Download Recent Advances in Pulmonary Imaging

Recent Advances in Pulmonary
Imaging*
Daniel D. Maki, MD; Warren B. Gefter, MD; and Abass Alavi, MD
Recent years have witnessed an explosion in imaging technology applicable to chest medicine.
These include CT and magnetic resonance angiography (MRA) for the diagnosis of pulmonary
embolism, and high-resolution CT for the detection and characterization of diffuse lung diseases
and the quantification of emphysema. Newly developed approaches to pulmonary functional
imaging using CT and MRI have been applied to the evaluation of pulmonary ventilation and
perfusion and to the detection of small airways disease. Volumetric CT imaging techniques
together with advanced image processing have made possible “virtual bronchoscopy.” Positron
emission tomography provides an important new approach to the accurate detection and staging
of chest malignancies and to the evaluation of pulmonary nodules. Finally, new digital imaging
techniques, which are rapidly replacing conventional x-ray film, offer the possibility of computeraided diagnosis.
(CHEST 1999; 116:1388 –1402)
Key words: CT; digital imaging; imaging; lung; MRI; positron emission tomgraphy
Abbreviations: CAD 5 computer-aided diagnosis; CR 5 computed radiography; 3D 5 three-dimensional;
DVT 5 deep venous thrombosis; ES 5 energy subtraction; FDG 5 fluorodeoxyglucose; FOB 5 fiberoptic bronchoscopy; HRCT 5 high-resolution CT; HU 5 Houndsfield units; LVRS 5 lung volume reduction surgery;
MRA 5 magnetic resonance angiography; MRI 5 magnetic resonance imaging; PACS 5 picture archiving and communication systems; PE 5 pulmonary embolism; PET 5 positron emission tomography; PFT 5 pulmonary function
test; PIOPED 5 prospective investigation of pulmonary embolism diagnosis; SPECT 5 single photon emission CT;
SPN 5 solitary pulmonary nodule; SUV 5 standard uptake value; VB 5 virtual bronchoscopy; V̇/Q̇ 5 ventilation/
perfusion
past 20 years have witnessed a renaissance in
T hepulmonary
imaging. The development of both
CT and MRI has revolutionized imaging of the
lungs, and advances in nuclear medicine such as
positron emission tomography (PET) have opened
the door to noninvasive characterization of lesions
that previously was not possible. Furthermore, the
development of digital chest radiography is rapidly
replacing more traditional methods to acquire, transmit, and view chest radiographs. In addition, computer-aided diagnosis (CAD) is now becoming feasible.
In this review, recent advances in pulmonary
imaging that are having a marked impact on pulmonary medicine are highlighted. These new imaging
methods have advanced our ability to detect, characterize, and quantify pulmonary pathology. Moreover, many of these new imaging techniques can
provide functional as well as anatomic information.
*From the Department of Radiology, University of Pennsylvania
Medical Center, Philadelphia, PA.
Correspondence to: Warren B. Gefter, MD, Department of
Radiology, University of Pennsylvania Medical Center, 3400
Spruce St, Philadelphia, PA 19104; e-mail: gefter@oasis.
rad.upenn.edu
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Pulmonary Thromboembolism
Ventilation/Perfusion Scintigraphy
To date, ventilation/perfusion (V̇/Q̇) scintigraphy
has been the primary screening tool for clinically
suspected pulmonary embolism (PE). As reported in
the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, V̇/Q̇ scintigraphy
represents an excellent initial screening tool since
the modality has a very high sensitivity for PE.1
Specifically, the PIOPED study reported that 98% of
patients with PE will have an abnormal V̇/Q̇ study.
However, the specificity of V̇/Q̇ scintigraphy was
rather poor, as 72% of PIOPED patients demonstrated nondiagnostic (neither normal nor highprobability) V̇/Q̇ studies. In addition, among patients
with documented PE, only 41% had scans revealing
a high probability of PE, and 16% had scans revealing a low probability of PE. Thus, alternative methods for the accurate, noninvasive detection of PE,
including CT and MRI, are being evaluated.
All early studies of V̇/Q̇ scintigraphy for PE utilized planar imaging of the lung, which involved
static images of the lung taken in a single plane,
similar to a frontal or lateral chest radiograph. The
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planar technology remains the standard for V̇/Q̇
scintigraphy at most medical centers, even most
academic centers. Recent work has focused on the
use of single photon emission CT (SPECT) imaging
for V̇/Q̇ scintigraphy. With SPECT technology, images of the lung are obtained simultaneously by a
single- or multiheaded camera that is rotating around
the chest, similar to a CT scan. The resulting data set
can be reconstructed in any plane and is typically
viewed in three orthogonal planes (axial, sagittal, and
coronal). Preliminary work suggests that SPECT
imaging improves the specificity of V̇/Q̇ scintigraphy
by substantially decreasing the number of indeterminate studies by providing clearer perfusional data,
which allows a significant fraction of these studies to
be classified as normal or high probability.2 However, in the short run, the use of SPECT may be
limited by the lack of available multiheaded SPECT
cameras (which are ideally suited for this purpose) in
many medical centers.
Whether performed with the planar or SPECT
technique, the positive predictive value of a highprobability scan is sufficiently high (96%), and that of
a low-probability scan in the setting of low clinical
suspicion is sufficiently low (4%), that many patients
can be managed with V̇/Q̇ scans alone.
Helical CT Angiography
Helical CT allows rapid volumetric data acquisition, often within a single breathhold, during peak
levels of pulmonary vascular contrast enhancement.
Acute thrombi are identified as filling defects within
the contrast-filled vessels (Fig 1), and chronic
Figure 1. Helical CT in PE. Contrast-enhanced helical CT scan
demonstrates a small clot in distal right main pulmonary artery
(straight arrow) as well as a larger clot in the descending left
pulmonary artery (curved arrow).
thrombi may be seen as eccentric wall thickening of
the vessels.
A number of recent studies have evaluated helical
CT for the diagnosis of PE in comparison with
conventional angiography and scintigraphy.3–5 The
mean sensitivity and specificity for central thromboembolus (main, lobar, and segmental arteries) were
90% and 90%, respectively.5 The mean positive
predictive value was 93%, and the negative predictive value was 94%. However, when all pulmonary
vessels were analyzed, including subsegmental vessels, the sensitivity dropped to 77% and the negative
predictive value to 82%.5
The use of thinner slice collimation will undoubtedly improve the sensitivity of CT for PE. Two
studies have shown that the use of very thin collimation (2 mm) improved visualization of segmental and
subsegmental pulmonary arteries.6,7 Until recently,
the barrier to using thin collimation on PE studies
was speed, since the use of very thin collimation
slows scanning sufficiently to require multiple
breathholds and, thus, introduces misregistration
artifacts and allows contrast washout of the vessels.
However, recently developed multiple-detector row
helical CT scanners (eg, Lightspeed; GE Medical
Systems; Milwaukee, WI) are now available that
allow the acquisition of contiguous 1.25-mm thick
slices through the entire chest during a single breathhold, which should substantially improve the detection of small thromboemboli.
There is much debate over the incidence and
significance of isolated subsegmental emboli, which
are difficult (at best) to identify by helical CT. The
clinical significance of these subsegmental emboli is
debatable. It has been suggested that the significance of an isolated subsegmental PE is minimal, in
the presence of normal cardiopulmonary reserve and
in the absence of identifiable deep venous thrombosis (DVT). However, in patients with limited cardiopulmonary reserve, such as those with heart failure
or emphysema, isolated subsegmental PE may have
dire consequences. In one study, rapid clinical improvement following anticoagulation for subsegmental PE was seen in patients with underlying pulmonary disease, suggesting that subsegmental emboli
may significantly compromise pulmonary function in
patients with limited cardiopulmonary reserve.7
Several recent studies have concluded that the
sensitivity of helical CT is greater than that of V̇/Q̇
scintigraphy, reporting sensitivities of 87% vs 65%,
respectively.8 The interobserver agreement for CT
also has been reported to be higher than for V̇/Q̇
scintigraphy (k, 0.85 vs 0.61), and the specificity of
helical CT is reportedly greater than that of V̇/Q̇
scintigraphy in patients with unresolved diagnoses.9
CT has a substantial advantage over V̇/Q̇ scintigraphy
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and conventional angiography in that it provides a
comprehensive examination of the chest and can
frequently identify nonembolic causes of respiratory
symptoms in patients suspected of having PE. The
frequency of nondiagnostic CT scans has been estimated at roughly 15%, including 4% that were
technical failures and 12% that had inconclusive
findings.4,7
The exact role of helical CT in the imaging
algorithm for patients with suspected acute PE
remains unclear. Although there is still little prospective data comparing CT results with those of conventional angiography, many institutions have now
adopted helical CT as the initial imaging modality for
all patients suspected of having acute PE. This
decision may be supported by the higher specificity
and interreader agreement of CT as compared to
V̇/Q̇ scintigraphy. Helical CT clearly has a lower
sensitivity for subsegmental PE than does V̇/Q̇ scintigraphy. However, missing these small emboli may
not be clinically important, given that they arise
infrequently and may not require treatment in the
absence of preexisting cardiopulmonary compromise
and absence of DVT. Moreover, the interreader
agreement for such small emboli is poor even by
conventional angiography.
In such an algorithm, a negative or equivocal
result of a CT scan leads to a lower-extremity
ultrasound study. The potential of combining a
lower-extremity CT venogram with a helical chest
CT for PE is currently being investigated and may
eventually obviate the need for a subsequent ultrasound. It has been demonstrated that helical CT can
be utilized to evaluate for thrombus in the inferior
vena cava, pelvic veins, and proximal lower-extremity
veins.10 Under such an algorithm, if the results of the
CT venogram or ultrasound is negative for DVT,
then conventional pulmonary angiography is restricted to those patients with limited cardiopulmonary reserve or those with continued high suspicion
of PE.
Magnetic Resonance Angiography
Recent improvements in MRA techniques have
substantially increased the potential of MRA for the
evaluation of pulmonary thromboembolism. In particular, a variety of technical advances has led to
dramatic increases in speed for many MR imaging
sequences that allow for minimization of motionrelated and other imaging artifacts.
Recent work has focused on ultra-fast, gradientecho, three-dimensional (3D) gadolinium-enhanced
techniques (Fig 2), which often can be acquired
within a single breathhold, and are able to demonstrate clots in vessels at the segmental level. In a
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Figure 2. Pulmonary MRA. Top: this normal coronal, 3D,
gadolinium-enhanced pulmonary MRA was obtained in a single
breathhold. Bottom: coronal image from a gadolinium-enhanced
pulmonary MRA showing large embolus (arrow) in distal right
main and interlobar pulmonary artery.
recent study utilizing this 3D gadolinium-enhanced
technique, MRA detected 5 of 5 lobar and 16 of 17
segmental, angiographically proven emboli.11 The
reported positive predictive value of MRA for PE
was 87%, and the negative predictive value was
100%. However, none of the patients in this small
series had subsegmental emboli.
Subsegmental vessels can indeed be imaged with
MRA, but the accuracy of MRA for the detection of
a subsegmental clot is less impressive. A recent study
evaluated 3D gadolinium-enhanced magnetic resonance angiography (MRA) vs conventional angiography in 36 consecutive patients.12 Of 19 total emboli
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identified by conventional angiography, 13 were
identified prospectively by MRA. Of the six clots that
were missed by MRA, four were subsegmental.
Clearly MRA has a high sensitivity and specificity for
central, lobar, and segmental vessels but has limitations, which are similar to CT, in its ability to detect
subsegmental clots. MRA has the additional advantage of not requiring iodinated contrast material,
which is particularly important in patients with marginal renal function for whom conventional angiography might ultimately be necessary.
The volumetric data obtained by MRA and CT
offer some advantages over the limited projections
provided by conventional angiography, in that MR
and CT allow the display of the data in an infinite
number of planes and projections. Further improvements in pulmonary MRA will likely result from
several newly developed intravascular MRI contrast
agents that are currently undergoing trials. The
gadolinium in these compounds is bound to native
albumin or other macromolecules, which results in
their prolonged retention in the intravascular space,
and which is advantageous for pulmonary vascular
imaging and may also facilitate the coupling of MRI
venography with pulmonary MRA.
The ability to obtain MRI scans demonstrating
pulmonary perfusion is now possible. Such techniques allow MRI to provide the functional information such as that provided by V̇/Q̇ scan, in addition to
the anatomic data provided by MRA. Currently,
there are two techniques available to image perfusion with MRI. The first technique, known as spin
tagging, utilizes magnetization of blood flowing into
the lungs to yield images of pulmonary perfusion
without injection of any exogenous contrast agent.13
The second technique entails fast scanning of lung
parenchyma following IV bolus injection of gadolinium.14 Such techniques have demonstrated pulmonary perfusion defects due to emboli in both animal
and human patient studies.
The ability to image pulmonary ventilation with
MRI also has been demonstrated recently, with the
use of both hyperpolarized noble gases (129Xe and
3
He)15 as well as molecular oxygen.16 The noble
gases can be hyperpolarized by optical pumping with
a high-power laser so that they acquire a magnetic
moment and can thus generate a magnetic resonance
signal. The resultant magnetic resonance images
show the distribution of these gases in the lung and
central airways (Fig 3). Unfortunately, the images
are limited somewhat by the depolarization of the
gases following repeated radiofrequency pulses. Very
recently, it was shown that the weakly paramagnetic
effects of oxygen can be exploited to generate magnetic resonance images of the distribution of inspired
oxygen in the lung.16 While hyperpolarized gases are
Figure 3. Hyperpolarized 3He magnetic resonance ventilation scan. This sagittal image from a healthy subject demonstrates high signal from the gas throughout the airspaces of the
lung. The branching signal-void structures are pulmonary
vessels. (Courtesy of Rahim Rizi, PhD, University of Pennsylvania Medical Center.)
imaged directly, it seems that oxygen-derived images
reflect diffusion of the gas across the alveolar-capillary membrane.
Since PE and DVT are manifestations of the
same disease process, evaluation of the lower
extremities and pelvis for DVT plays an essential
role in the assessment of patients for suspected
acute PE. MR venography for DVT has been
shown to have very high sensitivity and specificity
for the detection of DVT.17 The technique has
advantages over ultrasound in that it is able to
image the pelvic veins and calves and is not
operator dependent. The potential to combine
MRI of the lower-extremity veins with pulmonary
MRI is, in fact, one of the compelling rationales
for pursuing MRI techniques for the evaluation of
acute PE. However, as noted previously, trials are
also currently underway that combine helical CT
pulmonary angiography with CT venography of
the lower extremities.
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Proposed Diagnostic Algorithm for Suspected Acute
PE
In summary, we would submit the following as the
most appropriate initial imaging study for working up
patients for PE: (1) CT (or MRI scan) when the
chest radiograph demonstrates lower-lobe opacities
or other significant cardiopulmonary disease, which
would likely lead to indeterminate V̇/Q̇ scans; (2)
V̇/Q̇ scan for patients with normal chest radiographs
and no prior history of PE; (3) angiography for
patients who are hemodynamically unstable or in
whom the need for an inferior vena cava filter is
anticipated. Obviously, in patients with clinical evidence of DVT, the algorithm should begin with a
DVT study, generally by ultrasound, which would
potentially eliminate the need for subsequent pulmonary imaging in those cases. The efficacy of such
a triage scheme remains uncertain.
It should be reemphasized that V̇/Q̇ scintigraphy
remains an excellent initial imaging study for the
detection of PE, whether it is performed with planar
or SPECT imaging, in patients with normal chest
radiographs and no prior history of PE or cardiopulmonary disease. The V̇/Q̇ scan in these patients has a
high likelihood of being diagnostic (normal or high
probability) and does not subject the patient to
iodinated contrast. In a V̇/Q̇ scan-first algorithm, a
DVT study is obtained if the V̇/Q̇ scan is nondiagnostic, and one may proceed to helical CT if the
result of the DVT study is negative. Conventional
angiography is, thus, again restricted to those with
limited cardiopulmonary reserve and indeterminate
CT, ultrasound (DVT), and V̇/Q̇ studies.
Emphysema
Imaging Prior to Lung Volume Reduction Surgery
Medical therapy for advanced emphysema is at
best palliative in many cases, and it is, therefore, not
surprising that there has long been a strong rationale
for seeking surgical means of treating the disease.
Because of the limited supply of organs available for
transplantation, lung volume reduction surgery
(LVRS) has emerged as the surgical approach with
the widest potential applicability. Imaging will likely
play an increasingly important role in patient selection for LVRS.
Chest radiographs and chest CT scans typically are
used to evaluate the severity and distribution of
emphysema and to identify potential exclusion criteria such as bronchogenic carcinoma, ongoing infectious or inflammatory processes, or pleural adhesions.18,19 Evaluation for nodules is particularly
important, since this population is at increased risk
for bronchogenic carcinoma. A recent study found a
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5% rate of incidental stage I bronchogenic carcinoma in patients being evaluated for LVRS.20
Recent studies have shown that findings on chest
CT scans, as well as on chest radiographs alone, are
highly predictive of postoperative outcome following
LVRS. Specifically, the severity and distribution of
emphysema, the degree of hyperinflation, the fraction of residual healthy lung, and the presence of
lung compression all showed significant correlation
with postoperative functional outcomes.18,19
Currently, a multicenter randomized clinical trial
of the relative effects of medical therapy alone vs
medical therapy plus LVRS for moderate to severe
emphysema is underway. The results of the National
Emphysema Treatment Trial are not expected for
several years.
CT, particularly high-resolution CT (HRCT), has
shown excellent correlation with pathologic studies
in evaluating the severity and extent of emphysema.
CT assessment has been based on both subjective as
well as quantitative measurements of CT attenuation
values in the lung. CT quantification of emphysema
has been correlated with pulmonary function; more
recently, such quantification has been used to demonstrate a decrease in emphysema after LVRS. The
most sophisticated techniques use software to distinguish pixels with abnormally low attenuation, representing emphysema, from those of healthy lung.
Applied to two-dimensional CT sections, the “density mask” technique was shown to represent accurately the morphologic extent of emphysema.
Automated techniques subsequently have been developed to increase the speed with which emphysema in the whole lung can be quantified, but such
software is not yet universally available.
Lung densitometry with 3D reconstruction of
helical CT data is a fast and accurate method for
quantifying emphysema (Fig 4). The method is
reproducible and has been shown to correlate with
pulmonary function tests (PFTs). The technique will
very likely play an important role in patient selection
for and follow-up after LVRS.21
Emerging Imaging Techniques for the Detection
and Quantification of Emphysema
Limitations of CT have included relatively low
sensitivity in detecting mild degrees of centrilobular
and panlobular emphysema (below the spatial resolution of HRCT and lack of functional information
(except for inspiratory/expiratory scanning). However, there are newly evolving pulmonary imaging
methods that have the potential to provide quantitative, volumetric measures of pulmonary emphysema,
including both morphologic as well as functional
displays of regional V̇/Q̇ abnormalities.
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additional research since they may be able to detect
the morphologic and/or functional changes of mild
emphysema prior to detectability by HRCT. In
addition, these techniques may provide for quantitative measures of structure/function relationships in
patients with emphysema that are not available from
CT images alone.
Pulmonary Nodule Characterization
Figure 4. Helical CT scan in patient with emphysema. In this
3D display of the lungs, acquired in one breathhold, white areas
represent pixels with CT attenuation values # 2950 HU, corresponding to areas of emphysema. Such volumetric displays
provide quantitative images of the regional distribution of emphysema.
Pulmonary ventilation imaging with hyperpolarized 3He gas, as previously indicated, can provide
high-signal, high-resolution, 3D magnetic resonance
images of gas distribution.22 Defects in gas uptake
have been demonstrated in patients with emphysema. Furthermore, the signal intensity data provided may potentially yield a measurement of the
enlarged airspaces created by emphysema below the
anatomic resolution of HRCT. It also should be
possible to obtain 3D maps of regional 3He washout
rates, thereby providing volumetric, quantitative displays of gas trapping in patients with emphysema.
While they are indirect measures of emphysema,
new methods of obtaining high-resolution, volumetric displays of regional pulmonary perfusion have
been developed both with MRI and CT. These
include the following: (1) dynamic gadoliniumenhanced MRI, from which quantitative parameters
of regional pulmonary blood flow, including mean
transit times and blood volume, can be measured
and displayed14,23; (2) a spin-tagging (magnetic labeling) MRI technique that requires no exogenous
contrast agent to create 3D images of pulmonary
perfusion13; (3) dynamic CT-based measurements of
pulmonary perfusion that can be directly correlated
with the high-resolution morphologic displays of
emphysema on HRCT24; and (4) 3D SPECT radionuclide perfusion and ventilation scans.25
These new pulmonary imaging approaches, which
are in the early stages of investigation, are worthy of
The characterization of a solitary pulmonary nodule (SPN) as benign or malignant remains one of the
more challenging problems in pulmonary imaging
today. Although currently most patients with SPN
undergo biopsy or resection for definitive diagnosis,
there has been a movement to develop a noninvasive
means of characterizing such SPN as benign or
malignant.
A long-accepted radiographic criteria for classifying SPN as benign has been the so-called 2-year
stability rule. However, a recent retrospective review
of the original data of Good and Wilson reveals that
a lack of 2-year interval growth conveyed only a 65%
predictive value of benign etiology.26 CT has been
long used to assess SPN. Initial work was based on
the theory that CT would be able to distinguish
benign from malignant lesions based on the presence
of small amounts of calcification in the former.
Measurements of density values of an SPN can be
valuable in determining the presence of calcification
or fat (the latter indicating a hamartoma). However,
thin sections and a smooth reconstruction algorithm
should be used. In addition, care must be taken
concerning volume averaging effects from the adjacent lung.
A great deal of interest recently has focused on the
use of time-enhancement curves for the characterization of SPNs. Dynamic CT scans are performed
through the same slice of an SPN every few seconds
during and following the IV injection of iodinated
contrast material. The attenuation (or density) of the
SPN is plotted vs time to yield a time-enhancement
curve. The appearance of the curve will depend on
the vascularity of the lesion and the rapidity of
contrast washout, which are both thought to be
different for benign vs malignant SPNs. Wash-in of
contrast into a benign SPN is thought to be slower
than into a malignant SPN, as the former is typically
a less vascular lesion, and the washout is typically
slower, since benign SPNs are thought to have
slower diffusion within them.
A large, surgically proven series27 of 163 patients
found that malignant neoplasms enhanced significantly more (mean, 40 Houndsfield units [HU]) than
granulomas or benign neoplasms (mean, 12 HU).
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Utilizing a 20-HU enhancement threshold as “indicative of malignancy,” the technique was 100% sensitive and 77% specific, with an overall accuracy of
93%. Several smaller series have reported similar
results.28,29 False-positive results for malignancy occur occasionally in inflammatory lesions, such as
active granulomas or round pneumonias, or in any
richly vascular inflammatory lesion. False-negative
results for malignancy have been reported rarely,
and were thought to have occurred because of
central (nonenhancing) necrosis of the tumor, which
was evident in retrospect in these cases.
Advances In Computed Tomography
HRCT Scans
HRCT has proven invaluable in the characterization of many diseases of lung,30,31 particularly for the
characterization of diffuse interstitial lung disease.
HRCT is performed with a thin-section technique,
utilizing 1- to 2-mm thick slices and a high spatial
frequency reconstruction algorithm.
HRCT has emerged as an important tool for
evaluating patients with suspected diffuse interstitial
lung disease prior to performing a biopsy. Among
many indications for HRCT is its important role in
guiding lung biopsy.32 CT can suggest the relative
efficiency of endobronchial or transbronchial vs open
lung biopsy for the diagnosis of acute and chronic
infiltrative lung disease. Moreover, HRCT can suggest those areas of the lung in which a biopsy is most
likely to provide specific histologic diagnoses or to
allow assessment of disease activity.
A number of diseases have sufficiently characteristic appearances that, in the appropriate clinical
setting, a diagnosis may be possible by HRCT alone,
obviating the need for biopsy. Patients with a reticular pattern and evidence of honeycombing have, by
definition, diffuse lung fibrosis and generally do not
require further histologic evaluation. While controversial, sarcoid and lymphangitic carcinomatosis,
when classic in appearance, may be confidently
diagnosed without the need for confirmation with a
biopsy. In patients with centrilobular “groundglass”
nodules, a diagnosis of subacute hypersensitivity can
often be made without a biopsy.
The great majority of cystic lung diseases can be
easily distinguished by their appearance and by the
pattern of distribution of cysts, together with ancillary findings of nodules and the clinical history.
These include Langerhans cell histiocytosis (eosinophilic granuloma) (Fig 5), lymphangioleiomyomatosis/tuberous sclerosis, emphysema, and bronchiectasis. Thus, biopsy in most of these cases is also
unwarranted.32,33
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Figure 5. HRCT in a patient with Langerhans cell histiocytosis
(eosinophilic granuloma). HRCT demonstrates upper lung zone
cystic changes and small nodular lesions that are characteristic of
this disease.
Small Airways Disease
PFT measurements of small airways function are
highly variable, and their use is limited. Furthermore, virtually all measures of airway function are
global tests that cannot detect potential regional
heterogeneity of bronchial reactivity and airflow
obstruction. Nor can they localize the distribution or
generations of airways involved.34
HRCT is an established technique for the detailed
evaluation of the pulmonary parenchyma, and it can
characterize anatomic details of the lung as small as
200 to 300 mm, which corresponds to the proximal
7th to 9th airway generations. The healthy intralobular bronchioles cannot be identified because the
thickness of their walls is , 0.15 mm. However,
bronchiolar abnormalities may be detected when
there is thickening of the bronchiolar wall, peribronchiolar inflammation or fibrosis, and bronchiolectasis
with or without filling of the dilated bronchial tubes
with secretions.35
The development of helical scanning techniques
enables volume data sets to be acquired through
broad regions of interest in a single breathhold.
When acquired during different phases of suspended
respiration or under different physiologic conditions,
these image sets can reveal relationships between
airway structures and functions. By imaging at 10%
and 90% of vital capacity, the decreased lung attenuation due to lung destruction in patients with
emphysema can be differentiated from the expiratory air trapping seen in those with chronic bronchitis.34 Asymptomatic patients with asthma can be
distinguished from healthy subjects by the expiratory
mean pixel index (percentage of pixels below 2900
HU) at the lung bases on CT, being significantly
higher in asthmatics.36 Comparing cross-sectional
areas of small airways as well as frequency distribuGlobal Theme Issue: Emerging Technology in Clinical Medicine
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tion curves of lung attenuation of asthmatics and
healthy subjects at baseline and following bronchoprovocation with methacoline, significant differences
in the percentage of change have been found. At
baseline, measures of expiratory airflow were similar
between healthy and mildly asthmatic subjects; however, the percentage of change in lung attenuation
between functional residual capacity and residual
volume was less in patients with asthma than in
healthy subjects. If confirmed in future studies,
these preliminary results suggest that functional
information derived from physiologic imaging may
help to clarify discrepancies between clinical symptoms and the results of traditional PFTs.
HRCT allows identification of airways that are 1 to
2 mm in diameter and of vessels that are 0.1 to 0.2
mm in diameter, as well as abnormalities corresponding to the level of the secondary pulmonary
lobule.
Constrictive (Obliterative) Bronchiolitis
An example of the important use of combined
inspiratory and expiratory HRCT scans to detect
small airways disease is the detection of constrictive
bronchiolitis.
Constrictive bronchiolitis involves the inflammation of bronchial tubes that leads to obstruction of
the bronchiolar lumen. There are numerous causes
of constrictive bronchiolitis, among which is chronic
rejection in heart and lung transplantation.
Direct signs of constrictive bronchiolitis shown on
HRCT include centrilobular branching structures
and centrilobular nodules caused by peribronchiolar
thickening and bronchiolectasis with inspissated secretions. Indirect findings include bronchiectasis and
bronchiolectasis, mosaic pattern of lung attenuation,
and air trapping (Fig 6).37,38
In obliterative bronchiolitis, the mosaic pattern of
lung attenuation is caused by hypoventilation of
alveoli distal to bronchiolar obstruction, which leads
to secondary vasoconstriction, which is seen on CT
scans as areas of decreased attenuation. Uninvolved
segments of lung show normal or increased perfusion with resulting normal to increased attenuation.
The combination of low attenuation changes in
involved regions with higher attenuation areas in
uninvolved regions is referred to as a “mosaic pattern” of lung attenuation.37,38
Air trapping is seen on CT scans as the failure of
portions of lung to change volume or attenuation
between inspiratory and expiratory images.37,38 Using paired CT scans in inspiration and expiration is
useful for distinguishing small airways disease from
primary vascular lung disease. In small airways disease, the lucent regions of lung seen at inspiration
Figure 6. Inspiratory (top) and expiratory (bottom) HRCT scans
in a patient with bronchiolitis obliterans. Note the mosaic
attenuation pattern evident in the expiratory image (bottom),
showing areas of relatively higher attenuation in regions of
healthy lung, in contrast to areas of persistent low attenuation
(arrows) representing regions of air trapping due to small airways
disease. This patient had progressive dyspnea due to bronchiolitis
obliterans associated with rheumatoid arthritis. (Courtesy of
Wallace T. Miller, Jr, MD, University of Pennsylvania Medical
Center.)
remain lucent at expiration due to air trapping, and
show little increase in lung attenuation or decrease in
volume. In contrast, the relatively opaque healthy
lung will increase in attenuation and decrease in
volume as expected. In primary vascular disease,
because there is no air trapping or airways disease,
the attenuation of both the hyperemic and oligemic
lung at inspiration will increase in a similar fashion,
and the volume of both will decrease at expiration.35
Imaging-based methods that allow the detailed
assessment of airway morphology and dynamic responses to pharmacologic interventions, characterization of patterns of parenchymal abnormalities,
and quantitation of blood flow and ventilation parameters at the gas exchange interface are avidly
being pursued. Lung diseases are often viewed as
involving the whole lung equally, a situation reinCHEST / 116 / 5 / NOVEMBER, 1999
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forced by the results of PFTs, whereas regional lung
disease is likely more common in most instances.24
Virtual Bronchoscopy
It has been reported that axial CT is as accurate as
fiberoptic bronchoscopy (FOB) for evaluation of
central airways, with the exception of very small
mucosal abnormalities (, 3 mm), subtle mucosal
and submucosal irregularities, and infection. Compared to FOB, an axial CT can evaluate both intraluminal and extraluminal disease.39
Helical CT has improved the evaluation of central
airways by virtually eliminating slice misregistration
and respiratory motion artifacts. By obtaining a
continuous volume data set during a single breathhold, two-dimensional reformatted images and 3D
reconstructions can be generated utilizing a variety
of reconstruction/rendering techniques. In some circumstances, such as the evaluation of stenoses in
obliquely oriented bronchi, these reconstructions
may substantially improve the diagnostic accuracy or
facilitate the interpretation of anatomy.
So-called virtual bronchoscopy (VB), or CT bronchography, has received considerable attention in
the recent literature. Excellent internal images of the
tracheobronchial tree can be generated to the level
of the 4th or 5th generation bronchi. 3D reconstructions can be viewed from either an external or an
internal perspective (Fig 7, 8).
Proposed uses of VB include screening airways for
endoluminal malignancy, evaluating airway stenoses,
and using it as a “road map” for FOB. Experience
thus far suggests that VB probably does not accu-
Figure 8. Top: volume-rendered CT image from VB showing
endoluminal view of the foreign body (white area is dental
bridge). Bottom: corresponding video image from actual bronchoscopy. (Courtesy of Bernard A. Birnbaum, MD, University of
Pennsylvania Medical Center.)
Figure 7. Virtual bronchoscopy. Axial CT image shows highdensity object (arrow) representing an aspirated dental bridge in
left bronchus.
1396
rately detect and define small mucosal and submucosal lesions.39 On the other hand, several studies
document that VB accurately detects and quantifies
airway stenoses when compared to FOB, which may
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be important in stent planning. VB is probably
slightly more accurate than axial thin-section CT
scans for the evaluation of stenoses. However, the
role of VB (if any) in the evaluation of airway
stenoses remains controversial. VB may eventually
prove most useful as an adjunct to FOB, perhaps as
a means of following known stenoses after therapy or
in patients who cannot tolerate FOB. It may be
useful also in patients with stenoses that are too
narrow for the FOB device to pass through (since the
airway distal to the narrowing can be visualized and
the “VB scope” can be turned retrograde to look at
the airway).
In a preliminary investigation, McAdams et al40
found that VB was useful for directing transbronchial
needle aspiration in patients with enlarged nodes.
The potential applications of VB are numerous,
although the technology remains, as yet, in its infancy. Only time will tell what, if any, important role
VB plays in clinical practice.
Multi-detector Row CT
Multi-detector row CT represents a recent advance in helical CT technology. The Lightspeed CT
(GE Medical Systems) mentioned earlier is currently
capable of acquiring four channels of helical data
simultaneously.
The advantages of multi-detector row CT for
imaging the thorax include faster volumetric acquisitions, thin-section volumetric studies of large imaging volumes, retrospective reconstructions of thin
sections from data used for routine thick-section
imaging, and improved 3D rendering.41 Applications
that may be substantially improved over singledetector row scanners include the following: (1)
pulmonary CT angiography with improved detection
of small isolated subsegmental emboli; (2) detection
of fat or calcium within a pulmonary nodule that was
detected on routine imaging; and (3) 3D imaging of
the airways.
One significant price to be paid for these advances
is the creation of huge image data sets involving
hundreds of images, which will necessitate advances
in the transfer, 3D display, and storage of these large
volumes of CT image data.
CT Fluoroscopy
Another recent advance in CT technology is that
of real-time CT fluoroscopy.42 The most frequent
application of CT fluoroscopy has been for real-time
guidance during the biopsy of pulmonary nodules.
Although conventional and helical CT have been
used for this purpose for many years, lack of realtime visualization of target lesions has been an
important limitation, especially for small lesions and
in patients who are unable to cooperate with breathholding.
When performing the biopsy of small nodules, the
puncture of vital structures (eg, with lesions near the
heart) can be avoided. Complex pleural drainages
and catheter placements are facilitated particularly
well, with an average procedural time-saving of 25 to
30 min. Another important use of CT fluoroscopy in
the chest has been for the guidance of transbronchial
biopsy via the fiberoptic bronchoscope. With this
technique, CT fluoroscopy allows accurate transbronchial needle placement into enlarged lymph
nodes or masses, with the avoidance of major vascular structures. Considerable attention, however,
must be paid to reducing the relatively high radiation
exposures involved in CT fluoroscopy.
PET
Despite the many recent technological advances
made in CT scans and MRI of the chest, these
modalities continue to show some limitations in the
following specific settings: in the SPN; after extensive postsurgical and postradiation changes; and in
subcentimeter-sized lymph nodes in patients with
prior malignancy. PET is a functional imaging technology that has shown great promise in this arena.
The majority of PET scans are performed utilizing
(18F)fluorodeoxyglucose (FDG), which is the radiotracer of choice for tumor imaging. The use of FDG
is based on the fact that increased glucose metabolism has been noted in many neoplasms. Recently,
we have noted that uptake of FDG by tumors
increases over time, while the metabolic activity of
inflammatory sites either remains stable or declines
between 60 and 90 min following injection of the
radiotracer. We are currently testing the validity of
this dynamic FDG uptake curve in lung tumors.
Many lung malignancies present as SPNs with a
potential for cure after surgical resection. Unfortunately, up to one third of patients with SPNs who
undergo surgery are found to have benign lesions at
thoracotomy. This problem is even greater in geographic regions where there is a high prevalence of
granulomatous disease, such as the Northeastern
United States. PET scanning with FDG appears
extremely useful in characterizing SPNs, as studies
have reported sensitivities and specificities of
. 80%.43 However, most studies exclude patients
with diabetes, in whom sensitivities are somewhat
lower. The criterion that characterizes an SPN as
malignant on a PET scan is the degree of FDG
uptake 1 h after injection, which should be greater
than that seen in the mediastinum (Fig 9). SemiCHEST / 116 / 5 / NOVEMBER, 1999
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Figure 9. PET in lung cancer. This 79-year-old female underwent a left upper lung cancer resection 14 months prior to the CT
scan of the lower chest shown above. Top: this image reveals a
new 2-cm right lower lobe nodule, while the rest of the study
including the mediastinum and the left lung, appeared without
evidence of recurrent disease. A curative surgery was planned if
the PET-FDG scan revealed no other abnormalities elsewhere.
Bottom: a PET-FDG scan of the chest and abdomen (selected
coronal planes are shown above) revealed significant metabolic
activity in the lesion seen on the CT scan (solid arrow), which was
interpreted to represent a malignant tissue at this site. However,
three more abnormalities were identified (broken arrows) in the
upper mediastinum, left hilum, and the posterior chest wall to the
left of the midline that also were suggestive of malignant lesions
at these sites. These findings resulted in a significant alteration of
the initial plans for the management of this patient. LUL 5 left
upper lobe; RLL 5 right lower lobe.
quantitative analyses have revealed that an SPN with
a standard uptake value (SUV) . 2.5 is likely to
represent a malignant lesion; however, visual inspection by an experienced observer is as accurate in
making such distinctions as SUV analysis. Most
false-positive results are due to increased FDG
uptake in inflammatory conditions such as granulomas. In geographic regions where the prevalence of
inflammatory conditions is high, an SUV threshold of
3.8 has been suggested to reduce the likelihood of
false-positive results. Two time-point imaging, which
we are currently studying, may obviate the need for
such SUV modification. Theoretically, the sensitivity
1398
of PET may be low in lesions , 1 to 1.5 cm in
diameter, but, in general, false-negative results are
considered rare. The accuracy of PET scans in
characterizing SPNs is superior to CT scans when
only the morphology, pattern of calcifications, and
unenhanced density of the SPN are considered.44
However, as noted previously in this article, there is
a growing body of evidence to suggest that dynamic,
contrast-enhanced CT is also highly sensitive and
specific for characterizing SPNs. Clearly, a direct
comparison of dynamic, contrast-enhanced CT and
FDG-PET scans should be carried out to better
define the strengths and weaknesses of each modality in the characterization of SPNs.
Increasingly, algorithms are being proposed to
incorporate PET into the work-up of patients with
SPN. Cost-effectiveness studies have demonstrated
potential savings by sparing patients from unnecessary surgery if such algorithms are adopted.44 Recent
studies have suggested that the probability of cancer
after a normal PET scan is very low (5%). Hence,
PET is expected to play an increasing role in the
characterization and work-up of patients with SPN.
Accurate staging of lung cancer by CT remains a
challenge in many cases. Patients with stage IIIb or
more advanced cancer are not candidates for aggressive surgery. The assessment of the malignancy
potential of mediastinal lymph nodes by CT is based
on the short axis dimension of the node, and, hence,
patients with subcentimeter malignant nodes may be
incorrectly considered free of metastases and may
undergo inappropriate surgery. Similarly, patients
with benign inflammatory nodes . 1 cm in diameter
may inappropriately be denied potentially curative
surgery. Utilizing this size criterion, the Radiology
Diagnostic Oncology Group found sensitivities and
specificities of 50% and 65%, respectively, for both
CT and MRI.45
Multiple studies have shown that FDG-PET is
more sensitive and specific than CT in detecting
stages N2 and N3 disease, with some false-positive
results due to inflammatory adenopathy, usually
related to granulomatous disease. A recent study46
reported a sensitivity and specificity of 89% and
99%, respectively, for PET imaging of stages N2 and
N3 adenopathy, compared with 57% and 94%, respectively, for CT. Clearly, adopting PET to assess
mediastinal disease in the staging of lung cancer
reduces costs and morbidity by sparing patients from
unnecessary surgery. A recent report showed that
PET imaging uncovered 29% additional lesions,
which led to alterations in management in 41% of
patients, thereby eliminating surgery in 18% of the
population.
FDG-PET is also useful for differentiating recurrent lung cancer from postoperative or postradiation
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changes, including radiation pneumonitis (Fig 10).
In this setting, both visual inspection and SUV
analysis appear to provide useful results. Some investigators have found that an SUV of $ 2.5 is
sufficiently sensitive and specific for tumor, while
others recommend higher values, such as 5.0, in
order to improve the specificity while maintaining
sensitivity of . 90%.47 Clearly, PET will serve an
increasingly important role in patients whose CT or
MR scans prove indeterminate for recurrent or
residual tumor following radiation, surgery, or both.
Recently, we reported preliminary data on the role
of FDG-PET imaging in the management of malignant mesothelioma.48 The uptake of FDG was sig-
nificantly higher in malignant pleural lesions than in
benign abnormalities. The overall sensitivity and
specificity of PET were 91% and 100%, respectively.
Recent studies also have shown that PET reveals
additional sites of disease involvement, not demonstrated by CT, in both non-Hodgkin’s lymphoma and
Hodgkin’s disease. A preliminary cost-effectiveness
analysis which substituted whole body PET for routine CT and MR scans revealed a substantial savings
during initial staging and restaging of Hodgkin’s
disease and non-Hodgkin’s lymphoma.
Clearly, FDG-PET provides valuable information
for the management of patients with lung cancer,
lung nodules, and mesotheliomas. In this era of cost
containment and “evidence-based” medicine, the
data support the use of PET in these settings. The
breadth of applications for FDG-PET is staggering,
and its role in a variety of oncologic settings, including lymphoma and esophageal cancer, is becoming
evident. The potential of its application to sarcoid
and other inflammatory diseases is also rapidly becoming evident. The role of PET in gene therapy as
a molecular imaging technique is in its infancy, but
appears promising.
Unfortunately, very few medical centers in the
world have access to this technology despite its
proven efficacy. Since January 1998, Medicare has
approved reimbursement for staging of lung cancer
and characterizing lung nodules by PET. Recognition by Medicare as a cost-effective technique further consolidates the position of PET as a powerful
tool in thoracic imaging.
Digital Imaging and Computer-Aided
Diagnosis
Digital Techniques
Figure 10. PET scan in patient with lung cancer. Top, left: CT
image revealing a right lung Pancoast tumor in a 62-year-old man
who underwent radiation and chemotherapy in preparation for a
curative surgery. Top, right: a repeat CT scan (the image on the
right) prior to surgery demonstrated two new nodules in the right
lung field. The degree of the disease activity of the original tumor
and the nature of the new lesions were uncertain at this time.
Bottom: a PET-FDG scan of the chest and abdomen (selected
coronal planes are shown above) revealed moderate metabolic
activity in the lateral (arrowhead) and medial (solid arrow)
aspects of the primary tumor, respectively. These findings suggested that the primary tumor was still active in spite of
chemotherapy and radiation therapy (XRT). The two lesions in
the lower right lung were also active (broken arrows) and were
indicative of a malignant process. Bottom, left: in addition, at least
two lumbar vertebral bodies appeared to have metastatic lesions.
Again, by performing PET-FDG imaging, the extent of the
disease activity was more accurately determined than that estimated by state-of-the-art anatomic imaging techniques.
Rapid advances in electronics and computer technology over the past 20 years have created new
possibilities for imaging with x rays. Specific receptor
systems independent of film allow image formation
to be recorded in digital form for improved image
transportation, manipulation, and storage.49 Digital
imaging systems that use a photostimulable storage
phosphor imaging plate, commonly called computed
radiography (CR) systems are now used widely in
practice.
The primary advantage of a CR system is that it is
designed to optimize image optical density and
contrast resolution largely independently of incident
x-ray exposure levels. For portable bedside radiographic applications, such as in ICUs, CR systems
are reported to produce images of very high quality
and of consistent optical density (reducing the need
for repeated examinations). When incorporated as
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part of a picture-archiving and communication system (PACS), CR images can be displayed in the
clinical wards or ICU within minutes of exposure.
For standard inpatient chest radiography, CR images
have been reported to be superior to conventional
film radiography for the visualization of the mediastinum, retrocardiac region, and subdiaphragmatic
recesses, and to be equivalent or superior to conventional film in the detection and evaluation of pulmonary nodules and opacities.49
Digital images can be viewed at any of a number of
workstations distributed around the hospital in the
wards, clinics, operating rooms, and teaching conference areas.50 Prior and current images can be viewed
together. The images can be manipulated in various
ways to improve accuracy. Moreover, images from
several different modalities (eg, chest radiographs,
chest CT scans, and MRI scans) can be viewed
simultaneously on the workstations. The images can
be linked with their corresponding radiologic reports
and demographic data, and diagnostic annotations
and measurements can be added if needed.
All of a hospital’s images for many years can be
archived on relatively small long-term computer
archives. Coordination among the hospital information system, radiology information system, and PACS
allows all of a patient’s images to be made available
whenever needed. In addition to its key clinical role,
the PACS database provides a unique research and
teaching archive. A further improvement feature of
the digital imaging system is the fact that images can
be transferred electronically to other institutions.
This will have profound implications in the future for
centralization of expertise, for teaching and research
collaboration, and for improved clinical communication.50
Energy Subtraction Radiography
A further advance in digital chest radiography is
dual energy subtraction (ES) radiography. Here,
instead of a single storage phosphor plate, two plates
are used with a copper filter interposed between
them.51 The full energy spectrum of the primary
beam is recorded by the first plate as usual. Radiation passing through the first plate and filter undergoes low-energy filtration before encountering the
second plate. Thus, the image recorded by the
second plate consists mainly of the high-energy
components of the beam. By performing a weighted
subtraction of the two images, soft tissue and calcium/bone components are separated. Three chest
images are produced: a standard image; a soft tissueonly image; and a bone/calcium-only image. Dual ES
radiography can improve detection accuracy for certain types of pathology. The soft-tissue ES image
1400
clearly improves detectability of focal soft-tissue
opacities in the lungs, such as pulmonary nodules
that are obscured by overlying ribs. The “bone
images” are useful for confirming the presence of
calcification in benign pulmonary nodules, thereby
potentially obviating the need for thin-section CT.
Rib abnormalities such as sclerotic metastases, which
can mimic lung nodules, are correctly identified on
the “bone” ES images. In addition, calcified pleural
plaques easily can be differentiated from pulmonary
nodules.51
CAD
Digital radiography also provides the opportunity
for the images to be analyzed directly by the computer for the purpose of detecting, localizing, and
characterizing radiographic abnormalities.51 Digital
imaging techniques are now allowing for the development of CAD, an exciting new area of research.
CAD, the application of computer techniques to
radiologic diagnostic decision making, includes programs that enhance diagnostic images for visual
examination by separating components of the same
image (eg, ES) or by integrating different images (eg,
temporal subtraction).52 Another group of CAD
programs includes those designed to automatically
detect pathologic abnormalities in the image (eg,
nodule detection) and highlight them for the radiologist or clinician. These techniques have all proven,
in preliminary studies, to significantly increase the
film reader’s sensitivity for detecting nodules and
other subtle abnormalities.
A third form of CAD also encompasses programs
that use available clinical data, radiologic data, or
both to determine the most probable diagnosis. Such
techniques include the use of an artificial neural
network for differential diagnosis of interstitial disease or pulmonary nodules. Preliminary data has
shown that the use of this technology can significantly improve diagnostic accuracy, even for experienced radiologists.52
Summary
The past 5 to 10 years have witnessed an explosion
of new technologies for evaluating the lung. Newer
techniques have recently allowed for the possibility
of evaluating pulmonary function as well as anatomy.
Digital imaging is rapidly changing the practice of
chest radiology and is leading to the development of
CAD. Although helical CT and HRCT have become
the cornerstone of pulmonary imaging, newer modalities such as PET and MRI may soon become
critical components in the arsenal of tests used to
evaluate pulmonary disease.
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Global Theme Issue: Emerging Technology in Clinical Medicine
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