathic, although
some patients may have nonspecific autoantibody positivity (88). Familial cases
and PPFE following bone marrow transplant have also been described (88–90).
PPFE has been reported in patients ranging from 23 to 85 years of age (median,
50–60 years) and has no sex predilection (1,88). The most common symptoms
are dry cough and shortness of breath present for several months or years prior to
diagnosis (88). Approximately 50% of patients have a history of recurrent lower
respiratory tract infections (1,88). The chest radiograph typically shows marked
pleural thickening mainly in the upper lung zones associated with cephalad hilar
retraction (87,88,91). The characteristic histologic findings consist of marked
thickening of the visceral pleura due to a homogeneous mixture of elastic tissue
and dense collagen associated with intra-alveolar fibrosis and septal elastosis of
the adjacent parenchyma (87,88,91). Occasional fibroblastic foci may be present
(87,91,92). The histologic findings tend to be temporally homogeneous as
opposed to the temporally heterogeneous pattern seen in UIP (92). The border
between the subpleural fibroelastosis and normal lung parenchyma is relatively
abrupt (87,92). Occasionally, PPFE may be associated with other interstitial lung
diseases, particularly UIP (88). In approximately 60% of patients, the clinical
course is progressive despite treatment with corticosteroids and
immunosuppressants and death from the disease occurs in approximately 40% of
patients (1,88).
High-Resolution Computed Tomography Findings
The characteristic HRCT manifestations of PPFE consist of predominantly upper
lung zone pleural thickening and subpleural reticulation associated with upper
lobe volume loss and cephalad retraction of the hila (Table 9-6, Figs. 9-39 and 940) (87,88,91). Frankel et al. (87) described the HRCT findings in four patients
with idiopathic PPFE. The main abnormalities consisted of marked pleural
thickening associated with evidence of subpleural fibrosis. Associated findings
included upper lobe volume loss, architectural distortion, traction bronchiectasis,
reticulation, and honeycombing. The abnormalities involved mainly the upper
lobes, lower lobe involvement being less marked or absent. Reddy et al. (88)
described the HRCT findings in 12 patients with PPFE, including 10 with
idiopathic PPFE and 2 with a family history of interstitial lung disease. All 12
patients had bilateral irregular pleuroparenchymal thickening, most severe in the
upper and mid zones with an associated subpleural reticular pattern. Five of the
12 patients had evidence of interstitial fibrosis in regions remote from the
pleuroparenchymal changes and involving mainly the lower lung zones with an
HRCT pattern suggestive of NSIP or UIP. Serial CTs available in 6 of the 12
patients demonstrated stability or mild progression of the pleuroparenchymal
changes over an interval of 8 to 51 months (median, 14 months) (88). Kusagaya
et al. (91) reviewed the HRCT findings in five patients with idiopathic PPFE.
The abnormalities consisted of marked pleural thickening and volume loss
associated with evidence of fibrosis, predominantly in the upper lobes. In a
report of the findings in two patients with idiopathic PPFE, the HRCT
manifestations included bilateral pleural thickening, subpleural reticulation, and
interlobular septal thickening mainly in the upper lobes; one of the patients had
mild honeycombing (93). In a study of four patients with PPFE following bone
marrow transplantation, all presented with recurrent pneumothorax (89). HRCT
demonstrated upper zone pleural thickening and subpleural fibrosis as well as
pneumothorax and diffuse abnormalities consistent with bronchiolitis obliterans
in all four patients (89).
FIGURE 9-39 Idiopathic PPFE. HRCT image at the level of the lung apices shows bilateral
subpleural reticulation and irregular septal thickening. (Courtesy of Dr. David Hansell, Royal
Brompton Hospital, London, England.)
FIGURE 9-40 Pathologically proven PPFE. A and B: HRCT shows coarse fibrosis
predominating in the peripheral upper lobes. Traction bronchiectasis is present. C and D: Coronal
reconstructions show apical fibrosis, traction bronchiectasis, and elevation of the hila.
TABLE 9-6 HRCT Findings in Pleuroparenchymal Fibroelastosis
Subpleural reticulationa
Pleural thickeninga
Upper lobe predominancea
Superimposition of first three findingsb
Superior retraction of the hilaa
Honeycombinga
aMost common findings.
bFindings most helpful in differential diagnosis.
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10
Collagen-Vascular Diseases
IMPORTANT TOPICS
RHEUMATOID ARTHRITIS
PROGRESSIVE SYSTEMIC SCLEROSIS (SCLERODERMA)
SYSTEMIC LUPUS ERYTHEMATOSUS
POLYMYOSITIS-DERMATOMYOSITIS
MIXED CONNECTIVE TISSUE DISEASE
SJÖGREN SYNDROME
ANKYLOSING SPONDYLITIS
Abbreviations Used in This Chapter
ATS
American Thoracic Society
BOOP
bronchiolitis obliterans organizing pneumonia
CVD
collagen-vascular disease
DAD
diffuse alveolar damage
DLCO
carbon monoxide diffusing capacity
ERS
European Respiratory Society
FVC
forced vital capacity
IIP
idiopathic interstitial pneumonia
ILD
interstitial lung disease
IPF
idiopathic pulmonary fibrosis
LIP
lymphoid interstitial pneumonia
MALT
mucosa-associated lymphoid tissue
MCTD
mixed connective tissue disease
NSIP
nonspecific interstitial pneumonia
OP
organizing pneumonia
PFT
pulmonary function test
PM-DM
polymyositis-dermatomyositis
PSS
progressive systemic sclerosis
RA
rheumatoid arthritis
SLE
systemic lupus erythematosus
UIP
usual interstitial pneumonia
The collagen-vascular diseases (CVDs) are acquired immunologically mediated
inflammatory disorders that affect many organs (1–3). The CVDs that most
commonly involve the lungs are rheumatoid arthritis (RA), progressive systemic
sclerosis (PSS), systemic lupus erythematosus (SLE), polymyositisdermatomyositis (PM-DM), mixed connective tissue disease (MCTD), and
Sjögren syndrome (1–3). The CVDs can affect all components of the lung,
including the interstitium, the large and small airways, the pleura, and the
pulmonary vasculature (4). The most important manifestations are diffuse
interstitial lung disease (ILD) and pulmonary hypertension, which together
account for most of the morbidity and mortality in these patients (1,2).
The CVDs can cause a variety of ILDs, identical histologically to the
idiopathic interstitial pneumonias (IIPs), including nonspecific interstitial
pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia
(OP), and lymphoid interstitial pneumonia (LIP) (Table 10-1) (5–7). The ILD
may precede the clinical and laboratory manifestations of the CVD for up to
several years, present together with systemic manifestations at the time of
diagnosis of CVD or, more commonly, manifest later in the course of the disease
(2,8,9). It is estimated that up to 20% of patients who present with a chronic ILD
either have an occult CVD or subsequently develop a clinically overt CVD
(9,10). The most common pattern of interstitial fibrosis seen in CVDs is NSIP
(6,7,11). Therefore, CVDs tend to be associated with a finer reticular pattern and
less honeycombing than typically seen in patients who have idiopathic
pulmonary fibrosis (IPF), and ground-glass opacity is more common as a
predominant abnormality. Furthermore, pleural thickening or effusion may be
present in patients who have collagen diseases, but neither is a feature of IPF.
Also, CVD may be associated with other abnormalities, such as bronchiectasis,
bronchiolitis obliterans, and follicular bronchiolitis, not seen in patients who
have IPF and having distinct high-resolution computed tomography (HRCT)
appearances. It is important to note that pulmonary abnormalities in these
patients may be due to the underlying CVD or may result from complications of
treatment, such as opportunistic infection and drug toxicity (2,12). Methotrexate,
commonly used in the treatment of RA, may result in a variety of ILDs, most
commonly NSIP (13). In recent years, there has been a major increase in the use
of biologic disease-modifying agents in the treatment of CVDs (14,15). These
medications, particularly agents blocking tumor necrosis factor-α such as
etanercept and infliximab, may result in interstitial pneumonia, sarcoid-like
disease, and vasculitis (14) (see Chapter 15).
TABLE 10-1 Relative Frequency of Patterns of Abnormality in
Collagen-Vascular Diseases
RHEUMATOID ARTHRITIS
RA is commonly associated with thoracic abnormalities, including interstitial
fibrosis, OP (bronchiolitis obliterans organizing pneumonia [BOOP]),
bronchiectasis, bronchiolitis obliterans, necrobiotic nodules, and pleural effusion
or pleural thickening (2,3,16). Other common complications include pulmonary
infection and drug toxicity (12,17). The reported prevalence of ILD in patients
with RA is highly variable, depending on the method of detection (e.g.,
pulmonary function test [PFT], radiograph, HRCT) and the population selected
(asymptomatic, symptomatic, autopsy), ranging from as low as 4% and as high
as 68% (18,19). Population-based studies have shown, however, that clinically
significant ILD occurs in 5% to 10% of patients with RA (20,21) and fewer than
10% of patients die of respiratory failure (20,22). Findings consistent with ILD
are detectable on the chest radiograph in approximately 10% of patients (23–25).
The reported prevalence of ILD on HRCT in patients with RA ranges from 19%
to 56% (26–29). In many of these cases, the ILD was not associated with any
pulmonary symptoms. Asymptomatic ILD is common in patients with RA, and
its significance and implications for therapy is not clear (12). Symptomatic ILD
in RA usually follows the onset of joint symptoms by up to several years;
however, it may occasionally precede joint disease (12).
There is controversy in the literature about the relative prevalence of UIP and
NSIP on surgical biopsy in patients with RA. Some investigators have reported a
greater prevalence of UIP (18,30), some a similar prevalence (31,32), and some a
higher prevalence of NSIP (6). Lee et al. (30) reviewed the histologic findings in
18 patients with RA who underwent surgical biopsy for ILD using the American
Thoracic Society/European Respiratory Society (ATS/ERS) consensus
classification (15). Ten (55%) patients had a UIP pattern, six (33%) patients had
an NSIP pattern, and two (11%) patients had an OP pattern. RA preceded ILD in
12 patients; in 3 patients, ILD preceded RA, and in 3 patients, both conditions
were diagnosed simultaneously (30). Yoshinouchi et al. (31) reported the HRCT
and histologic findings in 16 patients with RA and ILD. Seven patients had UIP,
seven had NSIP, and two had both UIP and NSIP (31). In the study by Tansey et
al. (6) of 15 patients with RA and ILD, 7 had NSIP, 6 had follicular bronchiolitis
and a minor component of NSIP, and 2 had UIP. Despite this controversy,
perhaps because of the greater prevalence of the UIP pattern on HRCT and the
fact that patients with characteristic findings of UIP seldom undergo lung biopsy,
most recent reviews and studies consider UIP to be the most common pattern of
ILD seen in patients with RA (1–4,18).
High-Resolution Computed Tomography Findings
The HRCT findings of ILD in patients with RA are most commonly those of UIP
(Figs. 10-1 to 10-3, Table 10-2) and less frequently NSIP (Fig. 10-4) or OP
(27,33,34). Tanaka et al. (33) reviewed the HRCT findings in 63 patients with
RA seen at an ILD clinic. The most common abnormalities evident on HRCT
were reticulation (98% patients) and ground-glass opacities (90% patients). The
authors identified four major CT patterns: UIP (41%), NSIP (30%), bronchiolitis
(17%), and OP (8%). The UIP pattern was characterized by the presence of
irregular linear opacities (100% of patients) and honeycombing (96%), involving
predominantly the basal and subpleural lung regions with mild associated
ground-glass opacities (92%) (Figs. 10-1 to 10-3). Traction bronchiectasis and
architectural distortion, when present, were always observed concomitantly with
reticulation and honeycombing. NSIP was characterized by bilateral groundglass opacities (100%), with some predominance of subpleural and basal
regions, associated with fine reticulation (100%) and minor honeycombing
(53%) (Fig. 10-4). OP was characterized by the presence of multiple patchy
areas of airspace consolidation (80%) and ground-glass opacities (100%),
usually with subpleural or peribronchial distribution (33). In all but 2 of the 16
patients who underwent lung biopsy, the CT findings reflected the pathologic
findings (33). Biederer et al. (34) correlated HRCT and PFTs in 53 patients with
suspected ILD associated with RA. The most common finding was reticulation
seen in 40 of 53 (75%) patients, presenting as a mixed pattern with ground-glass
opacities in 15 of 40. A pure reticular pattern was most common in patients with
long-standing ILD. The extent of interstitial abnormalities was highly variable
and correlated with a decrease in carbon monoxide diffusing capacity (DLCO)
(34). Patients with a definite UIP pattern on HRCT seldom undergo lung biopsy,
but patients with RA and an NSIP pattern or indeterminate findings on HRCT
may have UIP or NSIP on surgical biopsy. Kim et al. (35) reviewed the HRCT
findings in 82 patients with RA who had ILD. The HRCT scans were interpreted
as definite UIP in 20 (24%), likely NSIP in 19 (23%), and indeterminate in 43
(52%). Definite UIP was considered present when there was basilar predominant
reticulation, traction bronchiectasis, and honeycombing, with limited groundglass opacity. Predominantly bibasilar ground-glass opacities with limited (or
no) reticulation and absent honeycombing was interpreted as likely NSIP. Of the
19 patients with a likely NSIP pattern on HRCT, 6 underwent surgical lung
biopsy, which showed UIP in 4 and NSIP in 2 patients. Six out of 43 patients
with an indeterminate pattern on HRCT underwent surgical lung biopsy, which
showed UIP in 5 patients and NSIP in 1 (35).
FIGURE 10-1 UIP in rheumatoid arthritis. HRCT shows reticular pattern and mild
honeycombing in the subpleural lung regions.
FIGURE 10-2 A–C: Prone HRCT at three levels in a patient with RA and lung disease.
Subpleural opacities in the mid-lung (A and B) have a small nodular or branching appearance,
consistent with that of follicular bronchiolitis. At a lower level (C), findings of intralobular interstitial
thickening and traction bronchiectasis are typical of fibrosis.
FIGURE 10-3 RA and end-stage UIP with honeycombing. A: HRCT at the level of the
tracheal carina shows subpleural honeycombing and interlobular septal thickening
indistinguishable from IPF. B: HRCT through the right lung base shows diffuse honeycombing and
septal thickening.
FIGURE 10-4 NSIP in rheumatoid arthritis. HRCT shows extensive bilateral ground-glass
opacities and mild reticulation.
TABLE 10-2 HRCT Findings in Rheumatoid Arthritis
Bronchiectasis without fibrosisa
Findings of fibrosis (i.e., traction bronchiectasis and bronchiolectasis, intralobular interstitial
thickening, irregular interlobular septal thickening, irregular interfaces)a
Honeycombing
Ground-glass opacitya
Peripheral and subpleural predominance of fibrosis or ground-glass opacitya,b
Lower lung zone and posterior predominancea,b
Pleural thickening or effusiona,b
Small centrilobular nodules (follicular bronchiolitis)
Large (rheumatoid) nodules
Findings of bronchiolitis obliterans (i.e., air trapping, mosaic perfusion)
aMost common finding(s).
bFinding(s) most helpful in differential diagnosis.
Overall, patients with CVD-related ILD, including patients with RArelated
ILD, have a better prognosis than patients with IPF (4,36,37), but patients with
RA and a definite UIP pattern on HRCT have a prognosis similar to that seen in
patients with IPF (35,37). In one study of 362 patients (269 with IIP and 93 with
interstitial pneumonia associated with CVD), the patients with interstitial
pneumonia associated with CVD survived longer (mean, 177 months) than
patients with IIP (mean, 66.9 ± 6.5 months; p = 0.001) (36). A multivariate
analysis showed that younger age, better pulmonary function, and the presence
of a CVD were independent prognostic factors. No significant differences were
found between CVD-associated NSIP and idiopathic NSIP in survival, clinical
features, or lung function. The mean survival of patients with UIP associated
with CVD was 177 months compared to 70 months in patients with IPF (36).
However, the study showed a trend toward worse survival in RA-UIP patients
than in RA-ILD patients with an NSIP pattern (p = 0.08) (36). Kim et al. (35)
compared the prognosis in 82 patients with RA-associated ILD with that in 51
patients with IPF. Twenty (24%) out of 82 patients with RA had HRCT findings
interpreted as definite UIP. These patients showed worse survival than those
without this pattern (median survival, 3.2 vs. 6.6 years), and a survival similar to
that shown by those with IPF. Analysis of specific HRCT features demonstrated
that traction bronchiectasis and honeycomb fibrosis were associated with worse
survival. Female sex and a higher baseline DLCO were associated with better
survival (35).
Patients with RA-associated UIP or NSIP may occasionally develop acute
exacerbation, i.e., rapid deterioration of respiratory symptoms without any
identifiable cause and new parenchymal opacities due to diffuse alveolar damage
(DAD) or, less commonly, OP superimposed on the ILD (Fig. 10-5) (38–41).
The HRCT findings of acute exacerbation consist of extensive bilateral groundglass opacities with or without associated dependent areas of consolidation
superimposed on a background of UIP or NSIP (38,42). The prognosis of acute
exacerbation in ILD in CVD is better than that of acute exacerbation of IPF (43).
In one study (43), the 90-day mortality of acute exacerbation in 15 patients with
CVD-associated interstitial pneumonias, including 6 with RA, was 33%
compared to 69% in 13 patients who had acute exacerbation of IPF (43). Rarely,
DAD may be the initial pulmonary manifestation of RA (44).
FIGURE 10-5 Acute exacerbation of ILD in rheumatoid arthritis. A: HRCT shows mild
peripheral reticulation, irregular thickening of the interlobular septa, and minimal ground-glass
opacities. The findings are consistent with UIP. B: HRCT 6 months later when the patient
developed acute respiratory failure demonstrates extensive bilateral ground-glass opacities with
associated linear opacities (crazy-paving pattern) and traction bronchiectasis consistent with
DAD. The diagnosis of acute exacerbation of UIP was made after exclusion of other potential
causes of DAD.
The most common abnormalities seen on HRCT in patients with RA are
bronchiectasis and findings consistent with bronchiolitis (Fig. 10-6, Table 10-2).
Bronchiectasis has been reported on HRCT in approximately 30% of patients
with RA (45,46). In one study of 84 patients with RA, 38 (49%) had abnormal
HRCT scans (45). The findings included (a) bronchiectasis and/or
bronchiolectasis (30%), (b) pulmonary nodules (22%), (c) subpleural
micronodules and/or pseudoplaques (17%), (d) nonseptal linear attenuation
(18%), (e) areas of ground-glass attenuation (14%), and (f) honeycombing (10%)
(45). Bronchiectasis and airways disease in RA can be associated with chronic
infection, which has an increased incidence in rheumatoid patients, or
bronchiolitis obliterans (46,47). For example, in a study of 20 nonsmoking RA
patients who had normal chest radiographs, 5 (25%) were found to have
unsuspected basal bronchiectasis on HRCT (48). Perez et al. (46) reviewed the
prevalence and characteristics of airways involvement in 50 RA patients who did
not have ILD. They found HRCT to be more sensitive in detecting airway
abnormalities than were PFTs. HRCT demonstrated bronchial or lung
abnormalities, or both, in 35 cases (70%), consisting of air trapping (n = 16;
32%), cylindrical bronchiectasis (n = 15; 30%), and mild heterogeneity in lung
attenuation (i.e., mosaic perfusion) (n = 10; 20%). In contrast, PFTs
demonstrated airway obstruction (i.e., reduced forced expiratory volume in 1
second/forced vital capacity [FVC]) in only nine patients (18%) and evidence of
small airways disease in only four (8%). PFT findings of airway obstruction and
small airways disease correlated with the presence of bronchiectasis and
bronchial wall thickening (p = 0.003) (46). RA is a common cause of
bronchiectasis in the general population. In a recent study of 106 patients with
bronchiectasis confirmed by HRCT, RA was the cause of bronchiectasis in 29%
of African American patients and 6% of European American patients (49). The
occurrence of bronchiolitis obliterans in patients who have RA is discussed in
Chapter 20.
FIGURE 10-6 Bronchiectasis and obliterative bronchiolitis in RA. HRCT shows extensive
bilateral bronchiectasis and areas of decreased attenuation and vascularity (mosaic perfusion),
mainly in the left lung.
An uncommon abnormality seen in patients who have RA or other CVDs is
follicular bronchiolitis (50,51). This is a benign condition characterized by
prominent hyperplasia of lymphoid follicles around the bronchioles and, to a
lesser extent, bronchi (51). HRCT findings of follicular bronchiolitis consist of
multiple small nodules in a predominantly centrilobular, subpleural, and
peribronchial distribution (see Fig. 11-23) (51,52). The nodules usually measure
1 to 4 mm in diameter but may occasionally be 1 cm or more in diameter (52).
Follicular bronchiolitis may also be associated with lung cysts similar to those
seen in LIP (see Fig. 11-24).
Single or multiple lung nodules seen in patients who have RA may represent
necrobiotic (rheumatoid) nodules. Rheumatoid nodules may range from a few
millimeters to several centimeters in size, are frequently subpleural, and are
usually multiple and asymptomatic (Fig. 10-7) (53–55). Cavitation occurs in
approximately 50% and calcification is uncommon (55). Occasionally,
rheumatoid nodules may result in bronchopleural fistula with associated
pneumothorax (54,56).
FIGURE 10-7 Necrobiotic nodules in RA. HRCT shows bilateral subpleural nodules. Also
noted are several irregular linear opacities consistent with mild interstitial fibrosis.
Pleural thickening occurs in 20% to 33% of patients with RA (20,57). In a
study by Fujii et al. (57), pleural thickening was visible on HRCT in 33% of the
91 patients studied and in 44% of the patients who had HRCT findings of
interstitial pneumonia. Pleural effusion has an incidence of 3% to 5% (20,58).
The pleural effusion is usually small and resolves spontaneously (54). Enlarged
central pulmonary arteries are seen on HRCT in approximately 46% of patients
with ILD and mediastinal lymphadenopathy is seen in 20%.
Utility of High-Resolution Computed Tomography
HRCT is more sensitive than chest radiography in the diagnosis of lung disease
in patients who have RA. Fujii et al. (57) reviewed the chest radiographic and
HRCT findings of 91 patients who had RA. On HRCT, 43 patients had findings
of UIP with fibrosis, 5 had findings consistent with bronchiolitis obliterans, and
43 had a normal HRCT. In approximately half of these 91 patients, chest
radiographic findings were similar to those shown on HRCT. However, 17 of 46
(37%) patients believed to have normal chest radiographs had HRCT
abnormalities consistent with rheumatoid lung disease. Furthermore, 14 of 43
(33%) patients believed to have abnormal chest radiographs had no evidence of
significant lung disease on HRCT (57). Also, HRCT can be useful in
demonstrating lung disease in RA patients who have normal chest radiographs
but have pulmonary function abnormalities (59,60). Some HRCT findings are
more frequent in symptomatic patients who have rheumatoid lung disease (45).
These include honeycombing, bronchiectasis, nodules, and ground-glass opacity.
PROGRESSIVE SYSTEMIC SCLEROSIS (SCLERODERMA)
PSS has a higher prevalence of pulmonary involvement than the other CVDs.
The most common manifestations and leading causes of death are interstitial
fibrosis, which occurs eventually in up to 75% of patients, and pulmonary
arterial hypertension (61,62). ILD most often complicates the diffuse cutaneous
form of PSS but can also be associated with the limited form of the disease or
with PSS without cutaneous involvement (20,61). Initial studies using
echocardiography suggested a prevalence of PA hypertension of up to 49% in
PSS, but more recent prospective studies using cardiac catheterization as the
gold standard for diagnosis have shown a prevalence of 8 to 12% (61,63,64).
Approximately 80% of patients with PSS and ILD have a histologic pattern of
NSIP (11,65). Bouros et al. (11) reviewed the histologic findings in 80 patients
with PSS and ILD. Approximately 78% had NSIP, 8% had UIP, 7% had endstage lung disease, and the remaining had other patterns. The most common
abnormality on chest radiography is a symmetric basal reticulonodular pattern.
The chest radiograph, however, may be normal in patients with abnormal PFTs
and abnormal HRCT (66). The incidence of radiographically recognizable
interstitial disease is probably around 25%, although various studies quote an
incidence ranging from 10% to 80% (67).
High-Resolution Computed Tomography Findings
The HRCT findings of interstitial fibrosis in PSS usually resemble those of
idiopathic NSIP and consist mainly of ground-glass opacities frequently with
superimposed fine reticulation and traction bronchiectasis (Figs. 10-8 and 10-9,
Table 10-3) (5,65). Associated focal areas of consolidation are seen in some
cases (Fig. 10-10) (68). Desai et al. (65) compared the HRCT findings in 225
patients with ILD associated with PSS with the findings in 40 consecutive
patients with IPF and 27 patients with idiopathic NSIP. Approximately twothirds of patients with PSS had predominant ground-glass opacities or a mixed
pattern with ground-glass opacities and reticulation, and one-third of patients
had a predominant reticular pattern. This was similar to patients with idiopathic
NSIP. The only difference was the overall extent of abnormalities, which was
smaller in patients with PSS (median extent of ILD was 13% of the lung
parenchyma compared to 30% for idiopathic NSIP). Although NSIP is the most
common pattern of abnormality seen in patients with PSS, reticulation may
sometimes be the predominant abnormality on HRCT and result in an
appearance similar to that of IPF (Figs. 10-11 and 10-12).
FIGURE 10-8 NSIP in progressive systemic sclerosis. A: HRCT performed on a multidetector
CT scanner shows extensive bilateral ground-glass opacities and mild superimposed reticulation.
B: Coronal reformation demonstrates predominantly peripheral and lower lung zone distribution of
the ground-glass opacities and reticulation.
FIGURE 10-9 A and B: Subpleural ground-glass opacity in a young patient with scleroderma.
A subtle but distinct increase in opacity is visible in the posterior lungs on prone scans.
FIGURE 10-10 Subpleural ground-glass opacity and consolidation in a patient with
scleroderma. Before treatment (A–C), subpleural opacities are the predominant abnormality.
Traction bronchiectasis (C) seen within areas of opacity in the posterior costophrenic sulcus
indicates some evidence of fibrosis. After treatment, scans at similar levels (D–F) show
considerable reduction in opacity. Persistent abnormalities in the posterior lungs and at the lung
bases, including irregular reticulation and traction bronchiectasis, likely represent fibrosis.
TABLE 10-3 HRCT Findings in Progressive Systemic Sclerosis
(Scleroderma)
Ground-glass opacitya
Findings of fibrosis (i.e., honeycombing, traction bronchiectasis and bronchiolectasis, intralobular
interstitial thickening, irregular interlobular septal thickening, irregular interfaces)a
Peripheral and subpleural predominance of fibrosis or ground-glass opacitya,b
Lower lung zone and posterior predominancea,b
Pleural thickening or effusiona,b
Small centrilobular nodules (follicular bronchiolitis)
Esophageal dilatationa,b
aMost common finding(s).
bFinding(s) most helpful in differential diagnosis.
Remy-Jardin et al. (69) reviewed the HRCT, PFT, and bronchoalveolar lavage
results of 53 patients who had PSS, emphasizing the frequency of ground-glass
opacity and honeycombing in these subjects. Among the 32 patients who had
abnormal HRCT findings, 26 (81%) had ground-glass opacities and 19 (59%)
had honeycombing. The honeycombing in PSS is usually of limited extent and
associated with areas of ground-glass opacity. In the study by Remy-Jardin et al.
(69), all patients who had honeycombing also showed ground-glass opacity.
These abnormalities had a distinct basal, posterior, and peripheral predominance.
Goldin et al. (70) reviewed the HRCT scans in 162 patients with symptomatic
PSS-related ILD. The main findings consisted of ground-glass opacities (90%)
including areas of ground-glass attenuation without evidence of fibrosis (49%),
evidence of fibrosis (93%), and honeycombing (37%). All findings involved
mainly the lower lung zones. The authors concluded that in the majority of cases
the findings were consistent with NSIP but that the presence of honeycombing in
37% of HRCT scans suggests that some patients may have a mixture or overlap
of NSIP and UIP patterns (70). The extent of pulmonary fibrosis seen on HRCT
scans was significantly negatively correlated with FVC and TLC, i.e., associated
with restrictive physiologic impairment, and negatively correlated with DLCO,
i.e., associated with impairment in gas transfer (70). The extent and severity of
fibrosis on HRCT also correlate with the peak PA pressures and may be helpful
in screening for pulmonary hypertension in patients with PSS (71).
Small nodules with or without associated honeycombing have also been
reported in patients who have PSS and are presumed to represent focal lymphoid
hyperplasia (follicular bronchiolitis), a common histologic finding in PSS
(69,72). However, nodules are not a prominent HRCT feature of this disease.
Other findings on CT in patients who have PSS include diffuse pleural
thickening, seen in one-third of cases (69); asymptomatic esophageal dilatation,
present in 40% to 80% of cases (Fig. 10-12) (73,74); and enlarged mediastinal
nodes, seen in approximately 60% of cases (73). The presence of esophageal
dilatation may be helpful in the differential diagnosis of PSS from other diffuse
ILDs. The coronal luminal diameter of the esophagus in patients who have PSS,
as shown on CT, has been reported to range from 12 to 40 mm (mean, 23 mm), a
finding that was not seen in a control group of 13 patients who had a variety of
other parenchymal and airway abnormalities (73).
FIGURE 10-11 A and B: Findings of fibrosis in a patient with scleroderma. Subpleural
honeycombing, traction bronchiectasis, and some irregular interlobular septal thickening are the
predominant features. These abnormalities closely mimic the appearance of IPF.
FIGURE 10-12 A and B: Prone HRCT in a patient with scleroderma with mild interstitial
fibrosis and esophageal dilatation. Irregular reticular opacities are visible in the peripheral lung,
consistent with fibrosis. The esophagus (e) is dilated and contains an air-fluid level.
Seely et al. (75) assessed the radiographic and HRCT findings in 11 children
(mean age, 11 years) with PSS. ILD was evident on the radiograph in 2 patients
and on HRCT in 8. The HRCT findings consisted of ground-glass opacity, seen
in all 8 patients; linear opacities, seen in 6; honeycombing, seen in 5; and small
subpleural nodules, seen in 7. There was no correlation between duration of PSS
and severity of ILD. Overall, the pattern and distribution of abnormalities were
similar to those seen in adults. However, whereas in adults honeycombing
predominates in the lower lung zones, in children the honeycombing was most
severe in the upper lung zones (75).
Follow-up of patients with PSS and ILD may show initial improvement (Fig.
10-10), but in the majority of cases the fibrosis progresses on long-term followup (Fig. 10-13). Kim et al. (68) reviewed the findings on serial HRCT scans in
40 patients with PSS and ILD over a mean follow-up period of 39 months. On
the initial HRCT, all patients had ground-glass opacities (mean extent 18%), 36
(90%) had irregular linear opacities (mean extent 4%), 13 (33%) had
consolidation (mean extent 1.9%), and 12 (30%) had honeycombing (mean
extent 2%). Follow-up HRCT showed increase in overall extent of disease in 24
patients and showed no change in 16 patients. The worsening was due mainly to
an increased extent of ground-glass opacity and honeycombing. The increase in
the extent of honeycombing on CT correlated significantly with the decrease in
DLCO (68). There was no significant difference in the extent of ground-glass
opacity, irregular linear opacity, and honeycombing on the initial HRCT between
patients who showed progression of disease or remained stable.
FIGURE 10-13 Disease progression in PSS. A: HRCT shows bilateral ground-glass
opacities, reticulation, traction bronchiectasis, and minimal honeycombing. B: HRCT 2 years later
demonstrates progression of fibrosis with more extensive reticulation and honeycombing. Also
noted is a fluid level within the dilated esophagus.
Utility of High-Resolution Computed Tomography
HRCT plays a major role in the detection and characterization of lung
involvement in PSS patients (70,76). HRCT is commonly performed to identify
the presence of ILD in patients with PSS because the clinical symptoms and
PFTs are nonspecific and the chest radiographic findings are often equivocal or
falsely negative (76). Dyspnea may result from ILD, pulmonary vascular
disease, or cardiac impairment and PFTs are limited by the wide range of
normal, typically 80% to 120% of normal values (76). Schurawitzki et al. (66)
studied 23 patients who had PSS using chest radiographs and HRCT. Chest
radiographs were abnormal in only 15 (65%), but HRCT showed evidence of
ILD in 21 (91%); the authors concluded that HRCT was clearly superior to chest
radiographs for detecting minimal lung disease.
Wells et al. (77) assessed the potential role of HRCT as a predictor of lung
histology on open-lung biopsy specimens in patients who had PSS. In this study,
CT discriminated correctly between inflammatory and fibrotic histologic
appearances in 16 of 20 (80%) biopsy specimens. Predominant ground-glass
opacities often correlated with the presence of inflammation, and the presence of
a predominantly reticular pattern on HRCT correlated closely with the presence
of fibrosis on the pathologic specimens (77). However, ground-glass on HRCT
in patients with ILD may also represent fibrosis particularly when there is
admixed reticulation or traction bronchiectasis (76–78). The current evidence in
the literature is that ground-glass opacities in patients with PSS-associated NSIP
are most commonly associated with irreversible disease (79,80). Shah et al. (79)
performed sequential HRCT in 41 patients with PSS over a mean follow-up
period of 27 months (range, 6–60 months). Ground-glass opacity was the most
common imaging finding, present in 66% of patients, and usually associated
with other signs of interstitial disease, including nonfibrotic interstitial opacities
in 27% and fibrotic interstitial opacities in 32%. Improvement was only
documented in two (5%) patients with ground-glass opacities and nonfibrotic
interstitial opacities (79).
The prognosis of NSIP associated with PSS is similar to that of idiopathic
NSIP and considerably better than that of IPF (36). The prognosis of ILD in PSS
is influenced more by the severity of lung involvement than the pattern of
parenchymal disease. Bouros et al. (11) correlated the initial histologic findings
with prognosis in 80 patients with PSS-associated ILD. The histologic
appearances included cellular NSIP (n = 15), fibrotic NSIP (n = 47), UIP (n = 6),
end-stage lung disease (n = 6), and other patterns (n = 6). Five-year survival
differed little between NSIP (91%) and UIP/end-stage lung disease (82%);
mortality was associated with lower initial DLCO and FVC levels (p = 0.004 and
p = 0.007, respectively). Survival and serial FVC and DLCO did not differ
between cellular and fibrotic NSIP. Increased mortality in NSIP was associated
with lower initial DLCO (p = 0.04) and deterioration in DLCO levels during the
next 3 years (p < 0.005). The authors concluded that outcome in PSS-associated
ILD is linked more strongly to disease severity at presentation and serial DLCO
than to histopathologic findings (11). Goldin et al. (70) reviewed the baseline
HRCT scan images of 162 patients with PSS-associated ILD randomized into a
prospective clinical trial and assessed the extent and distribution of pure groundglass opacity (i.e., increased lung attenuation in the absence of reticular
interstitial thickening or architectural distortion), pulmonary fibrosis (i.e.,
reticular intralobular interstitial thickening, traction bronchiectasis, and
bronchiolectasis), and honeycomb cysts. HRCT scan findings included evidence
of pulmonary fibrosis (93% of patients), areas of pure ground-glass opacity
(49%) and areas of honeycombing (37%). The extent of pulmonary fibrosis on
baseline HRCT scans was predictive of the progression rate in the absence of
active immunosuppressive therapy as well as the response to cyclophosphamide
therapy, which was greatest in those with the most extensive pulmonary fibrosis
seen on baseline HRCT scans (70). Pure ground-glass opacity and the extent of
honeycombing at the baseline HRCT did not significantly affect the FVC at 12
months (70).
Densitometry may be more reproducible than visual assessment of lung
changes on HRCT and may correlate better with functional impairment in
patients with PSS. Camiciottoli et al. (81) assessed the intra-and interoperator
reproducibility of visual and densitometric lung CT analysis in 48 PSS patients.
The intra-and interoperator reproducibility of mean lung attenuation
(intraobserver weighted kappa = 0.97; interobserver weighted kappa = 0.96)
were higher than those of visual assessment (intraobserver weighted kappa =
0.71; interobserver weighted kappa = 0.69). In univariate analysis, only
densitometric measurements correlated with exercise and quality of life
questionnaire parameters. In multivariate analysis, mean lung attenuation,
skewness, and kurtosis correlated significantly with FRC, FVC, DLCO, exercise
test, and quality of life questionnaire parameters, while visual assessment was
associated only with FRC and FVC (81).
The best estimate of prognosis in PSS-ILD is probably obtained by using a
semi-quantitative assessment of extent of disease on CT, integrated, if necessary,
with lung function. Goh et al. (82) evaluated the prognostic value of baseline
HRCT and PFT variables in 215 patients with PSS-ILD. Increasingly extensive
disease on HRCT was a powerful predictor of mortality (p < 0.0005), with an
optimal extent threshold of 20%. Patients with disease extent less than or equal
to 10% on HRCT were classified as having limited disease and those with extent
greater than or equal to 30% as having extensive disease. In patients with HRCT
extent of 10% to 30% (termed indeterminate disease), a FVC threshold of 70%
was an adequate prognostic substitute. On the basis of these observations,
Systemic sclerosis associated interstitial lung disease (SSc-ILD) was staged as
limited disease (minimal disease on HRCT or, in indeterminate cases, FVC ≥
70%) or extensive disease (extensive disease on HRCT or, in indeterminate
cases, FVC < 70%). This system (hazards ratio [HR], 3.46; 95% confidence
interval [CI], 2.19–5.46; p < 0.0005) was more discriminatory than an HRCT
threshold of 20% (HR, 2.48; 95% CI, 1.57–3.92; p < 0.0005) or an FVC
threshold of 70% (HR, 2.11; 95% CI, 1.34–3.32; p = 0.001). The system was
evaluated by four trainees and four practitioners, in PSS patients with minimal
and severe disease on HRCT defined as clearly less than 20% or clearly more
than 20%, respectively, and the use of an FVC threshold of 70% in indeterminate
cases. The staging system was predictive of mortality for all scorers. The authors
concluded that that discriminatory prognostic information in PSS-associated ILD
can be obtained using a staging system based on combined evaluation with
HRCT and PFTs (82).
SYSTEMIC LUPUS ERYTHEMATOSUS
SLE is a multisystem autoimmune CVD that typically affects young women
(female-to-male ratio of 9:1) (83,84). The age at diagnosis is usually between 15
and 45 years (84). SLE is commonly associated with pleural and pulmonary
abnormalities. An autopsy study of 90 patients with SLE found pleuropulmonary
involvement in 98%, the most common being pleuritis (78%), bacterial
infections (58%), primary and secondary alveolar hemorrhages (26%), followed
by distal airway alterations (21%), opportunistic infections (14%), and
pulmonary thromboembolism, both acute and chronic (8%) (85). Sepsis was
considered the major cause of death (85). Pleural effusion is seen on chest
radiographs in 30% to 50% of patients during the course of disease (3,84). The
pleural effusion may be uni-or bilateral, and is usually small to moderate in size.
Pleural involvement may be the first manifestation of SLE and is commonly
associated with pericarditis (86).
More than 50% of patients who have SLE have lung disease at some time
(87). Pulmonary parenchymal complications of SLE include pneumonia, acute
lupus pneumonitis, diffuse pulmonary hemorrhage, and ILD (86). The most
common pulmonary complication of SLE is pneumonia (86,87). Patients with
SLE are more susceptible to bacterial and opportunistic infections due to
immunosuppressive therapy with corticosteroids or other agents as well
immunologic dysfunction related to SLE (86). Acute lupus pneumonitis occurs
in 1% to 4% of patients with SLE and usually manifests with sudden onset of
fever, cough and dyspnea (86). It is characterized histologically by a
combination of DAD, edema, and alveolar hemorrhage (5,86). Diffuse alveolar
hemorrhage is an uncommon but severe manifestation of SLE, with a prevalence
ranging from 0.5% to 6% (86).
Clinically significant chronic ILD develops in 3% to 8% of patients with SLE,
there being a progressive increase in prevalence with disease duration
(86,88,89). Trivial interstitial abnormalities have been reported on HRCT in up
to 38% of patients with SLE and no clinical evidence of lung involvement
(4,90). Because significant ILD is uncommon in SLE, there is limited data on the
pathologic pattern. However, as with other CVDs, the most common pattern
appears to be NSIP followed by UIP (4,6,86). OP (BOOP) is also seen with
increased frequency in patients who have SLE (86,91) and LIP has been
described in a few patients (86).
High-Resolution Computed Tomography Findings
HRCT findings in patients who have SLE include (a) findings of fibrosis,
although they are less common than in patients who have RA or scleroderma; (b)
ground-glass opacity; (c) small nodules; (d) bronchial wall thickening or
bronchiectasis; and (e) pleural thickening or effusion (Table 10-4).
TABLE 10-4 HRCT Findings in Systemic Lupus Erythematosus
Ground-glass opacitya
Findings of fibrosis (i.e., intralobular interstitial thickening, irregular interlobular septal thickening,
irregular interfaces, bronchiectasis and bronchiolectasis)a
Honeycombing (less common than with IPF)
Peripheral and subpleural predominance of fibrosis or ground-glass opacitya,b
Lower lung zone and posterior predominancea,b
Bronchiectasis
Pleural thickening or effusiona,b
aMost common finding(s).
bFinding(s) most helpful in differential diagnosis.
The most common HRCT findings of interstitial fibrosis in patients with SLE
include interlobular septal thickening, intralobular interstitial thickening,
ground-glass opacities, and architectural distortion (Figs. 10-14 and 10-15)
(90,92,93). These findings tend to be mild involving a small percentage of the
lung parenchyma and usually are not associated with clinical symptoms or
abnormal pulmonary function (4,90,92). Diffuse interstitial disease with a
pattern characteristic of NSIP or UIP is considerably less common being seen in
approximately 4% of patients (Figs. 10-14 and 10-15) (94).
FIGURE 10-14 NSIP pattern in SLE. A: HRCT at the level of the aortic arch shows patchy
bilateral ground-glass opacities and mild reticulation. B: HRCT at the level of the lung bases
demonstrates more extensive abnormalities.
FIGURE 10-15 Supine (A) and prone (B) HRCT in a 34-year-old woman with SLE, ILD, and
progression of PFT abnormalities. Reticular opacities in the peripheral lung are consistent with
fibrosis.
Ground-glass opacity and consolidation in patients with SLE may be
associated with pneumonia, lupus pneumonitis (Fig. 10-16), pulmonary
hemorrhage (Fig. 10-17), or, occasionally organizing pneumonia (BOOP) (5,94).
Pulmonary infection, acute lupus pneumonitis, and diffuse alveolar hemorrhage
may result in clinical and radiologic findings of ARDS (84,95). Occasionally,
hazy or fluffy centrilobular perivascular opacities may be seen, likely related to
vasculitis (96).
FIGURE 10-16 HRCT in a 29-year-old woman with SLE and shortness of breath. A: Patchy
ground-glass opacities are visible. B: Four months later, there has been progression of the
abnormalities. Lung biopsy revealed lupus pneumonitis.
FIGURE 10-17 A and B: HRCT in a 19-year-old woman with newly diagnosed SLE and
pulmonary hemorrhage. Patchy areas of ground-glass opacity, which appear centrilobular and
lobular, are visible.
Findings of airways disease such as bronchial wall thickening and
bronchiectasis have been reported in 18% to 20% of patients who have SLE
(90,92). Pleuropericardial abnormalities were seen in 15% to 17% of cases in
two studies (92,93).
Utility of High-Resolution Computed Tomography
Several studies have shown that interstitial fibrosis is seen more frequently on
HRCT than on chest radiographs (90,92,93,97). Bankier et al. (90) performed a
prospective study in 48 patients who had SLE and no prior clinical evidence of
lung involvement. Three (6%) patients had evidence of fibrosis on radiographs.
Of the 45 patients who had normal chest radiographs, 17 (38%) had
abnormalities evident on HRCT. These consisted of interlobular septal
thickening in 15 patients (33%), intralobular interstitial thickening in 15 (33%),
architectural distortion in 10 (22%), small nodules in 10 (22%), bronchial wall
thickening in 9 (20%), bronchial dilatation in 8 (18%), areas of ground-glass
opacity in 6 (13%), and areas of airspace consolidation in 3 (7%) (90).
Fenlon et al. (92) assessed the radiographic and HRCT findings in 34 patients
who had SLE. Abnormalities were identified on chest radiographs in 8 (24%)
patients and on HRCT in 24 (70%). The most common findings on HRCT were
interstitial fibrosis seen in 11 (32%) patients, bronchiectasis in 7 (20%),
mediastinal or axillary lymphadenopathy in 6 (18%), and pleuropericardial
abnormalities in 5 (15%) (92). In another study of 29 patients who had SLE, the
chest radiograph was abnormal in 10 (34%) and the HRCT in 20 (72%) patients.
The most frequently detected abnormality on HRCT was ILD, which was seen in
11 (38%) patients. Of 15 patients who had normal clinical examination, normal
PFTs, and normal chest radiographs, 4 (26%) had HRCT features of ILD (93).
POLYMYOSITIS-DERMATOMYOSITIS
Polymyositis and dermatomyositis are chronic autoimmune disorders
characterized by weakness in the proximal limb muscles (98,99). Approximately
50% of patients have a characteristic skin rash, which enables distinction of
dermatomyositis from polymyositis. PM-DM is a rare disease, with an overall
incidence ranging from 2 to 10 new cases per million persons at risk per year
(99). Pulmonary complications occur in more than 40% of patients, and are
associated with significant morbidity and mortality (99). Common complications
include ILD, aspiration, pneumonia, and drug-induced lung diseases (99). The
risk of malignancy is also increased, particularly in DM, the standardized index
ratio for lung cancer being 5.9 for DM and 2.8 for PM (100).
It is estimated that 35% to 40% of patients with PM-DM develop ILD during
the course of their disease (101). The pattern of involvement is most commonly
NSIP (6,101–103). Other histologic patterns are OP, UIP, and DAD. LIP is
uncommon (99,101). Patients with PM-DM may have more than one pattern of
abnormality on lung biopsy, the most common combination being NSIP and OP
(6). The radiographic findings of PM-DM-associated ILD usually consist of
reticular opacities and/or areas of consolidation. In one study of 57 patients with
PM-DM-associated ILD, reticular opacities were seen in 95% of cases and areas
of consolidation in 25% (102). In more than 90% of patients, the findings
involved mainly the lower lobes (102).
High-Resolution Computed Tomography Findings
HRCT findings of PM-DM include (a) ground-glass opacity; (b) findings of
fibrosis, although honeycombing is uncommon; and (c) consolidation (Figs. 1018 to 10-20, Table 10-5). These findings are consistent with NSIP being the most
common histologic pattern followed by OP, UIP, and DAD. Ikezoe et al. (104)
reviewed the HRCT findings in 25 patients who had PM-DM; 23 had abnormal
HRCT scans. The most common findings seen in these 23 patients included
ground-glass opacities (92%), linear opacities (92%), irregular interfaces (88%),
airspace consolidation (52%), parenchymal micronodules (28%), and
honeycombing (16%). A relatively high prevalence of airspace consolidation
(52%) and a low prevalence of honeycombing (16%) were observed. Correlation
of HRCT with pathologic findings showed that 2 patients who had extensive
consolidation had DAD; 8 patients who had subpleural bandlike opacities or
airspace consolidation, or both, had OP; and 4 patients who had honeycombing
had UIP (104). Cottin et al. (103) assessed the HRCT and histologic findings in
17 patients with PM-DM. The most common HRCT findings were reticular and
ground-glass opacities. Histologic patterns included NSIP in 11 (65%) patients,
UIP in 2, OP (BOOP) in 2, LIP in 1, and unclassifiable interstitial pneumonia in
1 patient (60). Survival at 5 years was 50%. Douglas et al. (102) reviewed the
HRCT findings in 30 patients with PM-DM-associated ILD. The findings
included irregular linear opacities seen in 19 of 30 (63%) patients, consolidation
in 16 of 30 (53%), and ground-glass opacities in 13 of 30 (43%). In the majority
of patients the findings had a lower lobe predominance. None of the patients had
honeycombing (102). Surgical lung biopsies available in 22 patients showed
NSIP in 18, organizing DAD in 2, BOOP in 1, and UIP in 1 patient.
FIGURE 10-18 NSIP pattern in polymyositis. HRCT shows patchy bilateral ground-glass
opacities and minimal reticulation.
FIGURE 10-19 NSIP and OP in polymyositis. HRCT shows patchy bilateral ground-glass
opacities consistent with NSIP. Also noted are perilobular opacity (white arrow) and areas of
ground-glass opacity surrounded by a ring of consolidation (reversed halo sign) (black arrow)
consistent with OP (BOOP). Surgical biopsy demonstrated characteristic features of NSIP and
OP.
FIGURE 10-20 OP pattern in polymyositis. HRCT shows bilateral peribronchial and
subpleural areas of consolidation and patchy ground-glass opacities.
TABLE 10-5 HRCT Findings in Polymyositis-Dermatomyositis
Ground-glass opacitya
Findings of fibrosis (i.e., traction bronchiectasis and bronchiolectasis, intralobular interstitial
thickening, irregular interlobular septal thickening, irregular interfaces)a
Honeycombing (less common than with IPF)
Consolidation (secondary to OP)a,b
Peripheral and subpleural predominance of fibrosis or ground-glass opacitya,b
Lower lung zone and posterior predominancea,b
aMost common finding(s).
bFinding(s) most helpful in differential diagnosis.
Mino et al. (105) assessed the HRCT findings before and after treatment with
corticosteroids and immunosuppressants in 19 patients who had PM-DM.
Findings on the initial HRCT scans included pleural irregularities and prominent
interlobular septa (n = 19), ground-glass opacity (n = 19), patchy consolidation
(n = 19), parenchymal bands (n = 15), irregular peribronchovascular thickening
(n = 15), and subpleural lines (n = 7). Honeycombing was not detected on any
CT images. These findings were more severe in the basal and subpleural regions
of the lungs. In 16 of the 17 patients who underwent sequential CT, areas of
consolidation, parenchymal bands, and irregular peribronchovascular thickening
improved, becoming pleural irregularities and prominent interlobular septa,
ground-glass opacity, and subpleural lines on follow-up CT scans (105).
Akira et al. (106) performed sequential HRCT scans in seven patients who
had PM-DM, five of whom had histologic confirmation of pulmonary
involvement. The predominant finding on the initial CT scans in four patients
was subpleural consolidation, which was shown to be due to OP (BOOP). One
patient with bilateral patchy areas of ground-glass opacity and consolidation was
shown to have DAD. In most cases, consolidation improved with use of
corticosteroid or immunosuppressive therapy, or both; in two patients, however,
consolidation evolved into honeycombing. In one patient with subpleural linear
opacities, parenchymal abnormalities slowly progressed, and linear opacities had
evolved into honeycombing at the patient’s 8-year follow-up.
Bonnefoy et al. (107) assessed the changes in the pattern, distribution, and
extent of ILD on HRCT in 20 patients with PM-DM after a mean follow-up of
38 months. The patients were classified into four groups according to the
dominant pattern of abnormality on the initial HRCT: ground-glass opacity and
reticulation (45%), airspace consolidation (20%), honeycombing (20%), and
normal or almost normal lung (15%). Under medical treatment, the ground-glass
opacities and consolidation most commonly improved, while the extent of
honeycombing usually increased. Some patients showed marked clinical
deterioration with development of extensive consolidation on HRCT and DAD
histologically, regardless of the initial pattern on HRCT (107). In another followup study of 19 patients who had PM-DM and HRCT, the initial HRCT showed
findings consistent with predominant inflammation in 11 patients, mixed
inflammation and fibrosis in 2, fibrosis in 2, and was normal in 4 (108). All
patients were treated with high-dose glucocorticoids and other
immunosuppressive agents. Follow-up examination 12 to 238 weeks after the
initial examination was performed in 15 patients. None of the patients with
changes consistent with ILD in the initial HRCT experienced a complete
resolution at follow-up investigation. Of the 11 patients with predominantly
inflammatory findings at the first examination, 3 had developed fibrotic changes,
2 had mixed inflammatory and fibrotic changes, and 4 remained unchanged at
the last examination; 1 patient had died and 1 had no follow-up examination.
Three of the 4 patients with normal HRCT at the first examination underwent
follow-up investigation; 1 had developed fibrotic changes, 1 inflammatory
changes, and 1 linear opacity changes. The authors concluded that the course of
ILD in patients with PM-DM could not be predicted on the first examination
(108).
MIXED CONNECTIVE TISSUE DISEASE
MCTD is a condition characterized by clinical and laboratory findings
overlapping those of PSS, SLE, and PM-DM (109). A prerequisite for diagnosis
is the presence of high titers of circulating autoantibodies to uridine-rich small
nuclear ribonucleoprotein (anti-U1 RNP) (4,109). MCTD is much more common
in women (female-to-male ratio about 9:1) (110). Pulmonary abnormalities occur
in 25% to 85% of MCTD patients during the course of the disease (111,112).
The most common pulmonary complication is ILD, which has been reported in
21% to 67% of patients (3,112). The most frequent interstitial pattern in MCTD
is NSIP; less common patterns include UIP, LIP, and OP (3,94). HRCT is
superior to the chest radiograph in demonstrating the presence of ILD in MCTD
and in distinguishing ILD from other parenchymal abnormalities (112). Other
common complications of MCTD are pulmonary hypertension and pleural
effusion. Pulmonary arterial hypertension occurs in 10% to 45% of patients and
is associated with a poor prognosis (3). Pleural effusions, frequently transient in
nature, are seen in approximately 50% of patients (109,113). Less common
complications associated with MCTD include aspiration due to esophageal
dysmotility; diffuse pulmonary hemorrhage and pulmonary thromboembolism
(3,109).
High-Resolution Computed Tomography Findings
HRCT findings of MCTD include (a) ground-glass opacities, (b) subpleural
micronodules, (c) reticulation, (d) septal lines, and (e) honeycombing (Figs. 1021 to 10-23, Table 10-6). Kozuka et al. (114) reviewed the HRCT findings in 41
patients with MCTD-associated ILD. The predominant abnormalities included
ground-glass opacities seen in all patients, subpleural micronodules seen in 98%,
and nonseptal linear opacities seen in 80%. Other findings included intralobular
reticular opacities (61%), architectural distortion (49%), and traction
bronchiectasis (44%), and, less commonly, interlobular septal thickening, illdefined centrilobular nodules, and honeycombing. The abnormalities usually had
a peripheral distribution and lower lobe predominance (114). Saito et al. (115)
reviewed the HRCT scans of 35 patients with MCTD and ILD. Septal thickening
was seen in 100% of patients, subpleural micronodules in 94%, honeycombing
in 51%, subpleural linear opacities in 37%, and ground-glass opacities in 11%.
The predominant HRCT pattern was interlobular septal thickening in 83% of
patients, honeycombing in 11%, subpleural micronodules in 3%, and
consolidation in 3% (115). The differences between the results of the study by
Saito et al. (115) and the one by Kozuka et al. (114) are presumably related to
different patient populations and the different interval between onset of disease
and the HRCT. The patients in the report by Kozuka et al. (114) underwent
HRCT of the chest within 1 year (mean, 4.5 months) of the diagnosis of MCTD,
compared to a mean interval of 49.5 months in the study by Saito et al. (115).
Although pleural effusion or pleural thickening had been previously considered
to be seen in fewer than 10% of cases of MCTD (67), pleural thickening was
evident on HRCT in 66% of patients reviewed by Saito et al. (115).
FIGURE 10-21 MCTD with pulmonary fibrosis. A and B: HRCT at two levels shows a fine
reticular pattern posteriorly, which reflects septal thickening and intralobular interstitial fibrosis.
FIGURE 10-22 A–C: HRCT in a 26-year-old woman with MCTD, basilar crackles on physical
examination, and restrictive disease on PFTs. Intralobular interstitial thickening results in a very
fine reticular pattern in the subpleural lung and lower lobes. Traction bronchiectasis (A, arrows) is
also visible.
FIGURE 10-23 HRCT in a patient with MCTD, findings of interstitial fibrosis (architectural
distortion, honeycombing, and reticulation), and associated lung carcinoma. A: The findings of
interstitial fibrosis predominate in the peripheral lung regions (A and B). A peripheral
adenocarcinoma with infiltration of the pleura (B, arrows) is also present.
TABLE 10-6 HRCT Findings in Mixed Connective Tissue Disease
Ground-glass opacitya
Findings of fibrosis (i.e., honeycombing, traction bronchiectasis and bronchiolectasis, intralobular
interstitial thickening, irregular interlobular septal thickening, irregular interfaces)a
Peripheral and subpleural predominance of fibrosis or ground-glass opacitya,b
Lower lung zone and posterior predominancea,b
Pleural thickening or effusiona,b
Subpleural micronodulesa
Septal linesa
aMost common finding(s).
bFinding(s) most helpful in differential diagnosis.
Bodolay et al. (112) assessed the clinical findings, PFTs, and HRCT scans in
144 consecutive patients with MCTD. Ninety-six of the 144 patients (67%) had
active ILD. HRCT demonstrated ground-glass opacities in 75 of the 96 (78%)
patients and ground-glass opacities with mild fibrosis (interlobular septal
thickening and intralobular linear opacities) in 22%. The patients who had active
ILD received corticosteroids or corticosteroids in combination with
cyclophosphamide. After 6 months of therapy, the HRCT scans in 67 of 75
(89%) patients with ground-glass opacities were normal. However, ground-glass
opacity with mild fibrosis developed in 15 of 96 (16%) patients, mild fibrosis in
13 of 96 (13.5%) patients, and the HRCT showed subpleural honeycombing in 1
case (1%) (112).
SJÖGREN SYNDROME
Sjögren syndrome is an autoimmune disease characterized by the clinical triad of
keratoconjunctivitis sicca, xerostomia, and recurrent swelling of the parotid
gland caused by lymphocytic infiltration of the exocrine glands (116). The
prevalence (annual incidence) of primary Sjögren syndrome in North America is
320 per 100,000 population (117), which is greater than that of SLE. It has a
female-to-male ratio of 9:0. Secondary Sjögren syndrome occurs in association
with other autoimmune diseases, most commonly RA (116,118). More than half
the patients have respiratory symptoms, most commonly hoarseness (from dry
larynx) and cough (from xerotrachea) (4). However, clinically significant
respiratory disease was present in only 11% of patients in a study of 1,010
Spanish patients with primary Sjögren syndrome (119). The majority of patients
with ILD have a histologic pattern of NSIP (4,120,121). Less common patterns
include LIP, UIP, and OP (BOOP) (4,121). Occasionally, the interstitial disease
may represent primary pulmonary lymphoma or diffuse interstitial amyloidosis
(121). Airway abnormalities include bronchiectasis, chronic bronchiolitis, and
follicular bronchiolitis (6,52,94). A relatively common finding in patients with
Sjögren syndrome is the development of lymphoma, the prevalence being 40
times that in the general population (116). The prevalence of primary pulmonary
lymphoma is estimated to be 1% to 2% in patients with Sjögren syndrome (118).
The most common type is non-Hodgkin lymphoma, most frequently mucosaassociated lymphoid tissue (MALT) lymphoma (118).
The frequency of reported radiographic abnormalities ranges from 2% to 34%
(122). The most common radiographic finding consists of a reticular or
reticulonodular pattern, usually with a basal predominance (122,123). This
pattern may be caused by LIP, interstitial fibrosis, or, occasionally, lymphoma
(123,124).
High-Resolution Computed Tomography Findings
Common HRCT findings in Sjögren syndrome include (a) ground-glass opacity,
(b) findings of fibrosis, (c) centrilobular nodular opacities, and (d) lung cysts
(Figs. 10-24 and 10-25, Table 10-7). Franquet et al. (122) assessed the HRCT
findings in 50 patients who had Sjögren syndrome for a mean of 12 years (range,
2–37 years) after the onset of disease. Abnormalities were detected in 17 patients
(34%) on HRCT compared with 7 (14%) on chest radiographs. The most
common findings consisted of bronchiolectasis and poorly defined centrilobular
nodular or branching linear opacities (seen in 11 patients), areas of ground-glass
opacity (in 7), and honeycombing (in 4). The latter was bilateral, asymmetric,
and present almost exclusively in the periphery of the lower lobes (122). A treein-bud appearance related to infection or follicular bronchiolitis was visible in 3.
FIGURE 10-24 NSIP in Sjögren syndrome. HRCT shows bilateral ground-glass opacities and
mild reticulation.
FIGURE 10-25 LIP in Sjögren syndrome. A: HRCT at the level of the right upper lobe
bronchus demonstrates bilateral thin-walled cystic lesions in a random distribution. Also noted are
small foci of ground-glass opacity in the left lung. B: HRCT at the level of the lung bases shows
several thin-walled cysts and patchy bilateral ground-glass opacities.
TABLE 10-7 HRCT Findings in Sjögren Syndrome
Ground-glass opacitya
Findings of fibrosis (i.e., traction bronchiectasis or bronchiolectasis, intralobular interstitial
thickening, irregular interlobular septal thickening, irregular interfaces)a
Honeycombing
Peripheral and subpleural predominance of fibrosis or ground-glass opacitya,b
Lower lung zone and posterior predominance
Small centrilobular nodules (follicular bronchiolitis)
Cysts or small subpleural nodules (LIP)a,b
aMost common finding(s).
bFinding(s) most helpful in differential diagnosis.
Uffmann et al. (125) performed HRCT in 37 consecutive patients with
primary Sjögren syndrome and normal chest radiographs. Abnormal HRCT
findings were seen in 24 of 37 patients (65%) and consisted mainly of
interlobular septal thickening (n = 9), micronodules (n = 9), lung cysts (n = 5),
and ground-glass opacities (n = 4). Intralobular opacities, honeycombing, and
bronchiectasis were less frequent.
Lohrmann et al. (126) reviewed the HRCT scans of 24 patients with primary
Sjögren syndrome. Nineteen patients (79%) had abnormal HRCT findings,
including bronchiectasis, thin-walled cysts, and small pulmonary nodules (seen
in 46% of patients), ground-glass opacities and emphysema (38%), interlobular
septal thickening (29%), honeycombing (25%), tree-in-bud pattern (21%), and
mosaic perfusion (17%) (126).
Ito et al. (120) correlated the HRCT and histologic findings in 33 patients with
primary Sjögren syndrome. The most common histologic pattern was NSIP, seen
in 61% of patients; less common findings included bronchiolitis, LIP, MALT
lymphoma, and amyloidosis. A characteristic HRCT pattern of NSIP was defined
according to the ATS/ERS classification of IIPs as consisting predominantly of
ground-glass opacities, usually with associated irregular linear opacities in a
predominantly peripheral and basal distribution (120,127). HRCT-pathologic
correlation resulted in a 94% positive predictive value of this HRCT pattern for a
pathologic diagnosis of NSIP; however, the diagnostic value of HRCT was low
(15%) for patterns other than NSIP (120).
Parambil et al. (121) correlated the histologic patterns with the radiographic
and HRCT features in 18 patients with primary Sjögren syndrome and ILD. The
main HRCT findings in NSIP were ground-glass and reticular opacities
distributed peripherally in both lower lung zones. HRCT in patients with OP
(BOOP) showed bilateral patchy consolidation, mainly in the subpleural and
peribronchovascular regions, and patchy ground-glass opacities. UIP was
characterized by reticular opacities and traction bronchiectasis in a
predominantly basal and peripheral distribution and commonly associated with
subpleural honeycombing. The main findings in LIP and primary pulmonary
lymphoma consisted of patchy areas of consolidation, ground-glass opacities,
and nodules. Multiple cysts were seen in all three patients with LIP and one of
the two patients with primary pulmonary lymphoma. Prominent interlobular
septal thickening with small randomly distributed nodules were present in the
patient who had diffuse interstitial amyloidosis (121).
The HRCT manifestations of LIP in Sjögren syndrome are similar to those
seen in LIP associated with other conditions (see Chapter 9) (128,129). The
predominant findings consist of extensive areas of ground-glass opacity and
randomly distributed thin-walled cysts (Fig. 10-25) (128,129). The presence of
cystic lesions and focal regions of air trapping on expiratory HRCT have been
associated with follicular bronchiolitis in a patient with this disease (130). Other
common findings in LIP include interlobular septal thickening, intralobular
linear opacities, areas of consolidation, centrilobular nodules, and subpleural
nodules (129). Amyloidosis occurring in relation to Sjögren syndrome may
appear as multiple nodules and cystic lesions (131) or as septal thickening with
small randomly distributed nodules; the nodules may calcify (see Fig. 9-38)
(121).
Lymphoma in patients who have Sjögren syndrome may result in patchy areas
of consolidation, ground-glass opacities, and multiple nodules (Fig. 10-26)
(118,121).
FIGURE 10-26 Maltoma in Sjögren syndrome. HRCT shows bilateral focal areas of
consolidation and patchy ground-glass opacities. Bronchial dilatation is present within the areas of
consolidation, a finding commonly seen in patients with MALT lymphoma.
The prevalence of bronchiectasis was evaluated in a cohort of 507 patients
with primary Sjögren syndrome (132). Forty one (8%) patients were classified as
having bronchiectasis associated with primary Sjögren syndrome (40 women,
mean age of 64 years). The bronchiectasis was cylindrical and, in 29 cases
(71%), located in the lower lobes. During follow-up, patients with bronchiectasis
had a higher frequency of respiratory infections (56% vs. 3%, p < 0.001) and
pneumonia (29% vs. 3%, p = 0.002) than did patients without (132).
ANKYLOSING SPONDYLITIS
Ankylosing spondylitis is a spondyloarthropathy characterized by sacroiliitis,
spinal stiffness, and loss of spinal mobility (133). It is estimated to affect
approximately 0.1% of the population and to have a male-to-female ratio ranging
from 10:1 to 15:1 (134). The most characteristic pulmonary complication is
upper-zonal fibrosis, which usually manifests 15 years or more after the onset of
arthritic manifestations (134). Occasionally, however, pulmonary involvement
may occur before any skeletal symptoms, or in asymptomatic persons with earlystage ankylosing spondylitis (134,135). An early review of the records of 2,080
patients with ankylosing spondylitis disclosed 28 (1.3%) who had
pleuropulmonary manifestations, including 25 with apical fibrobullous lesions, 2
with pleural effusions, and 1 with apical fibrosis and pleural effusion (136). A
more recent study of 1,028 ankylosing spondylitis patients seen over a 10-year
period found 22 (2.1%) with apical lung fibrosis detected on chest radiography
(137). Radiologically, the process begins as apical pleural involvement, and then
apical opacities develop and progress to cyst formation. Generally, the disease
begins unilaterally and becomes bilateral. The chest radiographic findings may
closely mimic those of tuberculosis. Symptoms are usually absent, unless the
cavities become secondarily infected. The histologic lesions consist of
nonspecific inflammation and fibrosis. Mycobacterial or fungal superinfection of
the upper lobe cysts and cavities, most commonly by Aspergillus fumigatus with
formation of fungus balls, has been reported in up to one-third of the patients
(134). Such infection may lead to recurrent and sometimes massive hemoptysis
(134). Since the advent of HRCT several studies have shown that upper lobe
fibrosis is more common than previously evident on the radiograph and that
ILD, beyond apical fibrosis, is also a feature of ankylosing spondylitis (138).
The cause of ILD in ankylosing spondylitis is unclear and the histologic findings
have rarely been described.
High-Resolution Computed Tomography Findings
Common HRCT findings in ankylosing spondylitis include (a) apical fibrosis,
(b) septal lines, (c) bronchiectasis, and (d) pleural thickening (Fig. 10-27, Table
10-8). Apical fibrosis in ankylosing spondylitis is frequently associated with
apical bullae and cavities and may be complicated by aspergilloma formation or
necrotizing Aspergillus pneumonia (Fig. 10-27) (139–141). Fenlon et al. (142)
prospectively assessed the chest radiographic and HRCT findings in 26 patients
who had ankylosing spondylitis. Abnormalities were evident on the radiograph
in 4 (15%) patients and on HRCT in 18 (69%). The most common findings on
HRCT consisted of ILD, seen in 4 patients; bronchiectasis, seen in 6; mediastinal
lymphadenopathy, seen in 3; paraseptal emphysema, seen in 3; tracheal
dilatation, seen in 2; and apical fibrosis, seen in 2 (87). Chest radiography failed
to identify any of the patients who had ILD.
FIGURE 10-27 Apical fibrosis, cavitation, and aspergilloma in ankylosing spondylitis. A:
HRCT performed on a multidetector CT scanner shows left upper lobe cavity containing a large
aspergilloma and a crescent of air (air crescent sign). Also noted are patchy reticulation, focal
ground-glass opacities, and mild emphysema in the right upper lobe. B: Coronal reformation
demonstrates large left upper lobe cavity and aspergilloma and right upper lobe fibrosis with
superior retraction of the right hilum. Mild reticulation and focal ground-glass opacities are present
in the remaining lung.
TABLE 10-8 HRCT Findings in Ankylosing Spondylitis
Apical fibrosisa,b
Septal lines
Bronchiectasis
Mosaic perfusion and air trappinga
aMost common finding(s).
bFinding(s) most helpful in differential diagnosis.
Turetschek et al. (143) reviewed the HRCT findings in 25 patients with
ankylosing spondylitis who had a normal chest radiographs and no history of
smoking. Fifteen of 21 patients (71%) had abnormalities on HRCT, including
interlobular septal thickening (33%), mild bronchial wall thickening (29%), and
pleural thickening and pleuropulmonary irregularities (both 29%). Eight of 15
patients (53%) with abnormal CT and 4 of 6 patients (67%) with normal CT
findings had mild restrictive lung function. Senocak et al. (144) reviewed the
HRCT findings in 18 patients with ankylosing spondylitis. The most common
findings in nonsmokers were septal and pleural thickening seen in 40% of
nonsmokers. Apical fibrosis was present in 15% of patients; the fibrosis was
unilateral and right sided in all cases and was associated with emphysema even
in nonsmokers. Souza et al. (140) assessed the chest radiographs and inspiratory
and expiratory HRCT features in 17 patients with ankylosing spondylitis, 8 of
which were smokers. Pulmonary abnormalities were seen on chest radiography
in 2 (12%) patients and on CT in 15 (88%) patients. The abnormalities on CT
included evidence of airway disease in 14 (82%), interstitial abnormalities in 11
(65%), and emphysema in 6 (35%) patients. Airway abnormalities included
bronchial wall thickening in 7 (41%), mosaic perfusion pattern in 3 (18%),
centrilobular nodules in 3 (18%), bronchiolectasis in 2 (12%), and air trapping
on expiratory HRCT in 7 (41%) patients. Interstitial abnormalities included
parenchymal bands in 7 (41%), intralobular linear opacities in 2 (12%), and 1
patient each with irregular thickening of interlobular septa, subpleural lines, and
honeycombing. Two (12%) patients had coarse irregular linear opacities
predominantly in the upper lobes associated with focal lucencies consistent with
bullae or thin-walled cavities. One of the patients had an intracavitary soft-tissue
mass consistent with an aspergilloma. Two of the six patients with emphysema
were lifetime nonsmokers (140).
Sampaio-Barros et al. (145) performed a prospective study of 52 consecutive
asymptomatic patients with ankylosing spondylitis, using chest radiography,
PFTs, and HRCT. Of the 52 patients, 33 (63%) had never smoked, 14 (27%)
were current smokers, and 5 (10%) were ex-smokers. The chest radiograph
showed pulmonary abnormalities in four patients (8%) and the PFT presented a
restrictive pattern in 52% of the patients. Thoracic HRCT demonstrated
abnormalities in 21 patients (40%), consisting predominantly of linear
parenchymal opacities (19%), lymphadenopathy (12%), emphysema (10%),
bronchiectasis (8%), and pleural involvement (8%). The authors concluded that
nonspecific subclinical pulmonary involvement is frequent in AS.
In one study, the authors performed HRCT and PFTs in 20 patients with
ankylosing spondylitis, including 10 with less than 10 years’ disease duration
and 10 with 10 or more years’ disease duration. HRCT revealed abnormalities in
14 patients (70%) (146). The most common findings were apical fibrosis (45%)
and emphysema (25%). HRCT findings were more prominent in late ankylosing
spondylitis patients (disease duration ≥ 10 years) (p = 0.015). PFTs were
considered as abnormal in four patients (20%). Three of these patients had
concomitant HRCT abnormalities. On the other hand, 10 patients with normal
PFTs had abnormalities on HRCT. The authors concluded that HRCT is superior
to PFTs in detecting lung abnormalities in patients with ankylosing spondylitis.
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11
Diffuse Pulmonary Neoplasms and Pulmonary
Lymphoproliferative Diseases
IMPORTANT TOPICS
PULMONARY LYMPHANGITIC CARCINOMATOSIS
HEMATOGENOUS METASTASES
INVASIVE MUCINOUS ADENOCARCINOMA
KAPOSI SARCOMA
LYMPHOPROLIFERATIVE DISORDERS, LYMPHOMA, AND LEUKEMIA
Focal Lymphoid Hyperplasia
Follicular Bronchiolitis
Lymphoid Interstitial Pneumonia
Angioimmunoblastic Lymphadenopathy
Primary Pulmonary Lymphoma
Secondary Pulmonary Lymphoma
AIDS-Related Lymphoma
Posttransplantation Lymphoproliferative Disorder
Lymphomatoid Granulomatosis
Leukemia
Adult T-cell Leukemia/Lymphoma
Abbreviations Used in This Chapter
AIDS
acquired immunodeficiency syndrome
AILD
angioimmunoblastic lymphadenopathy
ARL
AIDS-related lymphoma
ATLL
adult T-cell leukemia/lymphoma
BAC
bronchioloalveolar carcinoma
BALT
bronchus-associated lymphoid tissue
CMV
cytomegalovirus
CWP
coal worker’s pneumoconiosis
EBV
Epstein-Barr virus
HAART
highly active antiretroviral therapy
HIV
human immunodeficiency virus
HL
Hodgkin lymphoma
HTLV-1
human T-lymphotropic virus, type 1
IMA
invasive mucinous adenocarcinoma
KS
Kaposi sarcoma
LIP
lymphoid interstitial pneumonia
MALT
mucosa-associated lymphoid tissue
NHL
non-Hodgkin lymphoma
PLC
pulmonary lymphangitic carcinomatosis
PTLD
posttransplantation lymphoproliferative disorder
REAL
Revised European-American Lymphoma
TB
tuberculosis
WHO
World Health Organization
Primary and metastatic neoplasms and lymphoproliferative diseases may present
with nonspecific symptoms and multiple or diffuse pulmonary abnormalities on
high-resolution computed tomography (HRCT). Because these may be
associated with diseases that produce other pulmonary abnormalities (e.g.,
collagen-vascular disease) or may occur in the setting of immunosuppression in
patients at risk for development of infections or other pulmonary complications
(e.g., AIDS, transplantation, or chemotherapy), knowledge of their appearances
is necessary if a correct diagnosis is to be made (1).
PULMONARY LYMPHANGITIC CARCINOMATOSIS
Pulmonary lymphangitic carcinomatosis (PLC) refers to tumor growth in the
lymphatic system of the lungs. It occurs most commonly in patients who have
carcinomas of the breast, lung, stomach, pancreas, prostate, cervix, or thyroid,
and in patients who have metastatic adenocarcinoma from an unknown primary
site (2,3). PLC usually results from hematogenous spread to the lung, with
subsequent interstitial and lymphatic invasion, but can also occur because of
direct lymphatic spread of tumor from mediastinal and hilar lymph nodes (3).
Symptoms of shortness of breath are common and can predate radiographic
abnormalities.
The radiographic manifestations of PLC include reticular or reticulonodular
opacities, septal lines, hilar and mediastinal lymphadenopathy, and pleural
effusion (4,5). However, these findings are nonspecific. In one study, an accurate
chest radiographic diagnosis was made in only 20 of 87 (23%) patients who had
PLC (5). Furthermore, the chest radiograph is normal in approximately 50% of
cases of pathologically proven PLC (5,6).
The pulmonary lymphatics involved in patients who have PLC are located in
the axial interstitial compartment (the peribronchovascular and centrilobular
interstitium) and in the peripheral interstitial compartment (within the
interlobular septa and in the subpleural regions) (7). Tumor growth in the
lymphatics located within these compartments and associated edema result in the
characteristic HRCT findings of PLC (8,9). This distribution of abnormalities
has been termed lymphatic or perilymphatic (10,11).
High-Resolution Computed Tomography Findings
PLC is characterized on HRCT by reticular opacities, sometimes associated with
nodules (Figs. 11-1 to 11-3). Specific findings include (a) smooth or nodular
thickening of the peribronchovascular interstitium surrounding vessels and
bronchi in the perihilar lung, (b) smooth or nodular interlobular septal
thickening, (c) smooth or nodular subpleural interstitial thickening, (d)
thickening of the peribronchovascular axial interstitium in the centrilobular
regions, and (e) preservation of normal lung architecture at the lobular level
despite the presence of these findings (8,9,12–14) (Table 11-1). These findings
correlate closely with the appearance and distribution of PLC on pathologic
specimens (Fig. 11-3).
FIGURE 11-1 Lymphangitic spread of breast carcinoma. A: Lung window image from a
contrast-enhanced volumetric HRCT shows extensive smooth interlobular septal thickening (red
arrows) and peribronchovascular thickening in the left upper lobe. Also noted is prominence of the
centrilobular vessels due to peribronchovascular tumor infiltration in a centrilobular location
(yellow arrow). B: Soft-tissue window contrasts peribronchovascular tumor (arrows) and opacified
pulmonary arteries.
FIGURE 11-2 Nodular interlobular septal thickening in lymphangitic spread of carcinoma. A–
C: Nodular interlobular septal thickening in a patient with metastatic colon carcinoma. Nodules are
clearly visible within the septa outlining a lobule in the lung apex (arrows, A). Nodules are also
visible involving the pleural surfaces.
FIGURE 11-3 Gross pathologic and microscopic appearances of lymphangitic
carcinomatosis. A: Pathologic specimen in a patient who has localized lymphangitic
carcinomatosis. Note thickening of the peribronchovascular interstitium (long arrow) and
subpleural interstitium (short arrow) due to lymphatic spread of tumor. (From Munk PL, Müller NL,
Miller RR, et al. Pulmonary lymphangitic carcinomatosis: CT and pathological findings. Radiology
1988;166:705, with permission.) B: Scanning micrograph of open-lung biopsy specimen shows
thickening of the interlobular septa (arrows) and peribronchovascular interstitium (curved arrows),
largely due to tumor deposits rather than fibrous tissue or edema. (From Munk PL, Müller NL,
Miller RR, et al. Pulmonary lymphangitic carcinomatosis: CT and pathological findings. Radiology
1988;166:705, with permission.) C: Lymphangitic spread of carcinoma shown on a lung slice.
Interlobular septa (white arrows) are thickened by tumor. Thickening of the subpleural interstitium
adjacent to the major fissure reflects similar tumor infiltration (yellow arrows) as does thickening of
the peribronchovascular interstitium (red arrows). (Courtesy of Martha Warnock, MD.) D:
Histologic findings of lymphangitic carcinoma. Nodules of tumor (black arrows) are visible within
the interlobular septa and the subpleural interstitium surrounding a single lobule in the lung
periphery. A tumor nodule is also visible in the centrilobular region (red arrow), and other nodules
of tumor are seen in relation to airways and vessels. (Courtesy of Kirk Jones, MD.)
TABLE 11-1 HRCT Findings in Lymphangitic Spread of Carcinoma
Smooth or nodular peribronchovascular interstitial thickening (peribronchial cuffing)a,b
Smooth or nodular interlobular septal thickeninga,b
Smooth or nodular thickening of fissuresa
Normal lung architecture; no distortiona,b
Prominence of centrilobular structures
Diffuse, patchy, or unilateral distribution
Lymph node enlargement
Pleural effusionb
a Most common findings.
b Findings most helpful in differential diagnosis.
Peribronchovascular interstitial thickening or peribronchial cuffing is
commonly visible on HRCT in the perihilar lung, and can be diffuse, focal, or
asymmetric (Figs. 11-1 and 11-3 to 11-5) (8,15,16). The thickened
peribronchovascular interstitium may be smooth, closely mimicking the
appearance of bronchial wall thickening, or it can be nodular (8); in both
instances, the thickened interstitium is sharply marginated from the adjacent
aerated lung. In patients who have peribronchovascular interstitial thickening
from PLC, pulmonary artery branches adjacent to the bronchi also appear larger
than normal, and nodular (8); in other words, the size relationship of the thickwalled bronchi and adjacent vessels is maintained.
FIGURE 11-4 A–C: HRCT in a 73-year-old man who has cough and shortness of breath.
Smooth interlobular septal thickening is visible on the right (A, arrows), typical of PLC. Thickening
of the peribronchovascular interstitium (B, arrows) and right major fissure are also visible (C,
arrows). Right pleural effusion is present. Bronchogenic carcinoma was diagnosed on
bronchoscopy.
FIGURE 11-5 A–C: HRCT at three levels in a patient who had prior partial left
pneumonectomy for lung carcinoma. A: Scan through the right upper lobe shows smooth
interlobular septal thickening and thickening of the peribronchovascular interstitium. There is no
distortion of lung anatomy on the right, and lobules appear to be of normal size and shape. The
left lung is reduced in volume because of surgery. B and C: Scans through the right lung at lower
levels show a similar appearance. Transbronchial biopsy showed lymphatics invaded by tumor.
Stein et al. (13) performed an extensive analysis of the CT patterns of
lymphangitic carcinomatosis, and found a localized or diffuse increase in
reticular opacities and an increase in the number and thickness of interlobular
septa in all patients who had PLC (Figs. 11-1 to 11-5). In patients who had PLC,
interlobular septal thickening is often most pronounced in the peripheral lung
regions. In the study by Stein et al. (13), thickened septa appeared 1 to 2 cm in
length, usually contacted the pleural surface, and were more numerous and
thicker than similar septa seen in healthy control subjects. In lymphatic spread of
carcinoma, the thickened septa usually appear smooth in contour. However,
these may also have a beaded appearance resulting from tumor growth in the
lymphatics, as contrasted with the irregular septal thickening seen in patients
who have fibrosis (8,9). In a HRCT study of postmortem lung specimens, 19 of
22 cases with interstitial pulmonary metastases showed the appearance of beaded
or nodular septal thickening. The beaded septa corresponded directly to the
presence of tumors growing in pulmonary capillaries, lymphatics, and the septal
interstitium (9). Smooth or nodular thickening of the subpleural interstitium is
also commonly seen; this is easiest to recognize adjacent to the fissures.
Stein et al. (13) observed septal thickening that outlined distinct pulmonary
lobules in approximately 50% of patients who had PLC. These lobules usually
contained a visible central branching opacity, or dot, representing the
centrilobular artery branch or branches, surrounded by the thickened
centrilobular peribronchovascular interstitium (Fig. 11-1A). This appearance is
one of the most characteristic HRCT features of PLC (13). Prominence of the
centrilobular artery is commonly seen in regions of lung in which septal
thickening is present. In a distinct minority of patients who have PLC,
centrilobular interstitial thickening predominates (17).
Five factors may account for thickening of the peribronchovascular
interstitium, interlobular septa, and centrilobular axial interstitium seen on
HRCT in patients who have PLC: (a) tumor-filling pulmonary vessels or
lymphatics, (b) the presence of tumor within the interstitium, (c) distention of
vessels or lymphatic channels distal to central vascular or lymphatic tumor
emboli, (d) interstitial pulmonary edema secondary to tumor obstruction of the
lymphatics, and (e) interstitial fibrosis secondary to the presence of interstitial
tumor or secondary to long-standing interstitial edema (4,7–9). In patients who
have HRCT findings of PLC, pathologic studies (8,9) have shown that the
visible thickening of the interlobular septa and peribronchovascular interstitium
was caused mainly by interstitial tumor growth, rather than by vascular
distension, edema, or fibrosis, although these abnormalities were also present
(8,9).
In approximately 50% of patients, the abnormalities of PLC appear focal or
unilateral rather than diffuse (Figs. 11-1, 11-2, 11-4, and 11-5). Focal disease
may involve the axial interstitium mainly or exclusively, leading to thickening of
the bronchovascular bundles, or mainly the peripheral interstitium, leading to
thickening of the interlobular septa (16).
It is characteristic of PLC that lung architecture appears normal despite the
presence of abnormal reticular opacities; pulmonary lobules surrounded by thick
septa are easily identified because the lobules appear normal in size and shape
(Figs. 11-4 and 11-5). There is no distortion of lobular size or dimensions in
PLC, as is typically seen in patients who have interstitial fibrosis. The
importance of this finding cannot be overemphasized; if there is lung distortion
associated with findings that would otherwise be typical of PLC, another
diagnosis should be considered. Although it is typical for abnormalities to
progress, even in patients receiving chemotherapy, stable or slowly progressing
abnormalities can be seen in some patients (18).
Hilar lymphadenopathy is visible on HRCT in only 50% of patients who have
PLC, supporting the supposition that PLC is often the result of hematogenous
spread of tumor to the interstitium, rather than central lymphatic obstruction with
retrograde spread of tumor or edema (13). In a study by Grenier et al. (19),
lymphadenopathy was visible in 38% to 54% of patients who had lymphangitic
carcinomatosis. Mediastinal lymph node enlargement can also be seen. Lymph
node enlargement can be symmetric or asymmetric. Pleural effusion may also be
present.
Utility of High-Resolution Computed Tomography
In patients who have PLC, characteristic HRCT findings can be seen in patients
who have normal chest radiographs. In such cases, the HRCT findings tend to be
focal and more pronounced in peripheral lung regions not well visualized on
chest radiographs (13). Furthermore, conventional CT is not adequate for
assessing the lung parenchyma in patients who have PLC; findings such as
interlobular septal thickening, which are characteristic of PLC, are not often
visible on scans obtained with thick slices (8,13).
Mathieson et al. (20) compared the diagnostic accuracy of HRCT to that of
chest radiography in a study of 118 consecutive patients who had various
chronic diffuse interstitial lung diseases. The CT and radiographic findings were
independently assessed by three observers without knowledge of clinical or
pathologic data. Of 18 patients who had lymphangitic carcinomatosis, a
confident diagnosis was made on chest radiography in 20% of cases; this
interpretation was correct in 64% of readings. In contrast, a confident diagnosis
of lymphangitic carcinomatosis was suggested on CT in 54% of readings, the
interpretation being correct in 93% of cases. Grenier et al. (19) assessed the
relative value of clinical, chest radiographic, and CT findings in making a
specific diagnosis of chronic diffuse interstitial lung diseases in 208 consecutive
patients, of whom 13 had pathologically proven lymphangitic carcinomatosis. A
confident diagnosis was made based on a combination of clinical and
radiographic findings in 54% of patients who had lymphangitic carcinomatosis
(the assessment being correct in 92%), and on a combination of clinical,
radiographic, and CT findings in 92% (correct in all instances).
In a patient who has a known tumor and symptoms of dyspnea, HRCT
findings typical of PLC are usually considered diagnostic, and a lung biopsy is
usually not performed in clinical practice. In patients without a known neoplasm,
HRCT can be helpful in directing lung biopsy to the most productive sites, as
PLC is often focal (8). Also, because transbronchial biopsy is usually positive in
PLC, typical HRCT findings can also serve to suggest this as the most
appropriate procedure.
Differential Diagnosis of Pulmonary Lymphangitic
Carcinomatosis
Although peribronchovascular interstitial thickening and smooth septal
thickening, often seen in patients with PLC, can also be seen in association with
pulmonary edema, the differentiation of these entities can be made on clinical
grounds. Also, nodular or beaded interstitial thickening is characteristic of PLC,
but not pulmonary edema. In the study by Ren et al. (9), nodular septal
thickening was not noted in any pathologic specimens of patients who had
pulmonary edema, fibrosis, or normal lungs.
However, it is clear that the presence of nodular septal thickening is a
nonspecific finding that reflects a perilymphatic distribution of abnormalities,
commonly seen in patients who have sarcoidosis (8,9) and less often visible in
coal worker’s pneumoconiosis (CWP) or silicosis, lymphoid interstitial
pneumonia (LIP), and amyloidosis (21). In sarcoidosis and CWP, although septal
nodules are commonly seen, septal thickening is usually less extensive than that
seen in patients who have lymphangitic spread of tumor; only an occasional
patient who has sarcoidosis shows extensive nodular septal thickening.
Moreover, in sarcoidosis and CWP, distortion of lung architecture and secondary
pulmonary lobular anatomy may be visible, particularly if septal thickening is
present; this distortion is not seen in patients who have PLC (22). However, the
presence of pleural effusion would be more in keeping with PLC than
sarcoidosis or silicosis.
In pulmonary fibrosis, nodular septal thickening is uncommon, and the
margins of the thickened interlobular septa are irregular. Distortion of the lung
architecture and lung destruction (honeycombing) are common in patients who
have fibrosis (14,23).
HEMATOGENOUS METASTASES
Most patients with hematogenous pulmonary metastases have discrete tumor
nodules, rather than the diffuse interstitial invasion present with PLC.
Hematogenous metastasis typically results in multiple, sharply marginated lung
nodules; in patients who have a history of carcinoma, this appearance on plain
radiographs is usually sufficient for diagnosis. In some patients, however,
widespread hematogenous metastases occur in the absence of a known primary
tumor, resulting in the radiographic or CT appearance of numerous small
nodules. In such patients, HRCT may be obtained to define the abnormality and
may be valuable in suggesting the correct diagnosis. Also, in patients with a
known primary tumor, HRCT may be obtained to distinguish metastases from
nonneoplastic abnormalities such as infection.
High-Resolution Computed Tomography Findings
In patients who have hematogenous metastases, HRCT typically shows small
discrete nodules with a basal predominance. When limited in number, nodules
may be seen primarily in the lung periphery (3); in patients who have
innumerable metastases, a uniform or random distribution throughout the lung is
common (Figs. 11-6 to 11-9, Table 11-2) (10,24,25).
FIGURE 11-6 A and B: Hematogenous metastases. The nodules are sharply defined.
Although some nodules (arrows) appear to be related to small vascular branches, most nodules
lack a specific relationship to lobular structures and appear to be random in distribution.
Subpleural nodules are visible. Septal thickening is absent.
FIGURE 11-7 A–D: Targeted views of the right lung in a patient who has hematogenous
metastases. The nodules are small and sharply defined. There is involvement of the pleural
surfaces, but overall the nodules appear to involve the lung diffusely. This pattern of distribution is
termed random. Septal thickening is absent.
FIGURE 11-8 A–C: Hematogenous metastases from a left upper lobe adenocarcinoma. The
nodules are very small and sharply defined. Subpleural nodules are visible at the costal pleural
surface (black arrows) and adjacent to the major fissure (white arrows). Lung involvement is
diffuse.
FIGURE 11-9 Maximum intensity projection image (10 mm thick) in a patient with
hematogenous metastases from testicular carcinoma. The random distribution of the lung nodules
is clearly seen. The relationship of some nodules to peripheral pulmonary arteries is best seen
using this technique.
TABLE 11-2 HRCT Findings in Hematogenous Metastases
Smooth, well-defined nodules with a random and uniform distributiona,b
Some nodules visible in relation to vessels or pleural surfacesa,b
Features of lymphangitic spread of carcinoma may be presenta,b
a Most common findings.
b Findings most helpful in differential diagnosis.
Typically, hematogenous metastases lack the specific relationship to lobular
structures and interlobular septa that are seen in patients who have PLC. Nodules
tend to appear evenly distributed with respect to lobular anatomy, or random in
distribution, although it is frequent to see nodules in relation to the pleural
surfaces or fissures (24–26). For example, in an HRCT study of 40 patients with
diffuse micronodules (<5 mm in diameter), all 5 with metastases had welldefined nodules with a random distribution, and in each case, a “studded fissure”
and “subpleural dots were visible” due to metastases in these regions (25). It is
not uncommon for some nodules to be seen in relation to small branches of
pulmonary arteries, a finding termed the feeding vessel sign, which is considered
to suggest a hematogenous abnormality (12). Although interlobular septal
thickening and peribronchovascular interstitial thickening, common findings in
PLC, are typically lacking in patients who have hematogenous metastases (Figs.
11-6 to 11-9), some overlap between the appearances of PLC and hematogenous
metastases is not uncommon. This overlap in patterns is uncommon in other
diseases and may be used to suggest the correct diagnosis.
To elucidate the HRCT characteristics of pulmonary metastatic nodules,
Murata et al. (26) compared HRCT and pathology in five lungs obtained at
autopsy from patients who had metastatic neoplasms. The relationship of
metastatic nodules to lobular structures was studied using HRCT, specimen
radiographs, and stereomicroscopy. Nodules were widely distributed throughout
pulmonary lobules as seen on HRCT, and no predominance in specific lobular
regions was noted. Eleven percent of small nodules (<3 mm in diameter)
appeared centrilobular, 68% were intralobular, and 21% were seen in relation to
interlobular septa. Similar results were reported by Hirakata et al. (24,27).
Occasionally, intravascular tumor emboli may result in nodular or beaded
thickening of the peripheral pulmonary arteries (see Chapter 21) (28). This
appearance may mimic tree-in-bud (29,30).
Detection of pulmonary nodules and assessment of their relationship to
vascular structures is improved with the use of sliding thin-slab maximum
intensity projection (MIP) technique (Fig. 11-9) (31,32). Using 1-to 3-mm
sections and spiral CT, Napel et al. (31) devised a method for rapidly computing
a series of either overlapping MIP or minimum intensity projection (MinIP)
images through a thin slab of lung, retaining a normal superoinferior or axial
orientation. This results in images of high-contrast resolution allowing enhanced
visualization of peripheral blood vessels, in particular, using MIP
reconstructions. This approach has proved of some value for detecting
micronodules in patients who have diffuse infiltrative lung disease (32).
Utility of High-Resolution Computed Tomography
CT is clearly more sensitive than plain radiographs in detecting lung metastases
(3). In one study (33), plain radiographs, CT, and surgery were compared as to
the number of nodules detected in 100 lungs from 84 patients who had
previously treated extrathoracic malignancies and showed new lung nodules. Of
237 nodules resected, 173 (73%) were identified with CT. Chest radiography
disclosed all resected nodules in 44% of cases, whereas CT disclosed all nodules
in 78%. Of the resected nodules, 207 (87%) were of metastatic origin, 21 (9%)
were benign, and 9 (4%) were bronchogenic carcinomas. Of those nodules seen
with CT and not with radiography of the chest, 84% were of metastatic origin.
Although axial HRCT may be used to characterize the distribution and
morphology of lung nodules in patients who have hematogenous pulmonary
metastases, volumetric spiral MDCT or volumetric HRCT is clearly of more
value and is more appropriate in the routine evaluation of patients suspected of
having this abnormality (3). MDCT can be performed using narrow detectors
(0.625–1.25 mm) and viewed using thin slices (1.25 mm) or thicker sections (5
mm). However, it is important to keep in mind that with 5-mm slices, small
nodules may be missed. For example, in a study of five autopsy lungs, 1,013
histopathologically proven metastatic nodules (0.5–30 mm in diameter) were
detected using MDCT with 1-mm collimation. The lungs were then assessed
using 5-mm slice thickness and four combinations of pitch and table speed. The
mean numbers of detected nodules using 5-mm slices ranged from 654 (65% of
the total) to 678 (67%) (34). Diederich et al. (35) assessed the sensitivity of
spiral CT in 13 patients who underwent surgical exploration with resection of 90
nodules. Spiral CT was performed using 5-mm collimation and reconstruction
intervals of 3 and 5 mm, and interpreted by two independent observers. For
lesions detected by at least one observer, the sensitivity of helical CT was 69%
for intrapulmonary nodules smaller than 6 mm in diameter, and 95% for
intrapulmonary nodules larger than or equal to 6 mm in diameter. For lesions
smaller than or equal to 10 mm in diameter, sensitivity was better using a
reconstruction interval of 3 mm rather than 5 mm (35).
INVASIVE MUCINOUS ADENOCARCINOMA
Adenocarcinoma is the most common cell type of lung carcinoma. In 2011, in
order to address advances in oncology, molecular biology, pathology, radiology,
and surgery, a new classification of pulmonary adenocarcinoma was published
by an international, multidisciplinary committee sponsored by the International
Association for the Study of Lung Cancer, the American Thoracic Society, and
the European Respiratory Society (36–39). It was determined that a new
classification was needed to provide uniform terminology and diagnostic criteria,
especially for what had been termed bronchioloalveolar carcinoma (BAC) in the
2004 World Health Organization (WHO) classification of lung cancer (40), a
tumor characterized by pure lepidic growth (tumor growth along alveolar walls)
without invasion of stroma, blood vessels, or the pleura (Fig. 11-10). An
international panel of experts was formed with oncologists/pulmonologists,
pathologists, radiologists, molecular biologists, and thoracic surgeons, and a
systematic review was performed under the guidance of the American Thoracic
Society (36–39).
FIGURE 11-10 Adenocarcinoma with lepidic growth. Tumor grows along alveolar walls
(arrows), using the alveoli as a scaffold. Alveolar spaces are preserved, and there is no invasion
present. In the current classification, this would be classified as adenocarcinoma in situ. (Courtesy
of Martha Warnock, MD.)
This new classification affects the radiologic interpretation of HRCT in the
diagnosis of pulmonary adenocarcinoma (41,42) as reflected in the 2013
Fleischner Society recommendation for the CT assessment of subsolid (at least
partially ground-glass opacity) nodules (43). Nonmucinous adenocarcinoma
often presents as a ground-glass opacity or part-solid nodule, although multiple
nodules may be seen (Fig. 11-11). Mucinous adenocarcinoma, which usually
shows some degree of invasion, may present as a solid nodule or larger focus of
consolidation or ground-glass opacity, or with multilobar lung involvement
consisting of a combination of consolidation, ground-glass opacity, and multiple
nodules which may be centrilobular.
FIGURE 11-11 Mulitple pulmonary adenocarcinomas in a patient with prior adenocarcinoma
resection in the right upper lobe. A and B: Multiple nodules of ground-glass opacity (arrows) are
consistent with multiple adenocarcinomas in situ. Such lesions, based on Fleischner Society
recommendations, may be followed. Other more subtle lesions are likely present.
As part of the Fleischner Society recommendatons, it is recognized that
pulmonary adenocarcinomas are multiple in up to 22% of cases and may appear
on HRCT as scattered focal or nodular areas of ground-glass opacity nodules,
part-solid nodules, or solid nodules (Fig. 11-11) (38,43). Diffuse lung
involvement by mucinous adenocarcinoma, formerly termed diffuse or
multicentric BAC, has been reclassified as “invasive mucinous adenocarcinoma
(IMA),” although it is unclear at present if all such tumors are of the mucinous
type (38,41,42).
While a lepidic pattern is common in patients with IMA, these tumors are
often predominantly invasive. When they are multifocal, multilobar involvement
is common. The HRCT findings of this entity vary widely and include regions of
consolidation or ground-glass opacity, and multifocal solid and subsolid (i.e.,
either part-solid or ground-glass opacity) nodules or masses, which tend to be
centrilobular or bronchocentric. Lower lobe predominance is common. These
appearances can mimic other lung diseases characterized by patchy ground-glass
opacity or consolidation, and need to be considered in the differential diagnosis
of these abnormalities. Diffuse lung involvement in these patients may represent
multifocal origin, endobronchial spread of tumor from a primary focus,
hematogenous metastases, or a combination of these.
The appearances and current classification of solitary nodules appearing as
ground-glass opacity or part-solid nodules, and recommendations for their CT
evaluation and follow-up, are beyond the scope of this chapter, and the reader is
referred to the excellent and comprehensive references cited earlier (38,41–43).
In this chapter, the appearances of what has been termed “diffuse BAC”, now
classified as IMA, will be reviewed. It should be emphasized that the studies
reviewed in this chapter reported the HRCT findings in patients with “diffuse
BAC.” It may be presumed that the majority of cases reported in these studies
represented IMA.
High-Resolution Computed Tomography Findings
Patients who have diffuse lung involvement from IMA can show (a) patchy areas
of consolidation, often associated with air bronchograms or air-filled cystic
spaces (Figs. 11-12 and 11-13) (44); (b) patchy or multifocal ground-glass
opacity with or without interlobular septal thickening (i.e., crazy paving) (Figs.
11-13 to 11-15) (45,46); (c) extensive centrilobular airspace nodules (Figs. 1112, 11-15, and 11-16); or (d) diffuse small nodules mimicking the appearance of
hematogenous metastases (Figs. 11-17 and 11-18, Table 11-3) (47–51). In a
study by Akira et al. (48) of 38 patients who had diffuse lung involvement, the
predominant finding on HRCT was consolidation in 22 (58%), multiple nodules
in 12 (32%), and ground-glass opacity in 4 (10%), although most patients
showed a combination of these findings. Overall, HRCT findings in the series by
Akira et al. (48) included consolidation (76%), ground-glass opacity (76%),
nodules (74%), centrilobular nodules (68%), air bronchograms (47%), pleural
effusion (13%), and lymph node enlargement (8%). A peripheral distribution was
seen in 50%, and lower lobe predominance in 48%. A peripheral distribution has
also been noted by others (51).
FIGURE 11-12 Invasive mucinous adenocarcinoma with consolidation and centrilobular
nodules. A: CT with 5-mm slice thickness shows patchy consolidation in the right lung. Air
bronchograms are visible. Numerous centrilobular nodules are also present. B: Histologic
specimen in a different patient with IMA. Findings of lepidic growth are visible (arrows). Mucin and
fluid produced by the tumor fill the alveoli. This occurrence with mucinous adenocarcinoma may
result in consolidation or ground-glass opacity as seen on HRCT.
FIGURE 11-13 Invasive mucinous adenocarcinoma with consolidation, ground-glass opacity,
and centrilobular nodules. A–C: Bilateral patchy and nodular areas of consolidation and groundglass opacity are associated with air bronchograms (B). D: Six months later there has been
marked progression.
FIGURE 11-14 Invasive mucinous adenocarcinoma with extensive ground-glass opacity. A
and B: HRCT shows extensive ground-glass opacity involving both lungs. Cystic lucencies likely
represent underlying emphysema, although a similar cystic appearance may be related to the
tumor itself.
FIGURE 11-15 Invasive mucinous adenocarcinoma with patchy consolidation, ground-glass
opacity, and centrilobular nodules. A–C: Lobular and larger areas of ground-glass opacity and
consolidation are visible. A cluster of centrilobular nodules of ground-glass opacity (arrows) in the
left lower lobe are likely due to endobronchial spread of tumor. D: Lung specimen in a patient with
diffuse IMA shows poorly marginated centrilobular nodules (arrows) in the lung periphery.
(Courtesy of Martha Warnock, MD.)
FIGURE 11-16 Invasive mucinous adenocarcinoma. Targeted HRCT image through the right
lung. Ill-defined nodules are visible throughout the lung, and most appear centrilobular in location.
FIGURE 11-17 Invasive mucinous adenocarcinoma in a 34-year-old man. A: HRCT
demonstrates areas of consolidation in the right lower lobe; ill-defined nodules, some of which
appear to be centrilobular; and multiple, small, well-defined nodules. B: Targeted view of the left
lung shows numerous small nodules, particularly in the left lower lobe. At least some of these
nodules show a random distribution, similar to hematogenous metastases. Note the presence of
subpleural nodules.
FIGURE 11-18 Invasive mucinous adenocarcinoma with multiple nodules. A and B: Multiple
small nodules are visible bilaterally. Although some of these may be centrilobular in location, this
appearance mimics the appearance of hematogenous metastases.
TABLE 11-3 HRCT Findings in Diffuse Invasive Mucinous
Adenocarcinoma
Ill-defined centrilobular nodulesa,b
Combination of first two findingsa,b
Peripheral distribution of abnormalitiesa,b
Stretched air bronchogramsa,b
Crazy paving
Air-filled cystic spaces
CT angiogram sign on enhanced scana
Features of hematogenous metastasesa
a Most common findings.
b Findings most helpful in differential diagnosis.
In patients who had multiple nodules as the predominant finding, nodule size
has ranged from 1 mm to 3 cm in diameter. The nodule margin was most often
ill-defined, or associated with a halo sign, but well-defined nodules were also
seen. The predominant nodule distribution most often appeared centrilobular, a
finding likely reflecting endobronchial spread of tumor. Bronchocentric nodules
were also common and may be due to lymphatic spread (48). Nodules with a
random distribution were less often visible; these may reflect hematogenous
spread of the tumor. Cavitation of nodules was sometimes present.
Areas of consolidation or ground-glass opacity associated with IMA can
represent the presence of intra-alveolar tumor growth or mucin and fluid
produced by the tumor; air bronchograms are commonly visible, as are cystic
lucencies or pseudocavitation (47,51,52). Bulging fissures may be seen in
patients with consolidation (50,51). Centrilobular nodules are commonly
associated with consolidation, seen in 73% of patients in one study (48). Also,
because fluid and mucus produced by the tumor are of low attenuation, if CT is
performed with contrast infusion, the CT angiogram sign can be seen (50,51).
The CT angiogram sign is said to be present if contrast-enhanced pulmonary
vessels appear denser than the surrounding opacified lung. In a study by Im et al.
(53), the CT scans of 12 patients who had lobular or segmental IMA were
reviewed; the CT angiogram sign was seen in nearly all patients. However, this
sign is dependent on the volume and concentration of contrast injected and has
been observed in bacterial pneumonia, lipoid pneumonia, pulmonary lymphoma,
pulmonary infarction, and pulmonary edema (54). The CT angiogram sign is
therefore of limited value in differential diagnosis.
Utility of High-Resolution Computed Tomography
In some patients who have consolidative or nodular lung disease, HRCT findings
may allow IMA and other diseases to be distinguished. In a study by Aquino et
al. (55), the CT findings of consolidative IMA were compared to those of
pneumonia to determine if a distinction could be made between these diseases.
Findings seen more often on CT scans of patients who had mucinous
adenocarcinoma included coexisting nodules (p = 0.001) and a peripheral
distribution of consolidation (p = 0.001) (55). However, differing results have
been found by others. In a study of 21 patients with pneumonic-type IMA and
pneumonia, a variety of CT findings were used in an attempt to distinguish
between these two entities (Table 11-4) (56). Findings significantly more
common in IMA included stretched or narrowed air bronchograms, air
bronchograms with widening of the branch angle at bifurcations, air
bronchograms having a sweeping appearance, and bulging of a fissure.
TABLE 11-4 Differentiation of Invasive Mucinous Adenocarcinoma
and Pneumonia Using CT
Akira et al. (48) also compared the findings of diffuse IMA with those seen in
patients who had other diffuse lung diseases. In patients who had a nodular form
of IMA, a centrilobular distribution was significantly more common than in
patients who had miliary tuberculosis (TB) or pulmonary metastases. In patients
who had consolidative IMA, lower lung predominance was more common than
in patients who had eosinophilic pneumonia and bronchogenic spread of TB.
Also, narrowing of involved bronchi, cavitation, heterogeneous consolidation,
bulging of a fissure, and associated nodules were significantly more common in
patients who had IMA than in those who had eosinophilic pneumonia.
CT can play a crucial role in the initial evaluation of patients with
adenocarcinoma who appear to have limited and potentially resectable lesions,
based on their plain radiographic appearance. CT can show the presence of
diffuse disease when unrecognizable on plain films, indicating unresectability
(57). However, as pointed out by Zwirewich et al. (58), CT is only 65% sensitive
in detecting multiple adenocarcinomas.
KAPOSI SARCOMA
Prior to the use of highly active antiretroviral therapy (HAART), approximately
10% to 25% of patients with AIDS developed Kaposi sarcoma (KS) (59). Since
the institution of this form of treatment, the incidence of KS in HIV-infected
individuals has decreased from about 30 per 1,000 patient-years to 0.03 per
1,000 patient-years (60). However, KS remains the most common cancer
identified in patients with HIV/AIDS (61).
KS is much more common among subjects who acquire AIDS through sexual
contact. Almost all cases occur in homosexual or bisexual men infected with
herpesvirus-8, and KS in intravenous drug users or patients exposed to HIV by
different means is less frequent (59,62).
Pulmonary involvement has been reported in 20% to 50% of AIDS patients
who have KS (63) and is usually, but not always, preceded by recognized
cutaneous or visceral involvement. Endobronchial lesions detected at
bronchoscopy tend to predict the presence of pulmonary disease (64). Chest
radiographs typically show bilateral and diffuse abnormalities, characterized by
the presence of interstitial opacities that are predominantly peribronchovascular,
poorly defined nodules that can be several centimeters in diameter, and illdefined areas of consolidation (Fig. 11-19) (59,62,64). Pleural effusions that are
usually bilateral are seen in 30% of cases. Hilar or mediastinal lymph node
enlargement is apparent on the chest radiograph in approximately 10% of
patients.
FIGURE 11-19 Kaposi sarcoma. A: Chest radiograph in a patient who has AIDS and KS
shows an increase in interstitial opacities, particularly in the right lung base. B: HRCT in this
patient shows irregular peribronchovascular infiltration typical of this disease. Posteriorly, the
opacities appear flame shaped. The more abnormal right lung can be contrasted with the more
normal appearance on the left. C and D: CT in a different patient who has AIDS and KS shows
typical findings of ill-defined and irregular or flame-shaped nodules occurring predominantly in the
perihilar and peribronchovascular regions. Several nodules surround bronchi or contain air
bronchograms. There is also evidence of peribronchovascular interstitial thickening. E: Lung
biopsy in a patient with KS shows tumor (arrow) in a peribronchovascular location (E). (Courtesy
of Martha Warnock, MD.)
High-Resolution Computed Tomography Findings
Pathologically, pulmonary involvement in KS is patchy but has a distinct
relationship to vessels and bronchi in the perihilar regions (59,63,65). Early CT
findings include thickening of the peribronchovascular interstitium, particularly
at the lung bases, mimicking the appearance of infectious AIDS-related airways
disease (63). Typical CT features of KS in more advanced cases include irregular
and ill-defined (flame-shaped) nodules that often predominate in the
peribronchovascular regions, peribronchovascular interstitial thickening,
interlobular septal thickening, pleural effusion, and lymphadenopathy (Figs. 1119 to 11-21, Table 11-5) (59,66). The presence of these nodules is helpful in
distinguishing the appearance of KS from that of AIDS-related airways disease
(63).
FIGURE 11-20 A and B: Kaposi sarcoma. HRCT in an AIDS patient with KS shows illdefined nodules (arrows) in the perihilar and peribronchovascular regions. This appearance and
distribution is typical of KS.
FIGURE 11-21 Extensive Kaposi sarcoma in a patient with AIDS. Irregular masses
predominate in the peribronchovascular regions. Interlobular septal thickening is also visible.
TABLE 11-5 HRCT Findings in Kaposi Sarcoma
Irregular and ill-defined peribronchovascular nodulesa,b
Peribronchovascular interstitial thickeninga,b
Interlobular septal thickeninga
Pleural effusionsa
Lymphadenopathy
a Most common findings.
b Findings most helpful in differential diagnosis.
In a study (62) of radiographs and CT in 24 patients who had intrathoracic KS,
22 of 24 patients (92%) had radiographic findings of bilateral perihilar opacities.
CT scans obtained in 16 patients confirmed the presence of perihilar opacities in
14 patients (88%), with extension into the lung parenchyma along the
peribronchovascular interstitium (Figs. 11-19 to 11-21). In a separate CT study
of 13 patients who had KS (67), all had multiple flame-shaped or nodular lesions
with ill-defined margins, which were usually symmetric (11 of 13 patients) and
peribronchovascular and perihilar in distribution (9 of 13 patients). Ten also had
pleural effusion, which was bilateral in nine. Five had mediastinal adenopathy,
and two had hilar adenopathy. In a study by Hartman et al. (66) of 26 patients
who had KS, the most common CT findings included nodules (85%), a
peribronchovascular distribution of disease (81%), lymphadenopathy (50%),
interlobular septal thickening (38%), consolidation (35%) or ground-glass
opacity (23%), and pleural effusion (35%). The “crazy paving” pattern has also
been identified, proven at pathology to be related to tumor infiltration of the
peribronchovascular interstitium, interlobular septa, and alveolar walls,
accompanied by pulmonary edema and hemorrhage (68).
Utility of High-Resolution Computed Tomography
In most patients, the presence of typical nodules on CT and a perihilar
distribution of abnormalities allow KS to be distinguished from other thoracic
complications of AIDS (63). In the study by Hartman et al. (66), which included
102 patients who had thoracic complications of AIDS, the accuracy of CT in
diagnosing KS was assessed in a blinded fashion. In patients who had KS, this
diagnosis was listed first in 83% of cases and was listed among the top three
choices in 92% (66). Kang et al. (69) assessed the diagnostic accuracy of CT in
139 patients who had AIDS. The CT scans were interpreted by two independent
observers. When the observers were confident in the diagnosis of KS, they were
correct in 91% of cases (31 of 34 interpretations).
However, a number of other diseases in patients with AIDS can be associated
with the presence of pulmonary nodules and may therefore mimic the findings
seen in KS. These include lymphoma, bronchogenic carcinoma, Pneumocystis
carinii pneumonia, TB, nontuberculous mycobacterial infection, and bacterial,
fungal, or viral infections (66,70). Despite this, a correct distinction of KS from
infection may often be made. In a study by Edinburgh et al. (71), CT scans in 60
HIV-infected patients who had multiple pulmonary nodules were evaluated for
nodule size, distribution, and morphology. Thirty-six of 43 patients (84%) with
opportunistic infection had a predominance of nodules smaller than 1 cm,
whereas 14 of 17 patients (82%) with neoplasm had a predominance of nodules
larger than 1 cm (p < 0.00001). Twenty-eight of 43 patients (65%) with
opportunistic infection had a centrilobular distribution of nodules, whereas only
1 of 17 patients (6%) with neoplasm had this distribution (p < 0.00001). Seven
of 8 patients (88%) with a peribronchovascular distribution of nodules had KS (p
< 0.00001). This finding, in association with nodule size greater than 1 cm,
strongly predicted KS.
LYMPHOPROLIFERATIVE DISORDERS, LYMPHOMA, AND
LEUKEMIA
Pulmonary lymphoproliferative disorders (LPDs) are characterized by an
abnormal proliferation of indigenous lymphoid cell lines or infiltration of lung
parenchyma by lymphoid cells. They comprise a complex group of diseases,
resulting in a spectrum of focal and diffuse lung abnormalities, which may be
classified as reactive or neoplastic on the basis of cellular morphology and
clonality, and which may be associated with either a benign or a malignant
course (72–77). Many of these diseases are related to abnormal proliferation of
submucosal lymphoid follicles distributed along distal bronchi and bronchioles,
termed mucosa-associated lymphoid tissue (MALT) or, more specifically,
bronchus-associated lymphoid tissue (BALT) (73,74). BALT consists primarily
of B lymphocytes, although T lymphocytes are also present.
Proliferations of BALT may be either hyperplastic or neoplastic, but a
distinction between them may be difficult without analysis of cell populations
using immunohistochemical techniques. Polyclonal cellular proliferations
demonstrated in this manner are usually hyperplastic and benign, whereas most
monoclonal cellular proliferations are malignant (72). However, in some cases,
hyperplasia and neoplasia may both be present, and some conditions formerly
thought of as benign have been shown to be associated with malignant elements
or have malignant potential. Many examples of diffuse lymphoid hyperplasia or
lymphoma occur in immunosuppressed patients or patients who have AIDS and
appear to be associated with the Epstein-Barr virus (EBV) (78). An association
of lymphoproliferative diseases with collagen-vascular disease is also common.
In patients who have benign lymphoid hyperplasia, the extent of lesions can
vary, presenting as (a) a focal lesion or nodule (focal or nodular lymphoid
hyperplasia), (b) a multifocal proliferation largely limited to the airway walls
(follicular bronchiolitis or follicular hyperplasia), or (c) multifocal or diffuse
lymphoid hyperplasia with interstitial involvement (lymphoid interstitial
pneumonitis) (73,74).
Malignant pulmonary lymphoproliferative diseases and those having at least
some malignant potential include (a) angioimmunoblastic lymphadenopathy
(AILD), (b) primary pulmonary lymphoma, including extranodal marginal zone
lymphomas of MALT origin (MALT lymphomas), diffuse large B-cell
lymphomas, and high-grade lymphomas, (c) secondary pulmonary lymphoma,
(d) AIDS-related lymphoma (ARL), (e) posttransplantation lymphoproliferative
disorder (PTLD), (f) lymphomatoid granulomatosis, and (g) leukemia (77).
Focal Lymphoid Hyperplasia
Focal lymphoid hyperplasia is an uncommon benign condition, characterized
histologically by localized, polymorphous proliferation of benign mononuclear
cells consisting of a mixture of polyclonal lymphocytes, plasma cells, and
histiocytes (74). The term focal lymphoid hyperplasia is used by some authors as
synonymous with pseudolymphoma (72,74). It is likely, however, that many
lesions previously called pseudolymphomas would currently be classified as
MALTomas (73,79); therefore, the term pseudolymphoma is not currently
recommended.
The most frequent radiologic manifestation of focal lymphoid hyperplasia
consists of a solitary nodule or a focal area of consolidation (72,80). The nodules
or nodular areas of consolidation usually measure 2 to 5 cm in diameter and
contain air bronchograms (80). Multiple nodules or regions of consolidation may
be seen (Fig. 11-22) (81). There is no associated lymphadenopathy.
FIGURE 11-22 Focal lymphoid hyperplasia, biopsy proven. CT in a patient with Sjögren
syndrome shows multiple nodular opacities containing air bronchograms.
Follicular Bronchiolitis
Follicular bronchiolitis, defined as hyperplasia of BALT, is characterized
histologically by the presence of diffuse proliferation of lymphoid follicles with
reactive germinal centers in the interstitial tissue adjacent to bronchioles and
bronchi (73,76,82). Follicular bronchiolitis is commonly present in patients who
have chronic bronchial inflammation (i.e., bronchiectasis), and is a common
incidental finding on lung biopsy; this is termed secondary follicular
bronchiolitis. Primary follicular bronchiolitis is much less common and is
usually seen in patients who have a history of an underlying immunodeficiency
(including AIDS), connective tissue disease (particularly Sjögren syndrome or
rheumatoid arthritis), hypersensitivity, or eosinophilia (73,76,82–84). Primary
follicular bronchiolitis is commonly associated with dyspnea. Prognosis is
related to age, with younger patients often having progressive disease (82).
Response to steroid treatment is variable (82).
In patients who have follicular bronchiolitis, chest radiographs
characteristically show a diffuse reticular or reticulonodular pattern (82). HRCT
typically demonstrates small nodular opacities in a centrilobular and
peribronchovascular distribution or lung cysts (Figs. 11-23 and 11-24)
(76,83,85,86). In the majority of cases, nodules measure 1 to 3 mm in diameter,
although occasionally they can measure as much as 1 cm in diameter (83). Lungs
cysts are the same as present in LIP.
FIGURE 11-23 Follicular bronchiolitis. HRCT in a patient who has rheumatoid arthritis shows
small nodules in a centrilobular (straight arrows) and peribronchovascular (curved arrow)
distribution. Also noted are subpleural nodules and nodules adjacent to the left interlobar fissure.
FIGURE 11-24 Biopsy-proven follicular bronchiolitis in a patient with juvenile rheumatoid
arthritis. Extensive cystic abnormalities are visible, similar to those in patients with LIP.
Howling et al. (83) reviewed the HRCT findings in 12 patients who had
biopsy-proven follicular bronchiolitis. The predominant abnormalities consisted
of small nodules and areas of ground-glass opacity. The nodules had a
centrilobular distribution in all 12 patients, corresponding to the location of
small bronchioles. In some patients, the centrilobular opacities had a branching
appearance, reflecting the morphology of the small airways involved. Additional
peribronchial nodules were present in 5 (42%) and subpleural nodules in 3
(25%) of the 12 patients. The nodules were diffuse but mainly involved the
lower lung zones. Nine (75%) patients had patchy bilateral areas of ground-glass
opacity. Additional findings seen in a small number of patients included mild
interlobular septal thickening, bronchial wall thickening, and peribronchial
consolidation (76,83). Diffuse air trapping on expiratory HRCT has also been
reported in association with follicular bronchiolitis (Fig. 11-25) (87).
FIGURE 11-25 Biopsy-proven follicular bronchiolitis in a patient with Sjögren syndrome. A
and B: Patchy areas of lucency representing mosaic perfusion are visible in the lower lobes.
These were associated with air trapping on expiratory views.
Lymphoid Interstitial Pneumonia
LIP is a benign lymphoproliferative disorder, characterized histologically by a
diffuse interstitial infiltrate of mononuclear cells consisting predominantly of
lymphocytes and plasma cells (73,76,88,89). It is distinguished from follicular
bronchiolitis in that the abnormality is not limited to the airways. LIP frequently
occurs in association with other conditions, most commonly Sjögren syndrome
(90–92) and other collagen-vascular diseases (93), congenital or acquired
immunodeficiency syndromes (e.g., AIDS) (94), primary biliary cirrhosis, or
multicentric Castleman disease (88,95,96). Except for AIDS, in which those
affected are most often children, the majority of patients who have LIP are
adults, with the mean age at presentation being approximately 50 years. The
main clinical symptoms are cough and dyspnea. LIP is illustrated in greater
detail in Chapter 9.
The radiographic findings of LIP consist of a reticular or reticulonodular
pattern involving mainly the lower lung zones (88,97,98). Less common
abnormalities include a nodular pattern, ground-glass opacities, and airspace
consolidation.
The HRCT findings of LIP depend at least in part on the underlying disease
present. HRCT abnormalities may consist of diffuse bilateral areas of groundglass opacity and poorly defined centrilobular nodules, subpleural nodules,
thickening of the bronchovascular bundles, lung cysts, and patchy ground-glass
opacity (Figs. 11-26 to 11-28, Table 11-6) (76,86,96,99,100). In some patients,
the appearance of LIP may closely mimic that of lymphangitic spread of
carcinoma. In Sjögren syndrome, LIP is typically associated with lung cysts that
are thin walled, round in shape, and limited in number (Fig. 11-26) (90,91). In
congenital immunodeficiency syndromes, LIP most often appears as patchy
ground-glass opacity (Fig. 11-27). In patients with AIDS, LIP most often appears
as centrilobular or perilymphatic nodules (Fig. 11-28) (94).
FIGURE 11-26 Lymphoid interstitial pneumonia in a patient with Sjögren syndrome. A and B:
Multiple thin-walled cysts are visible bilaterally. This appearance is most typical of LIP in Sjögren
syndrome.
FIGURE 11-27 Lymphoid interstitial pneumonia in a patient with common variable
immunodeficiency. Patchy areas of ground-glass opacity are visible bilaterally.
FIGURE 11-28 Lymphoid interstitial pneumonia in a patient with AIDS. Small sharply
marginated nodules are visible in relation to the right major fissure. Some septal nodules and
centrilobular nodules are also visible.
TABLE 11-6 HRCT Findings in Lymphoid Interstitial Pneumonia
Ground-glass opacitya
Poorly defined centrilobular nodulesa
Subpleural nodulesa
Interlobular septal thickening or nodulesa
Thickening of peribronchovascular interstitiuma
Cystic airspacesa,b
Lymph node enlargementa
a Most common findings.
b Findings most helpful in differential diagnosis.
Johkoh et al. (96) reviewed the HRCT findings in 22 patients who had LIP.
All patients had areas of ground-glass opacity and poorly defined centrilobular
nodules. Small subpleural nodules were seen in 19 (86%) patients, thickening of
the peribronchovascular interstitium in 19 (86%), mild interlobular septal
thickening in 18 (82%), and cystic airspaces in 15 (68%) (90). Lung cysts were
usually thin walled, were less than 30 mm in diameter, and involved less than
10% of the lung parenchyma (Fig. 11-26). Less common manifestations included
small nodules, airspace consolidation, bronchiectasis, and, occasionally,
honeycombing (96,101). Lymph node enlargement may be seen on CT (96).
Centrilobular nodules visible on HRCT correlate with the presence of
peribronchiolar infiltration with lymphocytes and plasma cells, whereas the
ground-glass opacities reflect a diffuse interstitial infiltration. Cystic airspaces
occurring in LIP are likely due to airway obstruction by the peribronchiolar
cellular infiltrates, resulting in air trapping (99). Supporting this contention is a
report of severe air trapping in a patient with follicular hyperplasia of BALT
(87).
In a study by Honda et al. (102), HRCT findings of LIP were compared to
those in patients who had malignant lymphoma. Several significant differences
in the appearances of these diseases were found. Cysts were more common in
patients who had LIP (82%) than in patients who had malignant lymphoma
(2%), whereas airspace consolidation and large nodules (11–30 mm in diameter)
were more common in patients who had malignant lymphoma (66% and 41%,
respectively) than in patients who had LIP (18% and 6%) (p < 0.001). Pleural
effusions (25%) were seen only in patients who had malignant lymphoma.
Nonetheless, MALT lymphoma may coexist with and be associated with typical
HRCT findings of LIP (77,103).
Angioimmunoblastic Lymphadenopathy
AILD is an uncommon systemic disease that commonly results in intrathoracic
lymph node enlargement (72,73,75). In some cases, the lung and pleura are also
involved. Histologically, abnormal lymph nodes show a proliferation of vessels
and infiltration by a heterogeneous population of lymphocytes, plasma cells, and
immunoblasts. T-cell proliferation is most common, and the EBV genome has
been detected in most cases. An association with drug treatment suggests that a
hypersensitivity reaction may also be involved in the development of AILD.
Progression to malignant lymphoma may occur, a condition termed AILD-like Tcell lymphoma.
AILD patients are usually older than 50 years. Constitutional symptoms are
typical with fever and weight loss; other findings include hepatomegaly,
splenomegaly, rash, generalized lymph node enlargement, polyclonal
hypergammopathy, and Coombs-positive anemia (75). The clinical course is
variable, with three distinct patterns being identified: 50% of patients have rapid
progression to death, 25% have prolonged survival with steroid and
antineoplastic treatment, and 25% have prolonged survival without treatment.
The radiographic appearance of AILD is similar to that of lymphoma
(72,73,104). Approximately 55% of cases show extensive mediastinal and hilar
lymph node enlargement. One-third of cases show lung involvement. Interstitial
infiltration in the lower lobes associated with septal thickening or patchy
consolidation is typical (Fig.11-29) (104,105). Pleural effusion may be present
(72). Enlarged lymph nodes may be enhanced if contrast infusion is used (106).
FIGURE 11-29 Angioimmunoblastic lymphadenopathy-like lymphoma. HRCT shows
extensive interlobular septal thickening. The appearance mimics that of lymphangitic spread of
carcinoma.
Primary Pulmonary Lymphoma
Lymphoma involving the lung can be considered primary pulmonary lymphoma
if there is no history of lymphoma, mediastinal lymph node enlargement is
invisible on chest radiographs, it is unassociated with extrathoracic disease, and
there is no evidence of extrathoracic dissemination for at least 3 months after the
initial diagnosis (75,107). Primary pulmonary lymphoma is an uncommon
neoplasm; in one study of 1,269 cases of lymphoma, less than 1% was deemed
to have a pulmonary origin (108).
Indolent B-cell lymphomas are most common as a cause of primary
pulmonary lymphoma, accounting for more than 80% of cases, and most are
low-grade MALT, termed extranodal marginal zone B-cell lymphoma of MALT
according to the Revised European-American Lymphoma (REAL) and WHO
classifications of lymphoid diseases (74,109–113). Diffuse large B-cell
lymphoma is another common cause of primary pulmonary lymphoma, with
some tumors occurring in relation to MALT (112,114). Non-MALT lymphomas
are generally considered to be intermediate or high grade. Primary T-cell
lymphomas are occasionally seen but are less common than B-cell tumors; these
include anaplastic large cell lymphoma, peripheral T-cell lymphoma, and other
cell types (112,114). Primary pulmonary Hodgkin lymphoma (HL) is rare.
Low-Grade MALT Lymphoma (Extranodal Marginal Zone B-Cell
Lymphoma of MALT)
The most frequent cause of primary pulmonary lymphoma is extranodal
marginal zone B-cell lymphoma of MALT, also known as MALT lymphoma or
MALToma (74,109–111,113). In two recent reviews, low-grade MALT
lymphomas accounted for 54% to 58% of primary pulmonary lymphomas
(112,114). In the lung, these tumors are believed to arise from cells present in
BALT and have also been termed BALT lymphoma or BALToma (111). This
tumor tends to remain localized to the lung for long periods of time, follows an
indolent course, and is associated with a good prognosis (111). For example, in
one study of 43 cases, the overall 5-year survival rate was 84% (115). They are
believed to arise because of chronic antigenic stimulation, associated with
smoking, local chronic inflammatory disease, or autoimmune diseases
(110,111,116). At least some of these tumors were previously classified as
pseudolymphomas, but they are now regarded as true neoplasms (73,79,80).
MALT lymphoma may be asymptomatic when localized. More diffuse lung
involvement may be associated with cough, dyspnea, and chest pain (116).
Systemic symptoms of fever, night sweats, and weight loss are relatively
uncommon with low-grade MALT lymphoma (110,112).
The most common radiologic manifestation of primary low-grade B-cell
lymphoma consists of a solitary nodule or a focal area of consolidation
measuring from 2 to 8 cm in diameter (Fig. 11-30) (117–120). Air bronchograms
are visible in approximately 50% of cases (107). Other patterns of lung
involvement include a localized area of consolidation, which may range from a
small subsegmental area to an entire lobe, or, less commonly, multiple nodules
or multifocal areas of consolidation (121,122). The parenchymal abnormalities
typically show an indolent course, with slow growth over months or years
(107,123).
FIGURE 11-30 MALToma in a 69-year-old woman. HRCT shows focal area of consolidation
in the right middle lobe. Follow-up 6 months later showed no interval change. The diagnosis was
proven at surgical resection.
On CT and HRCT, multiple or solitary nodules or masses or areas of
consolidation are most typical (76,111,116,124,125) (Table 11-7). They may be
seen as primarily peribronchial in location, and air bronchograms are frequently
visible. Bronchi within the affected lung parenchyma may appear dilated or
stretched and slightly narrowed (116,118,122,126). Pulmonary nodules or
masses may be associated with the halo sign (108). Enhanced vessels visible
within the nodules or masses (i.e., the CT angiogram sign) may be seen (116).
TABLE 11-7 HRCT Findings in Low-Grade B-cell Lymphoma
(MALToma or BALToma)
Multiple or solitary nodulesa,b
Halo sign
Multiple or localized areas of consolidationa
Air bronchogramsa
Peribronchial distributiona,b
Interlobular septal thickening
Slow growtha,b
Pleural effusion
a Most common findings.
b Findings most helpful in differential diagnosis.
A perilymphatic distribution of abnormalities is typical, with tumor involving
the peribronchovascular interstitium and interlobular septa (76,116). Rarely,
airway involvement is manifested by bronchial wall thickening and marked
narrowing of the bronchial lumen (127). Other findings seen on HRCT include
centrilobular nodules, interlobular septal thickening, ground-glass opacities, or
cystic or bubblelike lesions (119,126). Mosaic attenuation due to small airway
obstruction has also been reported with BALT lymphoma (128).
Abnormalities are bilateral in one-half to two-thirds of cases (111,116). In one
study (111) of CT findings in 22 patients with MALT lymphoma, pulmonary
abnormalities included a solitary nodule (23%), multiple nodules (32%), lung
mass or consolidation (45%), consolidation with air bronchograms (18%), and
patchy airspace or interstitial infiltrates (23%) (111). In a similar CT and HRCT
study of 24 patients with MALT lymphoma (116), one or more pulmonary
masses or masslike areas of consolidation larger than 3 cm in diameter were
found in 87%, while nodules 3 cm in diameter or smaller were seen in 75%.
Multiple masses, nodules, or areas of consolidation were present in 79%, while
17% had a solitary lesion. In 88%, air bronchograms were visible in relation to
nodules or masses, and in 58% of patients, the bronchi appeared dilated.
Pleural effusion is present in 10% to 33% of cases, usually in association with
evidence of parenchymal involvement (107,111,117). Lymphadenopathy is
evident in up to 30% of cases (111,126).
High-Grade Lymphoma
Most cases of high-grade primary pulmonary lymphoma are of B-cell type, and
some originate from MALT (110). These may arise from the transformation of
an indolent MALT lymphoma or occur in patients with an underlying disorder or
immunodeficiency such as AIDS or organ transplantation (posttransplant
lymphoproliferative disorder); these are described later in this chapter.
Occasional cases of anaplastic large cell lymphoma or peripheral T-cell
lymphoma have also been reported (110,129).
Generally, the radiographic and CT features of high-grade lymphomas are
similar to those of low-grade MALT lymphoma (116). The most common
radiographic presentation consists of solitary or multiple nodules, masses, or
regions of consolidation containing air bronchograms (Figs. 11-31 and 11-32)
(118,123). Lymph node enlargement may be present.
FIGURE 11-31 High-grade non-Hodgkin lymphoma. HRCT demonstrates bilateral nodules
with irregular margins and focal areas of subpleural thickening.
FIGURE 11-32 A–C: High-grade T-cell lymphoma in a 33-year-old man. HRCT demonstrates
well-defined nodules surrounding bronchi or containing air bronchograms (arrows).
Secondary Pulmonary Lymphoma
Pulmonary involvement in association with extrathoracic or diffuse lymphoma is
more common than primary pulmonary lymphoma. In one review of 651 patients
who had lymphoma, 54 (8%) had histologically documented pulmonary
involvement (130). Of these 54, the lung was the primary site of involvement in
21 (39%), whereas the lung was secondarily involved by tumor originating in a
variety of distant sites in 33 (61%) (130).
Intrathoracic abnormalities are common in patients who have lymphoma,
being seen at presentation in 67% to 87% of patients who have HL, and 43% to
45% of patients who have non-Hodgkin lymphoma (NHL) (131– 133). In the
majority of patients, intrathoracic disease is limited to lymph nodes. Pulmonary
involvement is apparent radiographically at presentation in approximately 5% to
10% of patients who have NHL and 10% to 15% of patients who have HL
(131–135). In patients who have HL, lung involvement at presentation is almost
always associated with hilar or mediastinal lymph node enlargement (135); this
is not the case with NHL. However, radiographic and CT appearances of lung
disease in HL and NHL are quite similar (123,130,136).
The most frequent CT and HRCT finding in secondary pulmonary lymphoma
consists of solitary or multiple nodules, masses, or masslike consolidation,
usually ranging from 0.5 to 8 cm in diameter, often shaggy or ill-defined, and
sometimes cavitary (Fig. 11-33) (130,132–134,136–138). In one study, air
bronchograms were visible within 47% of masses in NHL and 32% of masses in
HL (136).
FIGURE 11-33 Recurrent lymphoma. HRCT shows nodules in the lingula. Also noted is
interlobular septal thickening in the lingula and right lower lobe. The patient was a 38-year-old
woman who had recurrent NHL.
A diffuse reticular pattern with thickening of the interlobular septa may also
be seen, closely mimicking the appearance of lymphangitic carcinomatosis (Fig.
11-34) (118,123). This pattern may reflect interstitial tumor infiltration or
lymphatic or venous obstruction by mediastinal or hilar tumor. Thickening of the
peribronchovascular interstitium is seen in as many as 55% of cases (128) and is
often associated with other findings. Patchy airspace consolidation with air
bronchograms may also be seen (118,123,130) and is associated with a poor
prognosis (130).
FIGURE 11-34 A–C: Lymphoma with secondary lung involvement in a 79-year-old man.
HRCT demonstrates extensive interlobular septal thickening, thickening of interlobar fissures, and
peribronchovascular interstitial thickening identical in appearance to that of lymphangitic spread of
carcinoma.
Lewis et al. (136) reviewed the conventional CT findings in 31 patients who
had secondary pulmonary lymphoma, including 15 with HL and 16 with NHL
(Table 11-8); in most patients, pulmonary involvement occurred with relapse.
The most common pulmonary parenchymal manifestations were nodules or
masses larger than 1 cm in diameter or masslike areas of consolidation (68% of
patients) and nodules smaller than 1 cm in diameter (61% of patients) (136).
Nodules or masses larger than 1 cm often contained air bronchograms, but those
smaller than 1 cm did not. Both nodules and masses often had shaggy borders.
Although the findings seen in patients with HL and NHL were similar, the most
common finding with HL was mass or masslike consolidation (80% of cases),
whereas the most common finding with NHL was peribronchovascular
interstitial thickening (69%). Pleural effusion was visible in 42% of cases.
Lymph node enlargement was more common with HL (53%) than with NHL
(19%) (136).
TABLE 11-8 CT Findings (%) in Pulmonary Hodgkin Lymphoma and
Non-Hodgkin Lymphoma
Diederich et al. (138) reviewed the CT findings in 33 examples of secondary
pulmonary HL. Pulmonary nodules were recorded in 88% of studies. Nodules
were multiple in 86% and bilateral in 66% of cases, respectively. Nodule size
ranged from 2 mm to 10 cm. In 83% of cases, nodules were 30 mm or smaller,
and in 21%, they were 1 cm or smaller. In 83%, nodules were irregularly
marginated. Cavitation was visible in less than 1% of nodules. Regions of
diffuse lung infiltration were visible in 27% of cases, and more than half of these
also showed nodules. Infiltration was peribronchovascular in 56% of patients
with infiltration, nodular in 33%, and alveolar in 11%. It usually involved 25%
or less of the lung parenchyma. Hilar or mediastinal lymph node enlargement
was always present at the time of initial diagnosis. Not surprisingly, CT showed
more abnormalities than plain radiographs (138).
An example of diffuse pulmonary involvement by mycosis fungoides with
clinical and radiographic manifestations simulating pneumonia has been reported
(139). HRCT showed multiple, dense, peribronchovascular nodules with
surrounding ground-glass opacity and wedge-shaped peripheral opacities. The
autopsy specimen revealed angiocentric and peribronchovascular involvement
by mycosis fungoides and pulmonary infarctions distal to angiocentric
infiltration of the tumor cells.
AIDS-Related Lymphoma
Prior to the use of HAART, lymphoma was reported to have an incidence of
approximately 5% in patients with AIDS (140,141). HAART has reduced the
incidence of ARL and improved patient survival following chemotherapy (61),
but the incidence of ARL has not dropped to the same degree as it has for KS
(142).
Most frequently, ARL is a high-grade B-cell NHL (141,143,144). Ioachim et
al. (143) reviewed 111 cases of ARL; 100 represented NHL, whereas 11 were
HL. EBV has been implicated in at least some cases of both AIDS-related NHL
and HL (143,144).
ARL is typically characterized by advanced clinical stage and high histologic
grades (141). NHL in AIDS patients originates predominantly in extranodal
locations and frequently involves multiple sites, including bone marrow, central
nervous system, lung, liver, and bowel (143). ARL is associated with advanced
AIDS and low CD4+ counts (145). Prior to the use of HAART, it was
characterized by high aggressiveness, frequent posttreatment relapse, and short
periods of survival (143,144). In one study, the median survival time was 4
months, with progressive pulmonary lymphoma being the main cause of death
(144).
Thoracic involvement is common in patients who have ARL and is present in
up to 70% of cases at autopsy (145). In a study of 116 consecutive cases of ARL,
20 (17%) patients were considered to have thoracic involvement, and in 15
cases, the thorax was the major site of disease (146). In another study, 11 of 35
(31%) patients who had ARL had biopsy-proven thoracic involvement (147).
Primary pulmonary ARL is less frequent, and accounts for only 8% to 15% of
cases (118,144).
Pulmonary nodules or masses are the most common radiographic and CT
finding in ARL, typically ranging in size from 0.5 to 5 cm in diameter, although
most nodules are larger than 1 cm (Fig. 11-35) (65,71,118,141,144,146,147).
The nodules are usually multiple and well defined, but may appear spiculated,
and cavitation may be present (144). Localized consolidation or reticular
opacities may also be seen. Pleural effusion is common, usually in combination
with multiple nodules; this appearance is considered typical of ARL (147).
FIGURE 11-35 A and B: Non-Hodgkin lymphoma. CT in a patient with AIDS who has NHL
shows ill-defined nodules, many of which are perihilar and peribronchovascular, or contain air
bronchograms. This appearance mimics that of KS.
Mediastinal lymph node enlargement is more common in patients who have
lung involvement occurring in association with disseminated ARL than it is in
patients who have primary or localized pulmonary ARL. Node enlargement in
association with thoracic ARL was seen in 3 of 11 patients studied by Sider et al.
(147) and in 54% of patients studied by Eisner et al. (145), but it was not seen in
two recent studies of primary ARL of the lung (141,144).
The clinical, radiographic, and autopsy features of 38 patients who had AIDSrelated NHL associated with pulmonary involvement were reviewed by Eisner et
al. (145). Most patients had respiratory symptoms (87%) and signs (84%), and
systemic symptoms are common (144). The majority of patients had advanced
HIV infection, with a mean CD4+ count of 67 (±65). Thoracic CT revealed
pulmonary nodules (50%), lobular consolidation (27%), and lung mass (19%) as
the most common parenchymal abnormalities. Pleural effusion was visible in
68% of cases.
Posttransplantation Lymphoproliferative Disorder
Several histologic patterns of lymphocyte proliferation, known collectively as
posttransplantation lymphoproliferative disorder, can occur after bone marrow
or solid organ transplantation (148–150). The histologic patterns range from
benign hyperplastic proliferation of lymphocytes to malignant lymphoma (150).
Most cases of PTLD have been associated with EBV infection, and it is likely
that such infection is an essential step in the development of the majority of
cases (148,150–152). PTLD affects approximately 2% of transplant recipients
(153). The incidence is highest after lung transplantation, with PTLD being seen
in approximately 6% to 9% of lung transplant recipients (78,154). The majority
of patients present in the first year after transplantation. PTLD can manifest as
localized or disseminated disease and has a predilection for extranodal
involvement (78). Lung involvement may occur as part of multiorgan disease or
in isolation.
Thoracic PTLD can occur in any transplant recipient and should be regarded
as a potentially fatal complication. Heart and lung allograft recipients have the
poorest prognosis because significant mortality accompanies transplant rejection
with reduced immunosuppression necessary for treatment (150).
Eleven cases of primary thoracic PTLD were identified among 3,085 solidorgan transplant patients and 1,662 bone marrow transplant patients (lung
transplant, 3; kidney transplant, 3; kidney/pancreas transplant, 2; allogenic bone
marrow transplant, 2; and heart transplant, 1) (150). The median time from
transplantation to presentation was 8 months (range, 1–97 months). CT
evaluation revealed mediastinal lymph node enlargement or mass and pulmonary
masses or nodules in 55% of cases, and 55% of patients also had extrathoracic
disease. Pathologic analysis revealed diffuse large B-cell lymphoma in 7
patients, polymorphic PTLD in 2 patients, anaplastic large cell lymphoma in 1
patient, and HL in 1 patient. EBV infection was determined to be present in 84%
of patients tested. All patients were initially treated with a reduction in
immunosuppression therapy, and 6 patients (55%) received adjuvant
chemotherapy. The overall mortality rate was 64%. Four patients died from
complications of PTLD (kidney, 2; heart, 1; bone marrow, 1), and 3 patients (all
lung transplant recipients) died from rejection or infectious complications. The
median interval from diagnosis to death was 13 months (range, 1–42 months)
(150).
The most common CT findings in PTLD include (a) single or multiple, small
or large pulmonary nodules, which may be well-defined, ill-defined, or
associated with the halo sign (Fig. 11-36); (b) patchy or focal consolidation or
ground-glass opacity; (c) a predominantly peribronchial and subpleural or
diffuse distribution of parenchymal abnormalities; and (d) hilar or mediastinal
lymphadenopathy (Table 11-9) (118,149,150,155,156). In a review of the
radiologic manifestations in 28 patients by Dodd et al., nodules were identified
on the chest radiograph or CT in 16 patients (57%) (155). The nodules were well
circumscribed, measured between 0.3 and 5 cm in diameter, and were usually
multiple and distributed randomly throughout the lungs. Patchy, predominantly
peribronchial airspace consolidation associated with air bronchograms was seen
in 3 patients, 2 of whom also had lung nodules. Mediastinal and hilar
lymphadenopathy was seen in 17 of 28 (60%) patients, thymic involvement in 2,
pericardial thickening or effusion in 2, and pleural effusion in 4.
FIGURE 11-36 Posttransplantation lymphocytic disorder after double lung transplant. HRCT
demonstrates left lower lobe nodule with irregular margins and halo of ground-glass attenuation
(arrow). Also noted is a small left pleural effusion.
TABLE 11-9 HRCT Findings in Posttransplantation
Lymphoproliferative Disorder
Single or multiple nodules, well-defined or ill-defineda
Halo sign
Patchy or focal consolidation or ground-glass opacityb
Peribronchial, subpleural, or random distributionb
Lymph node enlargement
a Findings most helpful in differential diagnosis.
b Most common findings.
Carignan et al. (156) reviewed the HRCT findings in four patients who had
PTLD. All four patients had nodules on HRCT, two had hilar and mediastinal
lymphadenopathy, and one had pleural effusion. In three of the four patients, a
halo of ground-glass opacity was seen surrounding the lung nodules; this finding
has been reported in other studies, and pathologic correlation showed the halo to
be related to infiltration of the adjacent lung by a less dense infiltrate of
lymphoid cells (Fig. 11-36) (149). In another investigation of 17 patients who
had PTLD, 15 (88%) had multiple nodules on CT, 6 (35%) had interlobular
septal thickening, 5 (29%) had areas of ground-glass opacity, 4 (23%) had areas
of airspace consolidation, and 5 had hilar or mediastinal lymphadenopathy (78).
The nodules had a predominantly peribronchovascular or subpleural distribution.
Lymphomatoid Granulomatosis (Angioimmune
Proliferative Lesion)
The term lymphomatoid granulomatosis (also known as angioimmune
proliferative lesion or angiocentric immunoproliferative lesion) is used to refer
to a group of angiocentric, angiodestructive abnormalities characterized by a
lymphoid infiltrate and a variable degree of cellular atypia (72,74–76). Three
grades are considered to exist based on the degree of cytologic abnormalities and
necrosis, and their response to treatment (72). Progression to histologically overt
lymphoma occurs in as many as 47% of cases (157). B cells appear to constitute
the primary neoplastic proliferation in patients who have lymphomatoid
granulomatosis, although an exuberant T-cell reaction is present (74,158). EBV
has been detected in most cases investigated (72,158). The lung is the primary
site of disease, although other organs, including skin, brain, kidneys, and heart,
may be involved.
Radiographic and CT findings consist primarily of bilateral, well-or poorly
defined nodular lesions, ranging from 0.5 to 8 cm in diameter, with a basal
predominance (Fig. 11-37) (72,98,157,159). Nodules have a perilymphatic
distribution and tend to be located in relation to the peribronchovascular
interstitium or interlobular septa (157). In a review of five cases, the number of
nodules ranged from 5 to more than 60 (157). Lesions may progress rapidly and
cavitate, mimicking Wegener granulomatosis. Thin-walled cystic lesions may be
seen, resulting from necrosis pleural effusion, and mediastinal lymph node
enlargement may be present (157).
FIGURE 11-37 Lymphomatoid granulomatosis. A and B: HRCT demonstrates nonspecific
small sharply defined lower lobe nodules.
Leukemia
Pleuropulmonary infiltration is evident at autopsy in 20% to 66% of patients
who have leukemia (1,160,161). However, the radiographic abnormalities in
these patients are seldom due to pleuropulmonary leukemic infiltration alone. In
the majority of patients, parenchymal abnormalities seen on the radiograph are
due to pneumonias, hemorrhage, drug-induced lung damage, or pulmonary
edema (1,162,163). In an autopsy review of 60 patients who died from acute or
chronic myelogenous or lymphocytic leukemia, radiographically demonstrable
disease was related to hemorrhage in 74%, infection in 67%, edema or
congestion in 57%, and leukemic infiltration in 26%; only 5% were
radiographically normal (162). In a review of HRCT findings in 80 consecutive
patients with chest complications of leukemia, 29 of whom had undergone bone
marrow transplantation (BMT), the most common causes of pulmonary disease
included bacterial pneumonia (31.3%), leukemic infiltration (16.3%),
cytomegalovirus (CMV) infection (12.5%), pneumocystic pneumonia (10%),
fungal pneu