CHEST
Chest Imaging for Clinicians
Pictorial Essay: Multinodular Disease*
A High-Resolution CT Scan Diagnostic Algorithm
Suhail Raoof, MD, FCCP; Alexey Amchentsev, MD; Ioannis Vlahos, MD;
Ajay Goud, MD; and David P. Naidich, MD, FCCP
The evaluation of patients presenting with multinodular pulmonary disease provides an important clinical challenge for physicians. The differential diagnosis includes an extensive list of
benign and malignant processes making the management of these cases frequently problematic.
With the introduction of high-resolution CT (HRCT) scanning, the ability to assess various
patterns of diffuse multinodular disease has evolved into an essential part of the diagnostic
process. The purpose of this article is to develop an approach to the diagnosis of multinodular
parenchymal disease using HRCT scan pattern recognition as a point of departure.
(CHEST 2006; 129:805– 815)
Key words: algorithm; multinodular; multiple nodules
Abbreviations: HP ⫽ hypersensitivity pneumonitis; HRCT ⫽ high-resolution CT; ILD ⫽ interstitial lung disease;
LCH ⫽ Langerhans cell histiocytosis; LIP ⫽ lymphocytic interstitial pneumonitis; RB ⫽ respiratory bronchiolitis
the purposes of this report, multinodular
F ordisease
will be defined in a patient in which
there are too many nodules to easily count on routine
CT scan studies, with most of these nodules measuring ⬍ 1 cm in diameter. While the most common
cause of multiple pulmonary nodules is metastatic
disease, it is apparent that this definition encompasses a wide range of lung diseases, both benign and
malignant. It is our contention that use of a dedicated diagnostic algorithm1 based on characteristic
high-resolution CT (HRCT) scan features coupled
with clinical findings can provide either a specific
*From the Division of Pulmonary and Critical Care Medicine
(Drs. Raoof and Amchentsev), New York Methodist Hospital,
Brooklyn, NY; the Department of Radiology (Drs. Vlahos and
Naidich), Tisch Hospital, New York University Medical Center,
New York, NY; and the Department of Radiology (Dr. Goud),
Brigham and Women’s Hospital, Boston, MA.
No financial or other potential conflicts of interest exist for any of
the authors.
Manuscript received January 9, 2006; revision accepted January
14, 2006.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Suhail Raoof, MD, FCCP, Chief, Pulmonary
and Critical Care Medicine, Medical Director, Respiratory Therapy Department, New York Methodist Hospital, Pulmonary
Division, 506 Sixth St, Brooklyn, NY 11215; e-mail:
Sur9016@nyp.org
www.chestjournal.org
diagnosis or a markedly shortened list of differential
diagnoses in a majority of patients presenting with
diffuse lung nodules.
Algorithm Overview
Due to its ability to evaluate the lung parenchyma
in cross-section, eliminating the superimposition of
densities, CT scanning offers a unique opportunity to
evaluate lung nodules in exquisite detail.2 This includes first the ability to assess lesions by anatomic
distribution, and second by morphology.3–5
Anatomic Localization
This includes the consideration of the following
patterns: diffuse vs focal or clustered; central (peribronchovascular) vs peripheral (subpleural or perifissural); and upper vs lower lung distribution. Most
importantly, nodules also need to be characterized
by their relation to secondary lobular anatomy allowing a distinction between centrilobular nodules and
those that predominantly involve the lobular periphery, including the interlobular septa3–5 (Fig 1).
For example, diseases such as sarcoidosis that
localize within or adjacent to lymphatics predomiCHEST / 129 / 3 / MARCH, 2006
805
Figure 1. Secondary lobular anatomy. A side-by-side diagrammatic representation of two normal secondary pulmonary lobules.
Secondary lobules represent fundamental anatomic units of the
lung and are defined by centrilobular structures, including
pulmonary arteries/arterioles and their accompanying bronchi/
bronchioles, and peripheral structures, including the pulmonary
veins and lymphatics within the interlobular septae. As shown,
most of these structures are ⬍ 1 mm in size and therefore, with
the exception of the centrilobular arteries, lie below the resolution of even HRCT scans. Most importantly, note that centrilobular structures do not extend to the pleural or interlobular
septal surfaces. As will be illustrated, knowledge of basic lobular
anatomy is the key to differentiating between different etiologies
of diffuse pulmonary nodules.
nate in those regions in which lymphatics are most
extensive, specifically along the pleural and fissural
surfaces, within the interlobular septae, and along
the peribronchovascular axial interstitium (Fig 2).
Diseases that are primarily hematogenous in origin,
such as miliary infections or hematogenous metastases, give rise to nodules that are randomly distributed throughout the secondary lobule, with the
greatest profusion in the lung bases (Fig 3). These
patterns are clearly separate from nodules that result
from inhalational disorders such as occur in patients
with endobronchial spread of infection or hypersensitivity pneumonitis (HP), in which nodules are
predominantly centrilobular in distribution, sparing
the lobular periphery (Fig 4, 5).
Morphologic Characterization
This includes assessing a number of characteristics
including whether nodules are as follows: uniform or
variable in size; sharply or poorly marginated6 – 8;
solid or subsolid in density (so-called ground-glass
opacities) [Fig 5]5; or have a so-called tree-in-bud
appearance (Fig 4).9 Additionally, nodules may either be calcified, as occurs in fungal disease, or
cavitary, as is seen, for example, in patients with
septic emboli, metastatic disease, or Langerhans cell
histiocytosis (LCH).10
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Figure 2. Perilymphatic disease. A diagrammatic representation
of the characteristic distribution of lung nodules in patients with
perilymphatic disease. Note that nodules are preferentially subpleural, peribronchovascular within the axial interstitium, or
along lobular septae. While this appearance is especially characteristic of nodular sarcoidosis, less commonly a similar pattern
may also be seen in patients with silicosis or coal-workers
pneumoconiosis.
It should be emphasized that many of these
characteristics are best evaluated on high-resolution
CT scan images. With the introduction of multidetector CT scanners, it is now possible to routinely,
prospectively reconstruct both thick and thin sections through the lungs after a single breathhold,
provided that the initial data are acquired using
appropriately thin collimation. This approach also
enables the use of high-definition, multiplanar reconstructions, the use of which may be of value in
further characterizing lung nodules.11
Multinodular HRCT Algorithm: A StepWise Approach
The use of this algorithm begins by dividing CT
scans into two broad arms based on the presence
(group 1) or absence (group 2) of pleural or perifissural involvement (Table 1).
Step 1
Group 1: Those cases in which a striking proportion of nodules demonstrate pleural or perifissural
involvement characterize nodules as predominantly
perilymphatic or lymphohematogenous in origin,
constituting a separate arm of the algorithm (Table
1). The explanation for this pattern lies in the greater
density of lymphatic channels seen in the interlobuChest Imaging for Clinicians
Figure 3. Random nodules. A diagrammatic representation of
the characteristic distribution of randomly distributed nodules in
patients with lymphohematogenous disease. Note that in distinction with patients having predominantly perilymphatic disease,
random nodules may been seen adjacent to all secondary lobular
structures. Some nodules may also appear to be attached to
pulmonary arterial branches (so-called feeding vessels). Random
nodules are most commonly due to metastatic disease, and may
vary considerably in size and edge characteristics. The differential
diagnosis most importantly includes miliary infection. Lymphangitic carcinomatosis, while hematogenous in origin, is easily
distinguished from random metastatic nodules by the presence of
characteristically thickened interlobular septae, preferentially
involving the lung bases, and usually associated with asymmetric
hilar adenopathy and pleural effusions.
Figure 5. Centrilobular disease. A diagrammatic representation
of the distribution of diseases that predominantly affect the
centrilobular portion of secondary lobules, excluding those diseases that result in predominantly mucoid impaction due to
infected secretions. The most common cause of diffuse centrilobular disease is subacute HP. This characteristically results in
poorly defined, poorly marginated ground-glass opacities. Similar
to tree-in-bud opacities, these rarely involve the pleural or
fissural surfaces. While a number of different entities may result
in predominantly centrilobular opacities, the differential diagnosis most often includes RB/RB-ILD. In distinction with subacute
HP, RB in particular is less extensive, typically upper lobe in
distribution, and almost always occurs in smokers.
lar septa and subpleural regions, including along the
fissures.
Step 2
Once nodules are characterized as predominantly
perilymphatic or lymphohematogenous in origin,
further assessment requires determining whether or
not nodules are distributed diffusely or are patchy or
clustered, with particular attention paid to the presence or absence of the extent of axial interstitial
involvement. It is recalled that the axial interstitium
envelops the main pulmonary vessels and bronchi
extending from the hilum outward toward the lung
periphery.12
Step 3
Figure 4. Bronchiolar disease. A diagrammatic representation of
the typical appearance of bronchiolar inflammation resulting in
so-called tree-in-bud opacities. These characteristically result in
clusters of ill-defined nodules “attached” to adjacent branching or
tubular structures due to extensive bronchiolar mucoid impaction. Most importantly, note that, unlike the situation in patients
with either perilymphatic disease or random nodules, mucoid
impacted bronchioles do not extend to the pleural, fissural, or
septal surface. This pattern is nearly always due to infected
secretions resulting from virtually any cause of acute or subacute
bronchiolar infection.
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If nodules prove to be clustered in a predominantly subpleural/axial distribution, they are deemed
to be perilymphatic in distribution (Fig 2). In this
category, the main disease to be considered is sarcoidosis (Fig 6, 7).2,13,14 This diagnosis is further
suggested by nodules that are typically ill-defined,
frequently measuring only a few millimeters in size.
Clusters of these nodules often have a “grainy”
appearance and when sufficiently profuse may result
in an appearance of poorly defined nodules or
masses on corresponding chest radiographs (soCHEST / 129 / 3 / MARCH, 2006
807
Table 1—HRCT Algorithm for Multinodular Disease*
* CWP ⫽ coal workers pneumoconiosis; MAI ⫽ M avium intracellulare; MTB ⫽ M tuberculosis; PMF ⫽ progressive massive fibrosis.
called alveolar sarcoid). When coalescent, these may
simulate progressive massive fibrosis. Ancillary findings include a predominant upper lobe distribution,
focal air-trapping due to bronchiolar obstruction,
and diffuse adenopathy, often calcified. Calcified
nodules may also be present in later stages of the
disease.
The most important differential diagnoses for this
pattern of disease are silicosis and coal worker
pneumoconiosis.15,16 In both of these occupational
diseases, perilymphatic nodules are the primary abnormality, typically involving the mid and upper lung
fields. While these entities may simulate the appearance of sarcoidosis, they are usually easily diagnosed
when correlated with clinical history.15 This includes
other rare occupational lung disease, for example,
siderosis, that may also simulate the appearance of
sarcoidosis.17
While lymphangitic carcinomatosis may result in
perilymphatic nodules, in fact, CT scan findings are
most often characterized by markedly thickened
nodular interlobular septae usually asymmetrically
involving the lower lobes and usually associated with
adenopathy and effusions.18 Nodules, when present,
tend more often to be well-defined and are often
associated with discrete feeding vessels, further
identifying them as hematogenous in origin. Lymphangitic carcinomatosis rarely mimics findings that
are characteristic of sarcoidosis.
Step 4
Figure 6. Perilymphatic disease: sarcoidosis. An HRCT scan of
a 1-mm section at the level of the carina shows innumerable
ill-defined small nodules clustered in the mid-portions of both
lungs with relative sparing of the anterior aspects of both upper
lobes. Note that these preferentially involve the left major fissure
(arrow on left lung) as well as the walls of the peripheral airways
(curved arrow on right lung).
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If nodules prove to be diffuse instead of clustered,
they are properly considered to be random in distribution (Table 1). By definition, true random distribution will lead to nodules being identified along
pleural and fissural surfaces as well as along the axial
Chest Imaging for Clinicians
Figure 7. Perilymphatic disease: sarcoidosis. An HRCT scan of
a 1-mm section through the right mid-lung in a different patient
than the one in Figure 6 shows evidence of innumerable
ill-defined small nodules. Note that these tend to be clustered
with relative sparing of the right upper lobe anteriorly and clearly
preferentially lie adjacent to the right major fissure (arrow), along
pleural surfaces, and along central vascular structures (arrowheads). This distribution of nodules is rarely seen in any other
disease.
interstitium. However, in distinction from primarily
perilymphatic disease, random nodules may also be
identified in even greater numbers when dispersed
randomly throughout the lungs.
Included in this category most importantly are
hematogenous metastases.19 Unlike nodules in patients with sarcoidosis, metastatic nodules tend to be
smooth, well-defined lesions (Fig 8, 9).8 However, a
wide variety of morphologic appearances has been
noted. In a study20 comparing the HRCT scan
features of pulmonary metastatic lesions with autopsy findings, while nodules most often proved to
have well-defined margins (38% of cases), nodules
with well-defined irregular margins, poorly defined
smooth margins, and poorly defined irregular margins could be identified in 16%, 16%, and 30% of
cases, respectively. While nodules range from a few
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millimeters to ⬎ 1 cm, they are frequently similar in
size. A basilar predominance is typically noted due to
preferential blood flow to the lung bases. Individual
nodules may have “feeding vessels” consistent with
their hematogenous origin. On HRCT scans, a connection between nodules and the adjacent pulmonary vessels (ie, the mass-vessel sign) may be seen in
approximately 75% of cases.21 Nodules may also be
either cavitary or surrounded by a “halo” of groundglass attenuation, which is typical of hemorrhagic
metastases such as those due to choriocarcinoma.22
Features of lymphangitic cancer may also be present,
which again is consistent with a hematogenous origin
of disease.19
It should be noted that the reported incidence of
malignant disease as a cause of multiple pulmonary
nodules has been shown to vary greatly, from as low
as 10% to as high as 58% in some surgical series.23 In
133 patients with a known malignancy who underwent video-assisted thoracoscopy for multiple pulmonary nodules, 64% proved to have at least one
malignant nodule.24 A number of malignancies can
result in a miliary pattern, rendering differential
diagnosis more problematic. This includes tumors,
such as renal cell carcinoma, head and neck cancers,
and testicular tumors, that have their primary venous
drainage in the lungs.25
The differential diagnosis includes a number of
additional entities that result in random nodules. The
most important of these is miliary infection (Fig
10).26,27 In fact, while differentiation between miliary
infection and a miliary tumor may be impossible to
determine by imaging features alone, in general,
close correlation with the clinical history renders
these diagnoses relatively straightforward. Miliary
metastases are frequently due to metastatic thyroid
cancer, renal cancer, and melanoma, among other
cancers, while larger less profuse metastases tend to
be adenocarcinomas in adults, typically originating
from the lung, breast, or the GI tract.19,28 Less
commonly, diffuse nodules may be identified in
patients with septic emboli, invasive fungal infections, and pulmonary vasculitides.29 These entities
frequently result in cavitary nodules, some with a
distinct “halo” of ground-glass attenuation,22 and
have even been described in patients with organizing
pneumonia.30 Despite similarities between these entities and routine metastatic disease, it should be
emphasized that the numbers of nodules identified
in these cases usually fail to meet the criterion of “too
many nodules to count,” with the differential diagnosis again further aided by close clinical correlation.
Step 5
Group 2: In distinction with the patterns described in patients in group 1, group 2 includes those
CHEST / 129 / 3 / MARCH, 2006
809
Figure 8. Random nodules: hematogenous metastases. An HRCT scan of a 1-mm section through the
lower lobes shows innumerable sharply defined nodules throughout both lungs. Note that while many
of these lie along pleural and fissural surfaces, or less commonly appear related to adjacent vessels
(arrows), most are unattached to adjacent structures. When sufficiently well defined and generally
uniform in size, this pattern of diffuse nodularity is easily separable from that resulting from
perilymphatic disease.
patients in whom no or very few nodules are perifissural or subpleural in distribution. Anatomically,
these nodules are grouped together as being centrilobular in distribution.4 By definition, these entities
primarily involve centrilobular bronchioles and/or
their accompanying pulmonary artery branches. Anatomically, these structures taper peripherally, stopping 5 to 10 mm short of the pleural or interlobular
septal surfaces and consequently fail to involve pleural and fissural surfaces (Table 1). As will be discussed, these nodules typically fall into the following
two broad categories: those with a “tree-in-bud”
configuration; and those that appear as amorphous
“ground-glass” nodules.
Step 6
Once nodules are characterized as being primarily
centrilobular in distribution, further assessment requires determining whether or not these have a
tree-in-bud configuration. Tree-in-bud opacities are
characterized by the appearance of centrilobular
micronodular branching structures that end several
millimeters distant from nearby pleural or fissural
surfaces (Fig 11).31
Tree-in-bud opacities are nearly always the result
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of inspissated (ie, frequently aspirated) secretions
lodged within centrilobular bronchioles, accounting
for a branching configuration when coursing parallel
to the CT scan plane.9,32,33 Normal bronchioles,
which have a diameter of ⬍ 1 mm and a wall
thickness of ⬍ 0.1 mm, are below the limit of HRCT
scan spatial resolution.34 The presence of inspissated
secretions results in bronchiolar distension and increased density, allowing their direct visualization.
Not surprisingly, in many cases there is also evidence
of coexisting bronchiectasis. Another frequently encountered finding in patients with bronchiolar disease is so-called mosaic attenuation.33 In these cases,
bronchiolar occlusion results in air-trapping, hypoxia
of the poorly ventilated lung units with resultant
reflex vasoconstriction and air-trapping. This combination of findings causes decreased attenuation of
the affected areas of the lung with blood flow
redistributed to normal lung. The hypoattenuated
diseased lung is therefore surrounded by hyperattenuated, overperfused normal lung, resulting in
heterogeneous-appearing mosaic attenuation.
While classically described in patients with an
endobronchial spread of tuberculosis, in fact, treein-bud opacities can be identified in virtually any
Chest Imaging for Clinicians
Figure 9. Random nodules: metastatic thyroid cancer. An HRCT scan of a 1-mm section through the
mid-thorax shows innumerable small nodules. Note that, in addition to unattached nodules, many of
these lie along both the minor and right major fissures (arrows), as well as along the proximal middle
lobe pulmonary artery (arrowheads). Although there are fewer nodules than shown in Figure 8, in the
appropriate clinical stetting this pattern is again consistent with metastatic disease.
type of infectious bronchiolitis. This includes Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, bacterial, viral, and fungal infections, and
allergic bronchopulmonary mycosis. This pattern is
also frequently encountered in patients with AIDS in
whom recurrent episodes of bronchial infection are
frequent.35 Differential diagnosis also includes follicular bronchiolitis, an entity that is characterized by
the presence of hyperplastic lymphoid follicles and
germinal centers occurring along the bronchovascular bundles.36
Most often, infectious bronchiolitis results in clusters of tree-in-bud opacities. When they are widespread and diffuse, the differential diagnosis includes “Asiatic panbronchiolitis.”37,38 This entity has
a well-established predilection in Japanese, Chinese,
and Korean populations, appears to show a genetic
predisposition, and is usually seen in association with
chronic sinusitis. Diffuse tree-in-bud opacities are
also frequently encountered in patients with cystic
fibrosis and viral bronchiolitis.
It cannot be overemphasized that in the vast
majority of cases the finding of tree-in-bud opacities
should be taken as being indicative of bronchiolar
infection. While tree-in-bud opacities have been
described39 as occurring in patients with pulmonary
vascular tumor emboli, in our experience this entity
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is exceedingly rare. As noted in one retrospective
study9 of 141 patients with a variety of airway
diseases, including bronchiolitis obliterans, bronchiolitis obliterans-organizing pneumonia, HP, respiratory bronchiolitis (RB), and pneumonia, among others, the finding of tree-in-bud opacities was
identified in association only with pneumonia and/or
bronchiectasis in 17% and 25% of cases, respectively.
Even in patients with panbronchiolitis, while no
consistent infectious agent has been associated with
this disease, interestingly, most individuals respond,
at least initially, to low-dose erythromycin therapy.38,40 Some authors41 have suggested that the
therapeutic efficacy of macrolide agents may emanate from their inhibition of proinflammatory cytokines, and from mucus and water secretion from
airway epithelial cells.
Step 7
Those cases in which centrilobular nodules are
present in patients in the absence of tree-in-bud
opacities constitute the last part of this CT scan
algorithm (Table 1). Included in this category are a
variety of diseases or “mixed” entities that have in
common localization to the centrilobular portion of
the secondary lobule. This includes diseases that
CHEST / 129 / 3 / MARCH, 2006
811
Figure 10. Random nodules: miliary tuberculosis. A magnified
HRCT scan image through the right upper lobe shows innumerable tiny nodules throughout the lungs extensively involving the
pleural surfaces (black arrowheads) and along bronchovascular
structures (arrows). Numerous unattached nodules are also identifiable. This pattern is typical of a random, miliary distribution.
While typically resulting from either metastatic disease or infection, clinical correlation is usually diagnostic. Case courtesy of
Nestor Muller, MD, Vancouver, BC, Canada.
primarily affect the centrilobular bronchiole, as well
as those that are either primarily peribronchiolar or
perivascular in origin.2,4,5
Most often, this group of diseases results in a
pattern of diffuse, poorly defined ground-glass nodules, which are typically the result of a primarily
peribronchiolar distribution. The classic example of
this appearance is subacute HP (Fig 12).42,43 This
diagnosis is frequently first suggested on the basis of
CT scan findings and is usually established by a
combination of exposure history, clinical symptoms
of a flu-like illness, the presence of specific serum
antibodies when those data are available, increased
numbers of lymphocytes and neutrophils in BAL
fluid, and, when feasible, clinically significant improvement in symptoms when the patient is removed
from the offending environmental agent.44
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Figure 11. Bronchiolar disease: infectious bronchiolitis. A magnified HRCT scan image through the middle and lower lobes
shows numerous nodules associated with linear/branching densities throughout the lungs (arrows). These tree-in-bud opacities
are the result of infected mucoid impacted peripheral airways
and hence have a distinctly centrilobular pattern of distribution.
Note that none of these peripherally is in contact with either
pleural or fissural surfaces. Classically the result of the endobronchial spread of tuberculosis, this pattern may be seen in virtually
any patient in whom there is infection of the peripheral airways.
Not surprisingly, tree-in-bud opacities tend to be clustered rather
than truly diffuse and frequently are associated with CT scan
evidence of bronchiectasis.
The differential diagnosis encompasses a number
of important disease entities, most importantly including RB, lymphocytic interstitial pneumonitis
(LIP), and LCH. RB/RB-interstitial lung disease
(ILD) are smoking-related disorders that may also
result in poorly defined centrilobular nodules.45,46
RB typically results in far fewer ground-glass nodules
than the number in patients with subacute HP and
generally display a distinctly upper lobe predominance. RB-ILD is associated with widespread
ground-glass attenuation and reticular opacities,
which are findings that are not seen in patients with
subacute HP.45,46
Also included in the differential diagnosis of individuals with diffuse centilobular nodules are diseases
related to bronchiolar lymphatics. This includes muChest Imaging for Clinicians
in particular, the presence of randomly distributed
thin-walled cysts.47 Poorly defined centrilobular nodules may also be seen early in the course of LCH.49,50
However, these most often are associated with characteristic bizarrely shaped, thick walled cysts, some
of which represent cavitary nodules with characteristic sparing of the lung bases.51
Conclusion
Figure 12. Centrilobular disease: subacute HP. A magnified
HRCT scan section through the right upper lobe shows innumerable poorly defined, hazy ground-glass nodules throughout
the lung (arrows). In addition to a uniform distribution, none of
these nodules lies adjacent to the visualized pleural surfaces.
Note as well the lack of any tree-in-bud opacities that would
suggest the presence of mucoid impacted airways (compare with
Fig 11). Few entities besides subacute HP result in this pattern
of ill-defined nodules. Differential diagnoses includes RB, typically causing fewer nodules restricted to the upper lobes in
known smokers, and LIP, which is usually associated with either
Sjogren syndrome or AIDS.
cosa-associated lymphoid tissue lymphoma (maltomas) and, in particular, LIP. LIP is most often seen
in patients with underlying immunologic abnormalities, especially Sjögren syndrome and AIDS, and is
characterized histologically by diffuse hyperplasia of
bronchus-associated lymphatic tissue, resulting in a
diffuse, polyclonal lymphoid cell infiltrate surrounding the airways and expanding the lung interstitium.47,48 As reported by Johkoh et al,48 in a study of
22 patients with documented LIP, while subpleural
nodules could be identified in 86% of cases, likely
reflecting subpleural lymphatic involvement, poorly
defined centrilobular nodules could be seen in 100%
of cases. Additional imaging features include the
presence of thickened bronchovascular bundles and,
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The finding of multiple lung nodules is a characteristic that encompasses a number of disparate
parenchymal diseases. Although inexact, the use of
anatomic and morphologic features to characterize
nodules based on HRCT scan findings may help to
simplify the differential diagnosis. Most importantly,
the use of this imaging algorithm can prove to be an
aid in standardizing the clinical approach to differential diagnosis. In a study reported by Gruden et
al,4 four experienced chest radiologists independently evaluated HRCT scan images in 58 patients
with diffuse nodular disease. In each case, observers
were asked to place nodules in one of the following
four possible anatomic locations or categories: perilymphatic; random; associated with small airways
disease (ie, cases in which the primary abnormality
was tree-in-bud opacities); or centrilobular disease.
There was agreement among all four observers in
79% of cases, while three of four observers agreed on
an additional 17%. Observers were correct (based on
subsequent histologic/clinical correlation) in 218 of
232 localizations (94%) in the 58 cases. These data
suggest that this algorithm, which has been elaborated on in the present report, represents a reproducible method for categorizing patients with diffuse
pulmonary nodules.
It should also be noted that, in individual cases,
HRCT scan findings may be sufficiently characteristic, especially when coupled with close clinical correlation, to obviate the need to perform a biopsy.
Patients with classic HRCT scan findings of sarcoidosis, as well as those with subacute HP for which
biopsy confirmation may not be required, should be
included in this category. In patients with a known
history of smoking, the finding of scattered, tiny,
ill-defined centrilobular upper lobe nodules is sufficiently characteristic to warrant a clinical diagnosis of
RB, obviating the need for more invasive diagnostic
procedures, while the finding of scattered centrilobular opacities associated with bizarrely shaped
cysts predominantly involving the upper lobes sparing the lung bases is characteristic of LCH. Similarly,
the finding of characteristic tree-in-bud opacities in
the appropriate clinical setting may be taken as
diagnostic of small airway-bronchiolar infection. In
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813
distinction, the appearance of diffuse, poorly defined
centrilobular nodules in the absence of a clinical
history of established antigen exposure, infection, or
a history of smoking generally requires open-lung
biopsy for definitive evaluation. Given the wide
diversity of potential causes for this appearance, the
use of an HRCT scan algorithm should be considered an important, if not fundamental, component of
clinical assessment in these cases.
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