Dr. Nicholas is an Instructor of Radiology, University of
Vermont College of Medicine, Department of Radiology and Fletcher Allen
Health Care, Burlington, VT; Dr. Braff is a Resident in Radiology, University of Vermont College of Medicine and Fletcher Allen Health Care, Burlington, VT; and Dr. Klein is
an A. Bradley Soule and John P. Tampas Green and Gold Professor of
Radiology, University of Vermont College of Medicine and Fletcher Allen
Health Care, Burlington, VT.
There has been a dramatic
increase in the last decade in the utilization of multidetector computed
tomography (MDCT) in the evaluation of chest disease, resulting in an
increased detection of solitary pulmonary nodules (SPNs).1
Additionally, the recent preliminary results from the National Lung
Screening Trial (NLST) showing the effectiveness of low-dose MDCT
screening in reducing lung cancer mortality in high-risk patients will
almost certainly lead to increased utilization of chest MDCT, with a
resultant marked increase in the detection ofSPNs in asymptomatic
patients.2 Proper evaluation and management of SPNs requires
integration of clinical information with consideration of the cost and
availability of advanced imaging studies and invasive diagnostic and
therapeutic procedures. The primary goal of imaging the SPN is to
confidently determine if the lesion is benign, suspicious for
malignancy, or if indeterminate, whether it requires biopsy or
follow-up. The purpose of this article is to review the imaging features
of benign and malignant SPNs, and to provide a simplified management
algorithm for radiologists and clinicians who evaluate patients with
A solitary pulmonary nodule
(SPN) is a rounded or oval lesion measuring <3 cm in maximum diameter
and completely surrounded by lung parenchyma.3 In order to
be classified as an SPN, the lesion cannot be associated with lymph node
enlargement, atelectasis or pneumonia. SPNs have a broad differential
diagnosis (Table 1).
Artifacts and mimics of SPNs
all focal densities seen on chest radiography or CT are SPNs. Common
focal densities seen on radiography that may simulate an SPN include
overlying echocardiography (ECG) leads (Figure 1), skin lesions, bony
abnormalities, and pleural lesions. Skin features, commonly the nipples,
can mimic intrapulmonary lesions. Correlation with physical examination
and repeat radiography, perhaps with nipple or skin markers,may be
helpful in distinguishing these from SPNs. Dual-energy subtraction chest
radiography can be helpful in distinguishing calcified densities, such
as bone islands, costochondral osteophytes (Figure 2), and healing rib
fractures from lung nodules, and can more readily identify calcification
within SPNs, obviating the need for CT characterization.4
patterns of calcification seen within smoothly marginated pulmonary
nodules on thin-section CT are specific for benign etiologies.These are
central, laminated, or diffuse calcification as seen within granulomas,
and popcorn calcification seen in pulmonary hamartomas (Figure 3).5 All
other calcification patterns, including eccentric and amorphous
calcification, are indeterminate, as up to 10% of bronchogenic carcinoma
can demonstrate dystrophic calcification, and rarely a pre-existing
granuloma engulfed by malignancy can produce eccentric calcification
within a nodule (Figure 4). Rarely, solitary metastases from osteogenic
sarcoma or chondrosarcoma can demonstrate a benign calcification
pattern, although the correct diagnosis is usually readily evident from
the clinical history.
definition SPNs have a relatively spherical shape. Focal densities with a
flat or disk-like morphology can simulate an SPN when oriented in the
axial plane. Flat densities typically reflect plaque-like areas of
fibrosis or intrapulmonary lymph nodes (Figure 5). One study has shown
that a 3-dimensional ratio of >1.78 (ratio of greatest axial
dimension divided by greatest cranio-caudal dimension) has a 100%
specificity for benign etiologies.6 Benign perifissural
nodules on screening CT in current or former smokers are recognized by
their flat shape, multiplicity, distribution (ie, typically inferior to
the carina), triangular configuration, small diameter averaging 3 mm,
and the presence of an interlobular septal connection on thin-section
CT.7 Subpleural nodes are also commonly seen along the costal
pleural surfaces and demonstrate similar characteristics as
perifissural nodules. Multiplanar reconstructions and 3-dimensional
volumetric renderings can be helpful in characterizing the shape or
sphericity of these benign lesions.
60% of hamartomas will contain macroscopic fat, while only a minority
will demonstrate popcorn-type calcification. The identification of fat
attenuation within a smooth or lobulated SPN on thin-section CT is
diagnostic of a pulmonary hamartoma (Figure 6).8
A well-circumscribed, thin-walled fluid attenuation nodule without central enhancement represents a benign cyst.
Pulmonary arteriovenous malformation (PAVM)
identification of a smooth or lobulated SPN with feeding and draining
vessels extending toward the hilum from the medial aspect ofan SPN
allows for a confident diagnosis of a PAVM (Figure 7).9
mucocele is recognized as a tubular or branching opacity reflecting
mucus within an ectatic bronchus. This should be distinguished from a
nodule and is a relatively specific feature for benignity, as tumors
very rarely grow longitudinally within a central airway.
bundle of curvilinear bronchi and vessels extending from the hilar
aspect of a peripheral nodule or mass that lies adjacent to an area of
pleural thickening (the “comet tail” sign) and is associated with lobar
volume loss with displacement of an interlobar fissure on CT is
characteristic of rounded atelectasis (Figure 8). Rounded atelectasis
represents an unusual form of lung collapse that develops upon
resolution of an exudative pleural effusion, classically a benign
effusion due to asbestos exposure.10,11
Polygonal shape (concave margins)
finding of a nodule with concave interfaces with the surrounding lung
on thin-section CT has been shown to have 100% specificity for benign
etiologies, although it is an unusual finding (sensitivity = 20% to 28%
(Figure 9).6 Most often these polygonal lesions are also nonspherical on 3-dimensional analysis, another indication of their benign nature.
A cluster of small (3 to 15 mm diameter) nodules in a segment or
subsegment of lung is almost always indicative of a granulomatous
process, either from infection or sarcoidosis. Sometimes the cluster
takes the form of a dominant nodule surrounded by smaller
(“satellite”)nodules (Figure 10).12
Absence of growth >2 years
solid nodules, the absence of growth over a 2-year or greater period is
indicative of a benign SPN. Therefore any SPN should be compared to
prior radiographic or CT studies to determine if the lesion was present
previously and if so, whether there has been a change in size.
Features of SPNs suspicious for malignancy
general, the identification of a SPN >8 mm in diameter in a
high-risk patient that demonstrates imaging features suspicious for
malignancy will almost invariably undergo biopsy or resection.
opacities >3 cm are termed masses and are distinguished from SPNs
because of their much higher likelihood of malignancy, exceeding 90% in
some studies.5 Conversely, very small SPNs rarely reflect
malignancy. In the Mayo Clinic CT screening study of 1520 subjects,fewer
than 1% of nodules under 4 mm were found to be malignant.1
Lobulated or spiculated margin
compared to nodules with smooth margins, nodules with lobulated margins
are more likely to be malignant, although approximately25% of benign
nodules may have lobulated margins.13 Spiculated margins,
also described as showing a sunburst or corona radiata appearance, are
highly suspicious for malignancy (Figure 11), although this can also be
seen in benign nodules, particularly areas of resolving or organizing
pneumonia (Figure 12).5,14
Air bronchograms/bronchiolograms/cystic lucencies
SPN containing an air bronchogram, bronchiologram, or cystic lucencies
is highly suggestive of bronchogenic carcinoma, specifically
adenocarcinoma (Figure 13).15 Occasionally this finding can
be seen with lymphoma and in benign lesions such as organizing pneumonia
and sarcoidosis. For this reason, short-term follow-up of focal
opacities that may reflect infection or inflammation is a reasonable
approach to evaluation, particularly if there are symptoms suggestive of
a recent lower respiratory tract infection.
SPN that involves a peripheral bronchus, seen on CT as an endoluminal
filling defect or as bronchiectasis, mucus plugging, or peripheral
hyperlucency distal to the lesion, should suggest a malignant SPN due to
carcinoid tumor (Figure 14) or bronchogenic carcinoma, as granulomas
and hamartomas rarely arise endobronchially as depicted on CT.
Accumulating experience with CT for lung cancer screening has shown
that spherical subsolid lung nodules of pure ground glass opacity (GGO)
or mixed ground glass and soft tissue attenuation often represent
malignancy. This includes the premalignant atypical adenomatous
hyperplasia, bronchioloalveolar carcinoma and mixed subtype
adenocarcinoma (Figure 15).16 CT screening studies have shown that 34% to 43% of sub-solid SPNs are malignant.17,18
Furthermore, because of slow growth, relative hypometabolism and
nonspecific cytologic and histologic appearances, these lesions present
an additional challenge in that they are not readily identified as
malignant using growth parameters, contrast enhancement, positron
emission tomography/CT (PET/CT), or percutaneous biopsy.Recently
published expert opinion has suggested that pure GGO nodules that are
stable or growing over a 3- to 6-month follow-up period should be
resected, given the insensitivity of PET/CT and difficulties in
definitive pathologic diagnosis using percutaneous needle biopsy.19 The
same guidelines also recommend diagnostic/staging PET/CT evaluation of
mixed solid and GGO lesions >1 cm in size that are stable or growing
over a 3-to 6-month period prior to resection, as these lesions have a
higher likelihood of representing invasive tumors. Nodules <5 mm do
not necessarily require follow up, as the majority of these lesions
likely reflect benign disease, whereas pure GGO nodules 5 to 10 mm in
diameter are best followed with thin-section CT, for at least 3 years
given their inherently slow rate of change. While these guidelines are
aggressive, it is clear that given the high probability that a subsolid
nodule represents malignancy and the low diagnostic yield of currently
existing imaging and percutaneous biopsy techniques, subsolid nodules
require a different diagnostic approach than do solidSPNs.
Further characterization of indeterminate nodules
the utility of thin-section CT in SPN evaluation, a significant
percentage of SPNs will fail to demonstrate features that allow
confident characterization as either benign or likely malignant, and
will require more advanced imaging techniques for characterization.
Contrast-enhanced nodule densitometry
observation that malignant tumors are relatively hypervascular when
compared to benign lesions has led to the use of dynamic
contrast-enhanced CT and magnetic resonance (MR) studies to further
characterize indeterminate SPNs. A common protocol involves the
acquisition of images through a solid 6 to 30 mm SPN before, and 1, 2, 3
and 4 min following intravenous injection of iodinated contrast
material to measure maximum change in attenuation due to contrast
enhancement. A more elegant method of determining the degree of contrast
enhancement following a single postcontrast acquisition is with
dual-energy CT (Figure 16).20 A prospective study has shown
enhancement values of 15 Hounsfield units (HU) or less to be essentially
diagnostic of a benign etiology.21 Unfortunately, peak
enhancement>15 HU, while highly sensitive for malignancy, is
relatively nonspecific (50% to 60%), since active granulomas and other
benign lesions can demonstrate such enhancement. A more recent study
found that nodules with brisk peak enhancement of >25 HU in
combination with contrast washout of 5 to 31 HU on 15-minute-delayed
imaging showed high sensitivity (94%) and specificity (90%) for
malignancy.22 False negatives were all adenocarcinomas while
false positives included focal pneumonias and other benign nodules. Care
must be taken with the interpretation of dynamic enhancement results
for larger nodules with areas of central necrosis. Contrast-CT
densitometry is most useful in the evaluation of probably benign smaller
nodules when PET/CT or biopsy cannot be performed, and in the
evaluation of suspected carcinoid tumors presenting as SPNs, since these
tumors tend to be hypervascular (Figure 17) but are associated with an
approximately 25% false negative rate at PET/CT due to their low
(FDG) PET/CT has high sensitivity (97%) and lower specificity (78%) for
the characterization of malignantSPNs >10 mm in diameter (Figure
18).23 Malignancies that can produce false negative PET/CT
results include such well-differentiated adenocarcinomas as
bronchioloalveolar cell carcinoma and carcinoid tumors. Infections,
including granulomatous processes that present asSPNs, can produce false
positive examinations. Patients with low or intermediate pretest
probability for malignancy and a SPN >10 mm will most benefit from
PET/CT, as the results will often guide further management.24 PET/CT
is less useful in patients with very low (<5%) or very high
(>80%) pretest probability of malignancy, situations where the
results of the PET/CT study would be unlikely to change the diagnostic
approach to the patient due to relatively high false positive or false
negative rates, respectively.
A standardized uptake value (SUV)
>2.5 on FDG-PET/CT is typically used to define a positive study. The
low spatial resolution of PET imaging makes partial volume averaging an
issue in the evaluation of smaller nodules where SUV can be artificially
low. Some studies have shown that the application of size-based
correction factors to account for effects of partial volume averaging
effects can increase the sensitivity of PET/CT for malignancy in small
nodules.25 There has also been investigation of
dual-time-point imaging to exploit the propensity for malignant tumors
to show continued uptake of FDG for several hours after injection, a
characteristic not typically seen with benign lesions. With this
technique nodules are imaged twice, typically 60 min and 90 to 120min
after FDG injection. Nodules that demonstrate any increase in SUV at the
second time-point are more suspicious for malignancy. The clinical
utility of this technique remains unclear, with recent studies
recommending both for and against its use.26,27
methods exist for sampling of pulmonary nodules, including image-guided
transthoracic needle biopsy (TNB), bronchoscopicbiopsy using
fluoroscopic or electromagnetic guidance, video-assisted thoracoscopic
surgery and open thoracotomy. TNB can be performed under CT,
sonographic, or fluoroscopic guidance. Typically 20- to 22-gauge needles
can be used for aspiration biopsy to obtain cytologic specimens, while
18- to 20-gauge needles are used to obtain histologic samples when
indicated. The sensitivity for malignancy in SPNs >5mm in diameter is
>90%, while the accuracy for benign SPNs is considerably lower due
to their smaller size and nonspecific pathologic characteristics
(Figure 19).28 On-site cytopathologic analysis can be helpful
in determining the need for additional aspiration specimen for
diagnosis, obtaining material for stains and cultures when infection is
suspected, or the need for histologic samples using cutting biopsy
needles. The most frequent complications of TNB include pneumothorax
(~20%) and bleeding, both of which are usually self-limiting.29
SPNs, particularly nodules 5 to 8 mm in diameter, are most often benign
and are typically too small to be accurately characterized with PET/CT
or TNB. Most such lesions undergo follow up to monitor growth rates,
with lesions stable over a minimum of 2 years on radiographs or CT
accepted as benign, although this is likely not true for subsolid,
well-differentiated adenocarcinomas. For measuring growth rates, nodule
volume doubling time (VDT) has been used to help distinguish benign from
malignant solid nodules. Doubling time (Td) is calculated with the
Td = Ti x log 2/3 x log (Di/ Do) where
Ti = interval time, Di = initial diameter, Do = final diameter and
nodule diameter represents the average of 2 orthogonal measurements
through the center of the nodule.30 A diameter increase of
26% in a spherical SPN corresponds to a doubling of nodule volume. Most
malignant SPNs have doubling times in the 3-month to 1.5-year range,
while benign lesions typically grow more rapidly (ie, and infectious
lesion) or more slowly (ie, a hamartoma or granuloma) than malignant
lesions. In actual practice, any growth of a small indeterminate SPNas
detected on follow-up CT will likely prompt biopsy or resection given
the significant overlap in doubling times between benign and
slow-growing malignant lesions. Supporting this approach are the results
of recent CT screening studies that have found VDTs exceeding 450 days
and up to 928 days for malignancy, typically slow growing and less
Because of the
difficulty in measuring diameter changes of 1 to 2 mm on CT (an increase
in diameter that represents a doubling in volume of nodules in the 5 to
8 mm range), and the fact that lesions may not always grow in a
symmetric fashion, there has been significant interest in the use of
computer-aided analysis of multidetector CT datasets with volumetric
nodule analysis obtained during short follow-upperiods of 90 to 180
days.32,33 While these programs can be useful, they have
difficulty in segmenting subsolid lesions or lesions adjacent to vessels
or the pleura, are not always customizable by the operator, have yet to
complete outcome validation studies, and for the most part are not
integrated into picture archive and communication systems (PACS) to
allow easy access and efficiency of workflow in the clinical
environment. For these reasons these automated software programs have
not yet entered widespread use. Nevertheless, it is likely that with
advances in technology and PACS integration these programs will become
an important adjunct in the evaluation of small SPNs in the near future
Recommended approach to SPNs
Fleischner Society has published an evidence-based expert opinion
recommendation for the follow-up and management of incidental small
pulmonary nodules in patients >35 years. These recommendations are
based on the stratification of patients into high- and low-risk
categories (based upon lung cancer risk factors, including smoking
history, exposure to asbestos, uranium, radon, or a history of lung
cancer in first-degree relatives) and the size of the nodule. Nodules
<4 mm in low-risk patients do not require follow up. All other
nodules require follow up as outlined in Figure 21.34
present an imaging algorithm for the evaluation of SPNs that we have
employed at our institution, which is detailed in Figure 22. It should
be recognized that differences in patient populations, patient
socioeconomic and psychological factors, regional expertise, and
accessto advanced imaging modalities will lead to different approaches
at each facility.
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