is a Nuclear Medicine Fellow, Department of Radiology;
is a Musculoskeletal Fellow, Department of Radiology;
is a Professor of Radiology and Director of the Radiology
Residency Training Program, Radiology Department, and the Vice
Chairman of Education, The University of North Carolina School of
Medicine, Chapel Hill, NC.
is also a member of the editorial board of this journal.
The solitary pulmonary nodule (SPN) is a common and often
incidental radiologic abnormality. An estimated 130,000 new nodules
are identified each year in the United States.
Solitary pulmonary nodules are seen in 0.09% to 0.2% of chest
The presence of a pulmonary nodule raises questions and concerns
both to the patient and the physician, as it may represent lung
cancer or a solitary metastasis.
Most SPNs are benign; only 30% to 50% are malignant.
Solitary pulmonary nodules can be the initial presentation of lung
cancer in 20% to 30% of patients.
Various series have shown that the 5-year survival rate after
resection of a solitary bronchogenic carcinoma is 40% to 80%.
Therefore, the detection of the nodule may be the first and only
chance of cure in the patient with lung cancer. It is equally
important to identify benign lesions correctly, so as to avoid the
morbidity and mortality associated with thoracotomy. The goal of
radiologic evaluation of the suspected nodule is to noninvasively
and accurately differentiate benign from malignant lesions.
A solitary pulmonary lesion or a "coin" lesion has been defined
as a single spherical intraparenchymal opacity, completely
surrounded by lung without any associated atelectasis or adenopathy
and ≤3 cm in maximum diameter
(Figure 1). Solitary lesions ≤6 cm in size were previously
included, but it is now recognized that lesions >3 cm (now
) are almost always malignant.
Hence, the current convention is that SPNs are ≤3 cm in diameter.
Further, the detection of patterns of calcification in an SPN
allows confident diagnosis of benignity only when the nodule is
<3 cm in size.
The causes of an SPN comprise a variety of benign and malignant
processes (Table 1). Of the benign lesions, 80% are caused by
infectious granulomas, 10% by hamartomas, and the remaining 10%
encompass other rarer disorders, including noninfectious granulomas
and benign tumors.
Most malignant SPNs are bronchogenic carcinomas. Metastases from
extrapulmonary tumors constitute 10% to 30% of all malignant SPNs.
The Bayesian analysis has been used to determine the probability
of malignancy (pCa) in a nodule. This method assigns a likelihood
ratio (LR) for various clinical and radiological features
associated with the SPN to estimate the pCa. Clinical factors that
have been found to be associated with a high probability of
malignancy include advanced age at presentation, smoking history,
symptoms (especially hemoptysis), presence of previous malignancy,
exposure to carcinogens, and coexisting or prior pulmonary diseases
The most important radiographic characteristics to be considered
for assigning an LR are: size, margin, contour, thickness of cavity
wall, and pattern of calcification.
The LR for a given characteristic is derived as follows:
LR = No. of malignant nodules with the feature
No. of benign nodules with the same feature
An LR of 1.0 indicates a 50% chance of malignancy. Likelihood
ratios <1.0 indicate a benign lesion and LRs >1.0 typically
indicate a malignant lesion. By combining the LRs for all the
variables of a particular nodule, the odds of malignancy (Odds
) is calculated as follows:
Odds = LR
where LR is LR prior malignancy, LR
is LR size, LR
is LR smoker, LR
is LR edge, and LR
is LR calcification.
The pCa is calculated as follows:
pCa = Odds
The likelihood ratios for several clinical and radiographic
variables have been calculated and can be found in standard
A probability calculator using the Bayesian analysis to estimate
the pCa for any SPN can be found on Dr. J. Gurney's Web site at
The Bayesian analysis has not gained widespread use because of
the large number of variables to be considered, as well as the lack
of standardization due to differences in local practice. Further,
this approach was used before the advent of newer advanced imaging
technology, such as contrast-enhanced and thin-section computed
tomography (CT) and, recently, positron emission tomography (PET).
Recent studies have shown that a PET scan used as a single test
alone has the highest reliability in correctly classifying nodules
as benign or malignant.
This was found to be higher than Bayesian analysis using standard
Chest radiography (CXR) is the primary initial imaging modality
for most SPNs. The first step is to determine if the nodule is
actually within the lung. Equally important is to determine if the
lesion is new and to demonstrate any change in pre-existing
lesions. In the evaluation of an SPN, it is extremely important to
review prior CXRs for comparison. Stable appearance for 2 years is
more suggestive of a benign lesion, while growth and interval
development are more likely with a malignant condition
Chest radiographs provide useful information regarding nodule
size, contour, margin characteristics, calcification, cavitation,
presence of satellite lesions, and growth rate. Size <2 cm,
smooth contour, sharp margins, presence of satellite lesions,
absence of cavitation, and a slow or very fast doubling time (ie,
the time taken for the nodule to double in volume, which results in
a 25% increase in diameter for a spherical lesion) are associated
with benign lesions.
Most benign nodules have been shown to have smooth, well-defined
margins, while only 21% of malignant nodules have been shown to
have smooth margins.
sign (fine linear strands extending away from the nodule) is
associated with malignancy in 88%
Calcification within a nodule can also be of use in
differentiating benign from malignant lesions. Diffuse
calcification patterns are often associated with a benign
condition. The presence of laminated or central calcification is
typical of a granuloma, and popcorn calcification is most often
seen in hamartomas (Figure 4). Stippled or eccentric patterns of
calcification are more often associated with malignancy. On
standard CXRs, the sensitivity and specificity in detecting
calcification have been reported to be 50% and 87%, respectively.
The presence or absence of calcification in an SPN, as well as
differentiation of benign from malignant lesions, should not be
made with certainty using CXR criteria alone. CT is more sensitive,
specific, and accurate in this regard.
CT has become almost standard procedure in the investigation of
an SPN, to confirm the presence of the nodule and for further
morphological evaluation. CT can detect a nodule not identified by
CXR or may detect multiple nodules. It also clearly defines whether
the nodule is intrapulmonary, rather than within the pleura or
chest wall. CT provides an accurate assessment of nodule size,
contour, margin, and presence or absence of calcification. In
addition to conventional CT, thin-slice CT and high-resolution CT
(HRCT) are often used for further evaluation of the nodule.
The size of the SPN influences the probability that it is
malignant. Generally, benign lesions are smaller overall than
malignant ones. Although 80% of benign nodules are <2 cm in
size, the small size does not reliably exclude malignancy, as 15%
of malignant nodules are <1 cm in diameter and approximately 42%
are <2 cm in diameter.
In SPNs >3 cm in diameter, the likelihood of malignancy
Scanning with thin collimation and particularly HRCT is superior to
conventional CT in delineating the size and morphology of the
Observation of nodule growth is important in monitoring and
predicting outcome, especially in smaller nodules. This can be done
either with serial CXRs or CT scanning. Chest radiographs are
two-dimensional depictions, while nodules are generally spheres;
therefore, volumetric assessment of the nodule using CT is more
reliable and accurate in estimating growth.
The use of helical CT for monitoring SPN growth rates has become
an integral part of radiological evaluation of the SPN. Computer
programs that allow volumetric assessment of the nodule are now
available on CT. These techniques are more accurate and more
reproducible than are manual methods; they are also more sensitive
to small changes in volume that are not easily detectable on
standard two-dimension-al imaging.
Computer software programs can segment scans of SPNs and calculate
nodule volume to within an accuracy of 3%.
Early repeat CT, obtained 30 days after the initial scan, has been
shown to depict growth in most malignant tumors as small as 5 mm.
Growth rate measurements are generally based on estimating the
doubling time. The concept of doubling time is based on the fact
that the rate of tumor growth is exponential. Published series have
estimated the doubling time for most malignant tumors to range from
30 to 450 days, depending on the histology.
Thus, nodules that exhibit either a very rapid or a slow growth
rate are considered to be benign. Conventionally, stability over a
2-year time period has been accepted as a strong indicator of
Margins and contour
CT confirms the CXR findings and provides further information
regarding the margin and contour of the nodule. Margins of the
nodule are often categorized as smooth, lobulated, irregular, or
spiculated. Although most nodules with smooth, well-defined margins
are benign, 21% of malignant nodules can also have a smooth,
On the other hand, up to 58% of nodules with lobulated margins and
89% of nodules with irregular or spiculated margins are malignant
(Figure 5). However, 10% of nodules with spiculated margins are
; and 25% of benign nodules, especially hamartomas, can have
More recently, studies using HRCT reported that all nodules with
a halo margin, 97% with densely spiculated, 93% with ragged, 82%
with lobulated, 34% with round, and 20% with polygonal margins were
As there is significant overlap in the margin characteristics of
benign and malignant nodules, this feature cannot be used as a sole
predictor of malignancy.
Thin-section CT provides other features of the margins that can
be of diagnostic value. The presence of satellite nodules at the
periphery of a smooth dominant nodule is most suggestive of
The halo sign (presence of ground-glass opacity surrounding the
nodule) when present in a neutropenic patient is highly indicative
The presence of feeding and draining vessels entering the hilar
aspect of a smooth or lobulated nodule is often associated with
The internal density and the presence of calcification, fat, or
cavitation within a nodule provide additional information in
evaluating the SPN (Figures 6 and 7). In 1980, Seigelman et al
described the use of CT in identifying calcium in nodules. They
concluded that nodules with representative CT numbers >164 HU
were benign. CT scanning has a greater ability to detect
calcification than does CXR. Approximately 22% to 36% of nodules
considered as noncalcified by conventional CXRs are shown to
contain calcium on CT.
Definitive identification of calcification usually requires
thin-section CT using 1- to 3-mm collimation, reconstructed with a
high spatial frequency algorithm. A multicenter study using CT to
evaluate SPN showed that thin-section CT was better than standard
CT by 23.7% in the detection of calcification.
Dual-kilovolt peak CT scanning has also been used to detect
nodules with low levels of calcification. A recent prospective
study failed to show added clinical utility of using this method
for detection of calcification,
hence, this method has not been widely used in practice.
Other internal characteristics, such as the presence of fat,
cavitation, and homogeneous attenuation, are also considered in
evaluation of an SPN, but there is considerable overlap in these
features among benign and malignant nodules. The presence of
intranodular fat in an SPN with a smooth or lobulated margin is a
reliable indicator of hamartoma. Fat is seen in up to 50% of
hamartomas and is best visualized on thin-section CT.
Cavitation can occur in benign infiammatory lesions, as well as in
necrotic carcinomas (Figure 8). Benign cavities generally have
smooth, thin walls, whereas malignant nod-ules have thick,
irregular walls. Cavities with a wall thickness <5 mm are
usually benign, while those with a wall thickness >15 mm are
Homogeneous nodule attenuation is observed on thin-section CT in
55% of benign and 20% of malignant nodules.
There are distinct differences in the vascularity of benign and
malignant nodules. Malignant lesions are relatively hypervascular
compared with benign nodules. Theoretically, the level of
enhancement of a nodule depends on the amount of contrast material
that enters the extravascular space and on the degree of
vascularity of the nodule. In a large multicenter prospective
trial, Swensen et al
found that nodule enhancement <15 HU is strongly predictive of
benignity. With 15 HU as the threshold, the sensitivity for
detecting malignancy was 98%, for detecting specificity was 58%,
and for detecting accuracy was 77%. False-negatives can be caused
by central necrosis or mucinous neoplasms, such as bronchoalveolar
carcinoma, and false-positives can be caused by active infectious
Assessment of nodule enhancement after intravenous contrast
administration can be accomplished with the use of power injectors
and rapid data acquisition with helical CT. With helical CT, it is
possible to perform both the lung nodule enhancement assessment and
an optimally contrast-enhanced CT examination of the chest and
abdomen with the same injection of contrast material.
A suggested protocol is as follows: A spiral series of scans
through the chest is obtained after a delay of 20 seconds from the
onset of injection. Then, 1 minute after the onset of injection,
3-mm collimation spiral imaging through the nodule with a 1-mm
reconstruction interval is performed for 5 seconds. Between 1 and 2
minutes after injection onset, spiral images are obtained through
the lower chest and upper abdomen. Finally, spiral sections through
the nodule are obtained at 2, 3, and 4 minutes after the onset of
This combined protocol has been shown not to increase the cost or
the time to complete the examination. This technique should be used
in SPNs with a diameter <2 cm, as lesions larger than these have
a higher false-negative rate. Lesions <8 mm in size, cavitary
lesions, and nodules with central necrosis are not amenable to CT
Positron emission tomography
Positron emission tomographic (PET) scanning using Fluorine-18
(F-18) fiuorodeoxyglucose (FDG) emerged as a powerful modality in
the diagnosis and staging of malignancy in the early 1990s.
Positron emission tomography provides unique information that is
not available from other imaging modalities because of its ability
to image in vivo chemistry qualitatively and quantitatively.
On January 1, 1998, the Health Care Financing Administration
(HCFA) and various insurance companies in the United States
approved PET scanning for the evaluation of SPN.
The cyclotron-produced F-18 is attached to deoxyglucose to form
fiuorodeoxyglucose. Due to the relatively long half-life (110
minutes) of F-18, FDG is available commercially as a unit dose from
many sites on a regional basis. The availability of less expensive
PET scanners and the convenient access to the positron emitter FDG
has resulted in greater use of this technique.
The rationale of imaging with FDG is based on a basic property
of tumor cells-namely, increased glucose metabolism. In 1956,
described that malignant cells have an increased rate of
glycolysis. This is associated with increased activity of
glycolytic enzymes, namely hexokinase, 6-phosphofructokinase, and
pyruvate dehydrogenase, as well as increased membrane glucose
transport capability. FDG is recognized by these glucose
transporter proteins and enzymes, but after the initial step of
phosphorylation, FDG-6-phosphate is trapped and cannot continue the
normal pathway. This leads to increased FDG accumulation in
malignant cells, thus producing a detectable signal. As FDG
competes with serum glucose for cellular uptake, the blood glucose
level should be as low as possible physiologically. In order to
achieve this, patients are required to fast for at least 4 hours
prior to FDG administration.
FDG emits positrons that travel a few millimeters before
annihilating with an electron. This leads to the production of two
511 KeV photons in 180º opposite to each other. Simultaneous
detection of these photons produces a signal, which is used to
reconstruct the final image. Abnormal FDG uptake can be determined
either by simple visual inspection, or can be analyzed
semiquantitatively by calculating the standardized uptake value
(SUV). In general, an SUV >2.5 has been used as an indicator of
On visual inspection, an SPN that is hypermetabolic (ie, intensity
greater than the mediastinum) is considered malignant (Figure
Various series have reported the sensitivity of FDG-PET in
determining malignancy in SPNs to range from 83% to 100%;
specificity to range from 63% to 90%; accuracy to range from 86% to
98%; and the negative predictive value to be 95%.
The size of the lesion is an important determinant of the
sensitivity and specificity of FDG-PET imaging. A prospective
multicenter study of SPNs reported that the sensitivity and
specificity were 80% and 95%, respectively, in nodules ≤1.5 cm and
96% and 80%, respectively, in nodules >1.5 cm.
The study also found that visual inspection of the nodule was
equally accurate, with a sensitivity of 100% and specificity of 74%
in nodules ≤1.5 cm, and a sensitivity of 98% and specificity of 80%
in nodules >1.5 cm. It is important to note that as the
sensitivity of detection improves with a larger nodule, the
False-positives can occur and are primarily due to increased
glycolytic activity within activated macrophages. Common causes of
false-pos-itives are active granulomatous diseases, such as
tuberculosis, fungal infections (Figure 10), and sarcoidosis. Other
causes include silicoanthracosis, lipoid pneumonia, talc granuloma,
postobstructive pneumonia, and radiation pneumonitis.
False-negative scans occur with small lesions near the spatial
resolution of the scanner (approximately 6 mm), elevated serum
glucose levels that cause competitive inhibition of FDG uptake, and
inherently low-grade malignancies, such as bronchoalveolar
carcinoma. Bronchial carcinoid and mucinous neoplasms are
additional causes of false-negative FDG-PET scans (Figure 11).
Much work is being directed at observing the FDG uptake in the
suspected nodule over time following injection. Delayed scanning is
performed through the region of interest, and FDG uptake is
estimated either visually or by calculating SUV. As a general rule,
malignancies demonstrate a continually increasing uptake of FDG
Infiammatory lesions show gradual washout of FDG after a period of
initial increase. This dual-point imaging can increase the
specificity of FDG-PET assessment of SPNs by decreasing
false-positive scans secondary to infection or infiammation.
A recent meta-analysis of the accuracy of FDG-PET scans in the
diagnosis of pulmonary nodules determined that the joint maximum
sensitivity and specificity of FDG-PET was 91.2% (95% confidence
interval, 89.1% to 92.9%) for lesions of any size.
In current practice, most FDG-PET scanners are operated at a
threshold set to provide a sensitivity and specificity of 96.8% and
77.8%, respectively, in order to decrease false-negative results.
The corresponding likelihood ratios for positive and negative test
results are 4.36 and 0.04, respectively. The study also showed that
semi-quantitative analysis of the nodule did not improve the
accuracy of FDG-PET.
Positron emission tomographic scanning is an accurate test for
identifying malignancy in SPNs, but little information exists about
FDGPET performance in nodules <1 cm in diameter. Because the
lesion detectability on most current PET scanners is 7 to 8 mm, the
use of FDGPET for smaller nodules should await further
technological advances. An SUV of ≥2.5 or an intensity higher than
the mediastinum on visual inspection is the accepted criteria for
malignancy for nodules >1 cm in diameter (Figure 12). In a
nodule <1 cm, any FDG uptake should be considered suspicious for
An important issue to be addressed is whether or not the use of
FDG-PET helps in clinical decision making. Patients with a positive
FDGPET study require further evaluation by biopsy and/or treatment.
The negative predictive value of FDG-PET depends on the pretest
probability of malignancy. In high-risk patients (pretest
probability of malignancy = 80%) with a negative FDG-PET, the
post-test probability of malignancy can be as high as 14%,
and these patients need further evaluation by biopsy. For low-risk
patients (pretest probability of malignancy = 20%), a negative
FDG-PET has a post-test probability of approximately 1%.
FDG-PET cannot be evaluated correctly without consideration of
the anatomic information provided by CT. In the future, the routine
use of combined-modality PET/CT scanners will add the anatomic
detail necessary. Software programs are available that can fuse the
CT and PET images for image overlay and easy interpretation.
In centers in which dedicated PET scanners are not available,
multihead conventional gamma cameras, which are readily available
in most nuclear medicine departments, can be equipped with
ultrahigh-energy collimators to allow single-photon emission
computed tomography (SPECT) imaging using FDG. The spatial
resolution and sensitivity of the SPECT systems are inferior to the
dedicated PET scanners. Published series have reported a
sensitivity of 100% and a specificity of 90% for lesions >2 cm,
while sensitivity decreased to 50% for lesions <2 cm.
The main disadvantage is the inability to detect lesions <2 cm
in size. Coincidence detection SPECT cameras without collimators
have also been used for FDG imaging.
These techniques provide valuable information when dedicated PET
scanners are not available to the institute. Gould et al
have recently shown that accuracy was similar for studies performed
on a dedicated PET scanner to those performed using a modified
gamma camera. However, their estimates were based on a few small
studies and additional research is needed to clarify this
There is no single correct management approach to the SPN in all
patients; the clinical findings and the associated risk factors
must be taken into consideration to determine the etiology
cost-effectively. Whenever possible, comparison with previous CXR
should be performed.
Benign SPNs are those that demonstrate stability over 2 years
and/or characteristic benign features on CT. In low-risk groups
(ie, patients <35 years of age without additional risk factors),
follow-up with serial CXR or CT is recommended to decrease the
number of benign nodules resected.
Malignant SPNs are those with definite features of malignancy on
CXR or CT. In high-risk groups (ie, older patients with additional
risk factors), tissue sampling and/or resection is warranted.
In clinical practice, most SPNs are classified as radiologically
indeterminate. The management of the indeterminate pulmonary nodule
remains controversial and depends largely on the individual
physician's approach, as well as patient preferences and
co-morbidities. It is important to consider the surgical risk and
whether it is acceptable for the given probability of malignancy in
each individual patient. In a patient with minimal surgical risk,
surgery or tissue sampling may be performed even with a lower
probability of malignancy. However, in older patients with
concurrent medical illnesses and a high surgical risk, avoiding
unnecessary surgery becomes more important (Figure 13). The
location of the SPN (peripheral versus central) also plays an
important role in management. For a central nodule, a lobectomy may
be needed for excision and is much more extensive than a wedge
resection of a peripheral lesion. Equally important is to determine
whether additional diagnostic testing will alter the treatment
plan. Additional tests are most useful if a negative test result
would be sufficient for the clinician to defer surgery and elect a
strategy of careful observation. If there would be no change in the
treatment plan irrespective of the diagnostic result, then
proceeding to surgery is the accepted choice.
In current practice, the preferred ap-proach to an indeterminate
nodule on CT is FDG-PET scanning. Positron emission tomo-graphic
scanning allows more precise risk stratification for patients with
indeterminate nodules. If the PET scan is negative, follow-up with
serial CT scans at 6-month intervals for 2 years is recommended. A
positive PET scan requires further investigation either by biopsy
Gambhir et al
compared "watch and wait," surgery, serial CT, and CT plus PET for
the evaluation of SPNs and estimated that the potential cost
savings using CT plus PET ranged from $91 to $2200 per patient.
Depending on the pretest probability, FDG-PET has decreased
surgical procedures by an estimated 15%.
This translates to a yearly national savings of $62.7 million by
decreasing the need for thoracotomies and transthoracic needle
The SPN is a common radiologic finding. There is no single
correct management approach, and the workup can often involve
extensive and expensive evaluation. Comparison with prior
examinations, if available, should always be the first step in
evaluation. Additional imaging with con-trast-enhanced CT and PET
can provide valuable additional information. However, further
imaging techniques should be used with the understanding of the
true impact of the tests in clinical practice for each patient.
The authors would like to thank Dr. Marija Ivanovic, PhD, for
her assistance in acquiring the multiple PET images, without which
this article would not have been possible.