Lung Nodule Enhancement at CT: Multicenter Study

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http://www.radnet.ucla.edu/imageanalysis/lung_nodule_detection.htm


http://intl
-
radiology.rsnaj
nls.org/cgi/content/full/214/1/73






(
Radiology.

2000;214:73
-
80.)

©
RSNA
, 2000


Thoracic Imaging

Lung Nodule Enhancement at
CT: Multicenter Study
1


Stephen J. Swensen, MD, Robert W
. Viggiano,
MD, David E. Midthun, MD, Nestor L.
Müller, MD, Andrew Sherrick, MD, Keiji
Yamashita, MD, David P. Naidich, MD,
Edward F. Patz, MD, Thomas E. Hartman,
MD, John R. Muhm, MD and Amy L. Weaver,
MS

1

From the Dept of Diagnostic Radiology (S.J.S.,
T.E.H.) and Div of Pulmonary and Critical Care Medicine
and Internal Medicine (D.E.M.), Mayo Clinic and Mayo Foundation, 200 First St SW, Rochester, MN
55905; Div of Pulmonary Medicine (R.W.V.), Dept of Diagnostic Radiology (J.R.M.), and Section of
Biostat
istics (A.L.W.), Mayo Clinic Scottsdale, Ariz; Dept of Diagnostic Radiology, Vancouver General
Hospital, British Columbia, Canada (N.L.M.); Dept of Diagnostic Radiology, Memorial Medical Center,
Springfield, Ill (A.S.); Dept of Diagnostic Radiology, Shiga
Health Insurance Hospital, Otsu, Japan (K.Y.);
Dept of Diagnostic Radiology, New York University Medical Center, NY (D.P.N.); Dept of Diagnostic
Radiology, Duke University Medical Center, Durham, NC (E.F.P.). Supported in part by grants from GE
Medical Sys
tems, Bracco Diagnostics, and the Mayo Foundation. Recd Sept 22, 1998; revision reqd Nov
10; final revision recd Apr 15, 1999; accepted Apr 22.
Address reprint requests to

S.J.S.






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PURPOSE:

To test the hypothesis that absence o
f
statistically

significant lung nodule enhancement (
15
HU) at computed tomography

(CT) is strongly predictive
of benignity.


MATERIALS AND METHODS:

Five hundred fifty
lung
nodules were

studied. Of these, 356 met all entrance
criteria and had a diagnosis.

On nonenhanced, thin
-
section CT scans, the nodules were
solid,

5

40 mm in diameter, relatively spherical, homogeneous,

and without calcification
or fat. All patients were ex
amined

with 3
-
mm
-
collimation CT before and after
intravenous injection

of contrast material. CT scans through the nodule were obtained

at
1, 2, 3, and 4 minutes after the onset of injection. Peak

net nodule enhancement and time
-
attenuation curves were anal
yzed.

Seven centers participated.


RESULTS:

The prevalence of malignancy was 48% (171 of 356 nodules).

Malignant
neoplasms enhanced (median, 38.1 HU; range, 14.0

165.3

HU) significantly more than
granulomas and benign neoplasms

(median, 10.0 HU; range,
-
20
.0 to 96.0 HU;
P

< .001).
With

15 HU as the threshold, the sensitivity was 98% (167 of 171

malignant nodules), the
specificity was 58% (107 of 185 benign

nodules), and the accuracy was 77% (274 of 356
nodules).


CONCLUSION:

Absence of significant lung nodu
le enhancement (
15

HU) at CT is
strongly predictive of benignity.


Index terms:

Lung, CT, 60.12112, 60.12115 • Lung, nodule, 60.281 • Lung neoplasms,
CT, 60.12112, 60.12115
• Lung neoplasms, diagnosis, 60.30






Introduction



Evaluation of the solitary pulmonary nodule remains a substantial

and costly challenge in
modern medicine. Approximately 50% of

indeterminate lung nodules for which surgery
is performed
for

diagnosis are benign (
1

4
). Hospitalization for surgical

removal of a
nodule costs about $25
,000 (
5
). A means short of

biopsy that diagnostic radiologists can
Top

Abstract

Introduction

MATERIALS AND METHODS

RESULTS

DISCUSSION

References


Top

Abstract

Introduction

MATERIALS AND METHODS

RESULTS

DISCUSSION

References


use to substantially

reduce the percentage of benign nodules for which surgery is

performed for diagnosis is
desirable.


There are distinct differences in the vascularity and vasculature

of benign and malignant
modules (
6

19
). These differences

may offer an opportunity to distinguish benign from
malignant

lung nodules by using radiologic imaging technology. Researchers

have shown,
with every modality at their disposal, that lung

malignancies enhance more t
han benign
lung nodules. This has

been shown with angiography (
8
,
11
,
12
,
15
,
20
), contrast material

enhanced

co
nventional tomography (
21
), 2
-
[fluorine 18]fluoro
-
2
-
deoxy
-
D
-
glucose

positron emission tomography (PET) (
22

25
), gadolinium
-
enhanced

magnetic resonance
imaging (
26
,
27
), Doppler ultrasonography

(
28
,
29
),
and contrast
-
enhanced computed
tomography (CT) (
30

32
).

Others have shown that differential no
dule enhancement may
help

to distinguish benign from malignant lesions in the breast (
33
,
34
),

adrenal gland
(
35
), and kidney (
36
). Are any of these techniques

accurate enough in distinguis
hing
benign from malignant lung

nodules to be clinically useful?


A multicenter study was organized to test the following hypothesis:

Absence of
significant lung nodule enhancement (
15 HU) at CT

is strongly predictive of benignity.







MATERIALS AND METHODS



Between August 1995 and June 1997, we studied solid lung nodules

in 550 patients.
Nodules in 169 patients did not meet the entrance

criteria. Thus, a tota
l of 356 patients
(175 men, 181 women;

age range, 21

89 years; mean age, 64.3 years) had a nodule

with a
clinical or histologic diagnosis and a technically adequate

lung nodule enhancement
study. Seven centers participated in

this prospective study: Mayo C
linic Scottsdale, Ariz
(
n

= 134

[37.6%]); Mayo Clinic Rochester, Minn (
n

= 122 [34.3%]); Vancouver

General
Hospital, British Columbia, Canada (
n

= 49 [13.8%]);

Memorial Medical Center,
Springfield, Ill (
n

= 28 [7.9%]); Shiga

Health Insurance Hospital, Otsu
, Japan (
n

= 25);
New York University

Medical Center, NY (
n

= 17 [4.8%]); and Duke University Medical

Center, Durham, NC (
n

= 6 [1.7%]). The Japanese data were analyzed

separately because
they used a different enhancement protocol.


Top

Abstract

Introduction

MATERIALS AND METHODS

RESULTS

DISCUSSION

References


On nonenhanced, thin
-
se
ction CT images, the nodules were solid,

relatively spherical,
homogeneous, and without calcification

or fat. They were solitary on chest radiographs
but not necessarily

on CT images. Nodules measured 5 mm or larger in diameter. The

diameter was calculated

as a mean of the short
-

and long
-
axis

diameters at lung
-
window
settings on transverse CT images. All

patients were examined with 3
-
mm
-
collimation CT
before and after

the administration of contrast material (2 mL/sec; 300 mg of

iodine per
milliliter; 420 m
g of iodine per kilogram of body

weight). A 15
-
mm z
-
axis cluster of
scans was obtained through

the nodule at 1, 2, 3, and 4 minutes after the onset of
injection.

Peak nodule enhancement and time
-
attenuation curves were analyzed.


The nodules had to be rela
tively spherical (ie, short
-

and long
-
axis

diameters were within
a factor of 2 of each other). Nodules

were excluded if they had calcification or fat on thin
-
section

(1

3
-
mm
-
collimation) CT images (
2
,
37

39
). In the

judgment of the attending
radiologist (including S.J.S.
, N.L.M.,

A.S., K.Y., D.P.N., E.F.P., T.E.H., J.R.M.), there
was no substantial

CT artifact in the region of the nodule (eg, cardiac motion

artifact or
beam
-
hardening artifact from adjacent bone). All

nodules were relatively homogeneous
on preenhancement s
ections

(
Fig 1
) in
the judgment of the attending radiologist (ie, no

signs of necrosis, cavitation, calcification, or a low signal
-
to
-
noise

ratio) (
40
). Recent
(<1
-
month) transthoracic needle as
piration

biopsy of the nodule was an exclusion
criterion, because postbiopsy

hemorrhage in theory could result in decreased
enhancement,

which would lead to false
-
negative results.





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Figure 1a.

(a)

Transverse, nonenhanced spiral CT
image (3
-
mm collimation) through a relatively
homogeneous 15
-
mm right upper lobe lung
adenocarcinoma recurre
nce in a 71
-
year
-
old woman.
Note the manually placed region of interest (
1

) on a
nodule. The region of interest is positioned centrally,
and its shape approximates that
of the nodule on the
cross
-
sectional image. Its net enhancement value was
14 HU. This was one of the four false
-
negative
results.
(b)

Photomicrograph of this adenocarcinoma
shows an appearance consistent with lymphangitic
metastasis. Note the central zone
of necrosis (arrows).
There is little vascular stroma, which may have been
a factor in its relatively low enhancement value.
(Antibody to factor VIII
-
associated antigen; original
magnification,
x
50.)







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Figure 1b.

(a)

Transverse, nonenhanced spiral CT
image (3
-
mm collimation) through a relatively
homogeneous 15
-
mm right upper lobe lu
ng
adenocarcinoma recurrence in a 71
-
year
-
old
woman. Note the manually placed region of interest
(
1

) on a nodule. The region of interest is
positioned centrally, and its

shape approximates
that of the nodule on the cross
-
sectional image. Its
net enhancement value was 14 HU. This was one of
the four false
-
negative results.
(b)

Photomicrograph
of this adenocarcinoma shows an appearance
consistent with lymphangitic metastasi
s. Note the
central zone of necrosis (arrows). There is little
vascular stroma, which may have been a factor in
its relatively low enhancement value. (Antibody to
factor VIII
-
associated antigen; original
magnification,
x
50.)




All patients were referre
d for CT examination of a known pulmonary

nodule. Patients
who were allergic to iodinated contrast material

or who had creatinine levels of 1.5
mg/dL (133 µmol/L)

or greater were not enrolled. All patients were able to consistently

reproduce approximately
the same degree of inspiration on preenhancement

images. The
study protocol received institutional review board

approval at each institution.


Studies were performed with a HiSpeed Advantage (GE Medical

Systems, Milwaukee,
Wis) (
n

= 222), CT
-
Twin/RTS (Elsc
int, Hackensack,

NJ) (
n

= 134), or Quantex (GE
-
Yokogama Medical Systems, Tokyo,

Japan) (
n

= 25) scanner.


Preenhancement analysis consisted of analysis of 3
-
mm
-
collimation

spiral scans (pitch,
1:1) obtained through the entire nodule.

After the administrati
on of contrast material,
serial, 5
-
second,

3
-
mm
-
collimation spiral acquisitions were performed at 1
-
minute

intervals, beginning 1 minute after injection onset, for a total

of four acquisitions. The
following technique was used: 3
-
mm
-
collimation

spiral scan
ning with 2
-
mm
reconstruction intervals, 120 kVp,

280 mA, pitch of 1:1, 5
-
second scanning time, standard
reconstruction

algorithm, and 15
-
cm field of view.


We compared the median preenhancement attenuation among three

groups: (
a
) malignant
neoplasms, (
b
)
granulomas and benign nodules

at observation, and (
c
) benign neoplasms
and other benign nodules.


The dose of iodinated, low
-
osmolarity, nonionic contrast material

administered
intravenously was based on patient weight (
Table 1
).

All patients were carefully
instructed by a technologist

or radiologist (including S.J.S., N.L.M., A.S., K.Y., D.P.N.,

E.F.P., T.E.H., J.R.M.) that it was important to reproduce precisely

the same deg
ree of
inspiration. Patients were instructed to

"take a small breath in and hold it."




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TABLE 1. Contrast Material Doses




The degree of enhancement for each examination was quantified

in Hounsfield units by
one of the investigator chest radiologists

(S.J.S., N.L.M., A.S., K.Y.,

D.P.N., E.F.P.,
T.E.H., J.R.M.).

All measurements were made at the time of the CT examination

without
knowledge of the histologic diagnosis. A single region

of interest was carefully
constructed to approximate the transverse

shape of the nodule (
Fig 1
).


The region
-
of
-
inter
est diameters were approximately 70% of the

lung nodule's short
-

and
long
-
axis diameters as measured at

mediastinal window settings on transverse images. All
Hounsfield

unit measurements were performed on mediastinal
-
window images

to ensure
that partial vo
lume averaging was minimized.


The circular or oval region of interest was centered on the

image closest to the nodule
equator. The nodule equator was

identified by using lung
-
window settings in which small
vessels

could be visualized and could be used to
locate the same z
-
axis

level for the
multiple, serial Hounsfield unit measurements.

Nodule enhancement was defined as the
difference between the

maximum mean Hounsfield unit nodule measurement in the 4
minutes

after contrast material administration and the

preenhancement

mean Hounsfield
unit nodule measurement.


For the lung nodule enhancement on the CT study to be considered

technically adequate,
the following criteria had to be met:

(
a
) no sign at physical examination that there was
contrast

material extr
avasation at the site of injection, (
b
) assessment

by a radiologist that
there was appropriate enhancement of cardiovascular

structures imaged during
examination, (
c
) no clinically important

patient reaction to contrast material
administration that interfe
red

with image acquisition, (
d
) administration of the correct
dose

of contrast material, and (
e
) satisfactory patient breath holding

and respiratory
registration so that artifact
-
free images were

produced through the nodule equator.
Meticulous attention to

the details of this CT enhancement technique was critical.


On the basis of our previous work, we considered a nodule that

enhanced 15 HU or less
to have not enhanced significantly (
32
).

This was an indication to us that the nodule was
likely benign,

probably a granuloma.


If any of the images obtained after the injection of contrast

material showed enhancement
of greater than 15 HU, we considered

the examination to be adequat
e and the nodule to
have enhanced

significantly. For a nodule to be given an enhancement value

of less than
or equal to 15 HU, nodule
-
enhancement images had

to be available from each of the 4
minutes after the injection

of contrast material. For example, i
f nodule
-
enhancement
measurements

at 1, 3, and 4 minutes after the injection of contrast material

were all less
than 15 HU but no measurement was available at

2 minutes after injection because of
respiratory misregistration

or artifact, the entire study wa
s considered technically
inadequate.

We did this because the peak enhancement theoretically could

have been
missed at 2 minutes after injection, and the nodule

could have been misclassified as
"likely benign."


The clinical histories of all patients were r
eviewed subsequently

to determine whether a
clinical or histologic diagnosis had

been made. Nodules were classified as malignant only
if this

diagnosis was confirmed histologically or cytologically. All

bronchial carcinoid
tumors and fibrous tumors of the
pleura

were classified as malignancies (
41
). All benign
neoplasms (hamartomas)

were diagnosed histologically. Nodules were classified as
granulomas

if this diagnosis was confi
rmed histologically or if there was

radiologic
evidence of no growth during at least 2 years of

surveillance (
2
,
37
,
38
,
42
,
43
).


One hundred sixty
-
nine of the 550 patients were excluded. We

were unable to obtain a
clinical or a histologic diagnosis of

the nodule in 147 patients, because the surveillance
was less

than 2 years, the patient was no longer being treate
d at the

respective institution
and could not be contacted, or the diagnosis

could not be verified after death. These
patients were excluded

from statistical analysis.


In 19 patients, studies were technically inadequate because

the breath hold was
inconsi
stent after injection. No serious

reactions to contrast material occurred. One
examination was

interrupted because of a minor reaction.


One patient was excluded because an incorrect dose of contrast

material was
administered. The patient weighed 133.9 kg
and

received an injection of 100 mL of
nonionic contrast material.

The correct dose should have been 175 mL (
Table 1
). This
patient's

2
-
cm nodule enhanced 14.3 HU. The diagno
sis was melanoma metastasis.


One patient was excluded because the nodule diameter was 3 mm,

the same as the CT
collimation.


One other patient was excluded because transthoracic needle

aspiration biopsy of the
nodule recently had been performed.

This undi
agnosed nodule is being managed with
observation. It

enhanced 15 HU.


Two patients had multiple examinations performed at different

times. Only the first of
these was included.


The 25 patients in Shiga, Japan, were examined by using a different

enhancemen
t
protocol. After the injection of contrast material,

images were obtained at 30, 120, and
300 seconds. Because no

images were obtained at 60, 180, and 240 seconds after
injection,

we chose to analyze these data separately.


Thus, there was a clinical or h
istologic diagnosis and a technically

adequate study of lung
nodule enhancement in 356 patients.


To analyze the statistical significance and clinical relevance

of the data, we divided the
patients into two groups: patients

with malignant neoplasms and pat
ients with granulomas
or benign

neoplasms. The distributions of enhancement and diameters were

compared for
the two groups by using the Wilcoxon rank sum test

because the distributions of these
variables were nongaussian.

The
2

test was used to analyze nodule distribution. The
Spearman

rank correlation test was used to compare nodule diameter and

enhancement at
CT.


Sensitivity, specificity, accuracy, and positive and negat
ive

predictive values were
calculated, with an enhancement level

of greater than 15 HU signifying a positive test
result. "Sensitivity"

was defined as the percentage of patients with malignant neoplasms

who had a level of enhancement greater than 15 HU; "s
pecificity"

was defined as the
percentage of patients with granulomas or

benign neoplasms who had a level of
enhancement of 15 HU or

less. Ninety
-
five percent CIs for these diagnostic
characteristics

were calculated by using an exact method for obtaining a

CI

for a binomial
parameter (
44
).


Receiver operating characteristic analysis summarized the usefulness

of enhancement as a
marker for malignant neoplasms (vs granulomas

and
benign neoplasms). Estimates of the
area (and its standard

error) under the receiver operating characteristic curves for

the
current and previously reported series were made with nonparametric

methods, which
require no distributional assumptions (
45
). The

area measurements obtained from two
independent samples were

compared by calculating the critical ratio
z

score, Area
1

-

Area
2
/[SE(Area
1

-

Area
2
)], where SE is standard error,

and by

comparing the critical ratio
with the table of the normal distribution.







RESULTS



There were 171 malignant neoplasms, 163 granulomas, 19 other

benign nodules, and
three benign neoplasms (
Table 2
). The malignant

tumors comprised 78 adenocarcinomas,
Top

Abstract

Introduction

MATERIALS AND METHODS

RESULTS

DISCUSSION

References


29 squamous cell carcinomas,

20 non

small cell carcinomas, four small cell carcinomas,

27 other primary malignancies, and 13 metastatic carcinomas

of vario
us sites of origin.




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TABLE

2. Frequency of Nodule Diagnosis




Of the 163 granulomas, 44 had histologic proof of diagnosis.

The remaining 119 were
considered granulomas because there was

radiologic evidence of no growth during a
follow
-
up of at least

2 years or because the nodul
e decreased substantially in size

or
resolved. All three benign neoplasms were diagnosed as hamartomas

after surgical
removal.


The enhancement, preenhancement attenuation, location, and diameter

of all nodules are
summarized in
Table 3
. On the basis of the

results of the Wilcoxon rank sum test, the
median enhancement

(
Fig 2
) and median diameter of t
he malignant neoplasms were

significantly higher than those of the granulomas and benign

neoplasms (38.0 vs 10.0
HU,
P

< .001; 17 vs 13 mm,
P

<

.001, respectively). There was no significant difference
between

the preenhancement attenuation of benign nodule
s and that of

malignant nodules
(Wilcoxon rank sum test [two
-
sided],
P

= .244).

Malignant nodules were located in the
upper lobe more often

than were benign nodules (
2

tes
t,
P

= .001).




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TABLE 3. No
dule Characteristics







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Figure 2.

Graph shows the distribution of net
enhancement fo
r the benign and malignant nodules.
Note that the majority of benign nodules enhanced
15 HU or less and that all but four malignant
nodules enhanced more than 15 HU. Each
horizontal line indicates the median enhancement.

[in this window]

[in a new window]







Using enhancement greater tha
n 15 HU as a marker for malignancy,

we calculated the
sensitivity and specificity as 98% (95% CI:

94.1%, 99.4%) and 58% (95% CI: 50.4%,
65.1%), respectively (
Fig 3
)

(
Tables 4
,
5
). These rates are bounded by the 95% CIs
estimated

in the previous studies and thus would no
t be considered significantly

different
at an
level of .05.





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Figure 3.

Graph shows sensitivity and specificity
curves across the levels of net enhancement for 356
nodules. The threshold for a positive test result was
set prospectively at 15 HU. Using 15 HU as

the
threshold maximizes the sensitivity and therefore
reduces the likelihood that a malignancy will be
misclassified as benign.






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TABLE 4. Nodule Enhancement by Diagnosis






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window]




TABLE 5. Diagnostic Characteristics of 356 Nodules When a
Threshold of 15 HU Was Used




The accuracy estimated by using th
e area under the receiver

operating characteristic curve
for the Shiga cohort was not

significantly different from the corresponding value in the

protocol group (area ± standard error, 0.785 ±

0.161 vs 0.831 ± 0.023;
P

= .777).


A comparison of the areas u
nder the receiver operating characteristic

curves for the
current series (area, 0.831 ± 0.023) (
Fig 4
)

and a previously reported series (
32
) (area,
0.879 ±

0.046) showed no significant difference (
P

= .351).





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Figure 4.

Graph of the receiver operating
characteristic curve. The area under the curve is
0.831 ± 0.023.




We found poor correlations between nodule diameter and degree

of enhancement at CT
(Spearman rank correlation;
r

=
-
0.
280

for malignant neoplasms,
r

= 0.001 for
granulomas and benign

neoplasms).


We analyzed the degree of enhancement at each 1
-
minute interval

for the 319 nodules
with data recorded at every interval. The

profiles of benign and malignant nodules were
not si
gnificantly

different (
Fig 5
). We found that to maximize sensitivity, enhancement

must be measured at each of the four 1
-
minute intervals (
Table 6
).





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Figure 5.

Graph summarizes the re
sults at each 1
-
minute interval. Each horizontal line indicates the
median enhancement, which changes with time.
Each dot represents a nodule's peak enhancement
value (enhancement value minus precontrast
attenuation value) at that particular time. The
prof
iles of benign and malignant nodules were not
significantly different. To maximize sensitivity,
enhancement must be measured at each of the four
1
-
minute intervals. Note that although many
malignant nodules had one or more 1
-
minute
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interval enhancement lev
els below the 15
-
HU
threshold, only four malignant nodules had a peak
enhancement value (highest 1
-
minute enhancement
level during 4
-
minute period) of 15 HU or less.






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window]




TABLE 6. False
-
Negative and False
-
Positive Diagnoses as a
Function of Time




We compared the median preenh
ancement attenuation among three

groups: (
a
) malignant
neoplasms, (
b
) granulomas and benign nodules

at observation, and (
c
) benign neoplasms
and other benign nodules.

The median attenuation before the administration of contrast

material was not significant
ly different among the three groups

(
P

= .212)(
Fig 6
).
However, the median attenuation before the

administration of contrast material was 29
HU for the 22 benign

neoplasms and ot
her benign nodules compared with 16 HU and 15

HU for the other two groups.





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Figure 6.

G
raph summarizes the precontrast
attenuation according to diagnosis. The median
precontrast attenuation values for malignant
neoplasms (16 HU), granulomas and nodules
determined to be benign with observation (15 HU),
and benign neoplasms and other benign no
dules (29
HU) were not significantly different. The vertical
lines indicate the SDs, the solid circles indicate the
data points, and the open circles indicate the
median values.









DISCUSSION



The results of our current multicenter st
udy corroborate
the

hypothesis: The absence of significant lung nodule
enhancement

(
15 HU) at CT is strongly predictive of
benignity. We found

that our protocol allows satis
factory
measurement of the enhancement

of pulmonary nodules
(5

40 mm in diameter) with iodinated

contrast material.
Malignant nodules enhanced significantly

more than
granulomas and benign neoplasms (median enhancement,

38.1 vs 10.0 HU, respectively;
P

< .
001).


In the 8 years from August 1989 to June 1997, 626 nodules were

evaluated in the current
and previous studies (
30
,
32
). On the

basis of the results of the Wilcoxon rank sum test,
the median

enhancement and median diameter of the nodules and the median

age of
patients with malignant neoplasms were significantly

greater than those of patients wi
th
granulomas and benign neoplasms

(40.0 vs 10.0 HU,
P

< .001; 17 vs 12 mm,
P

< .001;
and

67 vs 64 years,
P

< .001, respectively).


Yamashita et al (
31
) reported results of lu
ng nodule enhancement

at CT that are similar to
ours, even though they examined a

different patient population. None of their 18 cases of
lung

cancer enhanced less than 25 HU. The 10 granulomas and three

of four hamartomas
in their study enhanced less than

15 HU.

Zhang and Kono (
46
) also reported
corroborating results. They

found that peak enhancement levels were significantly higher

for malignant (42 HU) and inflammatory benig
n (44 HU) nodules

than for non
-
inflammatory benign nodules (13 HU).


Results of the lung nodule enhancement technique appear to be

generalizable.
Histoplasmosis, coccidioidomycosis, and tuberculous

granulomas appear to have similar
lung nodule enhancement
characteristics.

Younger granulomas with active inflammatory
changes generally

enhance substantially more than 15 HU. As they mature and become

less active and more necrotic, their vascular stroma recedes

and they enhance less (
Figs 7
,
8
). We found no significant difference

in the precontrast attenuation among lung nodule
diagnoses (
Fig 6
).

A small proportion of lung nodul
es had negative Hounsfield

unit values
before the administration of contrast material.

We speculate that this may be secondary to
differences in calibration

between scanners at the seven institutions where the study was

performed. Another consideration is
that some nodules in truth

had an attenuation lower
than that of water, perhaps from necrosis

or a less compact tissue structure. We do not
believe that any

difference in calibration would have affected the measurement

of
enhancement, however.




Top

Abstract

Introduction

MATERIALS AND METHO
DS

RESULTS

DISCUSSION

References



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Figure 7.

Transverse, contrast
-
enhanced CT scan (3
-
mm collimation) obtained through a 16
-
mm
uncalc
ified nodule in the left lower lobe in a 75
-
year
-
old woman. Note the small amount of left inferior
hilar adenopathy (arrow). The peak enhancement of
this nodule was 15 HU. It has been stable for more
than 2 years and is therefore considered benign
(probabl
y a coccidioidomycosis granuloma because
the patient lives in Arizona). Note that the region of
interest (
1

) is centered within the nodule. This
nodule was studied on tw
o previous dates. Three
months before this examination, the nodule enhanced
42 HU. Five months before this examination, the
nodule enhanced 60 HU. Findings are compatible
with the resultant region of granulomatous organizing
pneumonia, with progression of
caseous necrosis and
decreased nodule vascularity.







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Figure 8a.

(a)

Transverse
, contrast
-
enhanced CT scan
(3
-
mm collimation) obtained through a left lower lobe
nodule in a 69
-
year
-
old man in 1995. The nodule
enhanced 25 HU.
(b)

Transverse, contrast
-
enhanced
CT scan obtained 4 months later than
a

in 1996 shows
no enhancement of the l
ung nodule. It now measures
10 mm. The nodule is benign according to follow
-
up
findings and is most likely due to a region of evolving
organizing histoplasmosis pneumonia (granuloma).







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Figure 8b.

(a)

Transverse, contrast
-
enhanced CT scan
(3
-
mm collimation) obtained through a left lower lobe
nodule in a 69
-
year
-
old man in 1995. The
nodule
enhanced 25 HU.
(b)

Transverse, contrast
-
enhanced
CT scan obtained 4 months later than
a

in 1996 shows
no enhancement of the lung nodule. It now measures
10 mm. The nodule is benign according to follow
-
up
findings and is most likely due to a region
of evolving
organizing histoplasmosis pneumonia (granuloma).




Reports from the United States and Europe show that approximately

50% of all
operations performed for indeterminate lung nodules

result in resection of a benign
nodule (
1

4
). If one were

to triage patients' conditions to either operation or radiologic

surveillance solely on the basis
of the CT enhancement value

(without regard to other
radiologic and clinical findings and

without utilization of transthoracic or bronchoscopic
biopsy),

the benign diagnosis rate at operation for indeterminate lung

nodules would
decrease to approximately 3
0%. This assumes a

50% prevalence of malignancy (78
benign nodules enhancing more

than 15 HU divided by 245 total nodules enhancing more
than

15 HU is 31.8%) (
Table 4
). It is

also likely that fewer malignancies

would be
managed initially with observation, given a sensitivity

of 98%. In practice, all
indeterminate lung nodules are assessed

in the context of clinical and radiologic findings,
which should

improve these prediction
s (
47
).


It appears that comparable results are attainable with 2
-
[
18
F]fluoro
-
2
-
deoxy
-
D
-
glucose

PET (
48
). Because of its inability to depict calcification,

limited availability, and expense,
use of that modality for

initial evaluation of an indeterminate lung nodule is unrealistic.


It is possible that a bias inherent in the study method has

led to

an underestimation or
overestimation of the accuracy

of this research. Our previous (
32
) and present findings
show

(
a
) that nodules ultimately diagnosed as benign are more li
kely

to be managed with
radiologic observation than with biopsy or

surgery and (
b
) that nonenhancing nodules are
more likely to

be managed with observation than with intervention. One hundred

forty
-
seven nodules in this cohort are being managed with observ
ation

rather than intervention.
A disproportionate number of these

nodules (71 of 147) enhanced 15 HU or less. We
believe that

most of the 147 nodules are benign, given stability for periods

of less than 2
years, even though they are still radiologically

i
ndeterminate. However, it is possible that
some of the nonenhancing

nodules that are being observed or that were lost to follow
-
up

are, in fact, malignant (ie, false
-
negative).


It is also possible that a bias inherent in the CT enhancement

measurement tec
hnique
increased the frequency of diagnoses made

for enhancing versus nonenhancing nodules
and thus affected

the accuracy. For 19 nodules, examinations were technically

inadequate
because of respiratory misregistration. Each of these

19 nodules had net enh
ancement
values of 15 HU or less but did

not have adequate equatorial measurements from each of
the 4

minutes after injection, and they were therefore excluded. This

bias, like the first
one acknowledged, disproportionately excluded

nonenhancing nodules, s
ome of which
could have been malignant.


Four of the 356 study results were false
-
negative. Case 1 was

a 27
-
mm, left upper lobe
primary adenocarcinoma in a 72
-
year
-
old

man that had a net enhancement value of 14
HU.


Case 2 was a 15
-
mm, right upper lobe lun
g adenocarcinoma recurrence

in a 71
-
year
-
old
woman (
Fig 1a
). Its net enhancement value was

14 HU. The histologic appearance was
consistent with lymphangitic

metastasis. It had a zone of central necrosis (
Fig 1b
).
Histologically,

there was little vascular stroma, which may have been a factor

in

its
relatively low enhancement value (
32
).


Case 3 was an 11
-
mm, left upper lobe primary squamous cell carcinoma

in a 60
-
year
-
old
woman that had a net enhancement value of 15

HU.


Case 4 was an 18
-
mm, right lower lobe squamous cell carcinoma

metastasis from a
laryngeal primary in a 71
-
year
-
old man. Its

net enhancement value was 14 HU. There was
a second laryngeal

metastasis that was studied during the same CT examination that

had a
net enhancement value of 42 HU.


On the basis of previous findings of lung nodule enhancement

at CT (
30

32
), we
prospectively selected 15 HU as the

threshold for a positive diagnosis. If we
retrospectively select

a threshold of 10 HU, the following calculations are obtained:

sensitivity, 100% (171 of 171; 95% CI: 97.9%, 100%); specificity,

50
.3% (93 of 185;
95% CI: 42.8%, 57.7%); accuracy, 74.2% (264

of 356; 95% CI: 69.3%, 78.6%); positive
predictive value, 65.0%

(171 of 263; 95% CI: 58.9%, 70.8%); negative predictive value,

100% (93 of 93; 95% CI: 96.1%, 100%). To further minimize the

likelih
ood that a
malignant lesion will be classified as benign

with this technique, it may be most prudent
to use 10 HU as

the threshold for a positive diagnosis.


With spiral CT, it is now possible to perform both the lung

nodule enhancement
technique and an op
timally enhanced CT examination

of the chest and the abdomen with
the same injection of contrast

material. To do this, we obtained a spiral series of scans
through

the chest after a delay of 20 seconds from the onset of the

injection of contrast
material.
Then, at 1 minute after injection

onset, we obtained 5 seconds of 3
-
mm
-
collimation spiral images

through the nodule, with a 1
-
mm reconstruction interval.
Between

acquisition of the 1
-

and 2
-
minute scans of the nodule, we obtained

spiral
images through the
lower part of the chest and the upper

part of the abdomen. This
allowed scanning of the liver during

optimal enhancement. Finally, the spiral sections
through the

nodule were obtained at 2, 3, and 4 minutes after injection

onset. It was
possible to perform

CT with this sequence without

tube overheating. The majority of the
patients were able to

tolerate the injection and breath
-
holding regimen.


We found this method to be useful to optimize CT staging of

the chest and abdomen in
patients with indeterminate
nodules

when there was a clinical suspicion of primary lung
cancer.

The combination of enhanced CT of the chest and abdomen with

the lung nodule
enhancement protocol did not add expense or

substantial time (<5 min) to the complete
examination.


The low fal
se
-
negative rate of the results of the CT nodule

enhancement technique is
potentially valuable in the treatment

of patients. A primary objective is to avoid
misclassifying

malignant lesions as benign. A nonenhancing lung nodule could

be
managed with radiol
ogic surveillance alone (in a supportive

clinical situation). Enhancing
nodules, with the associated

higher likelihood of malignancy, could be managed with
biopsy

or surgical removal. Because of the relatively low specificity,

enhancing nodules
may be appr
opriately managed with radiologic

surveillance in a clinical situation where
the physician's clinical

suspicion is extraordinarily low.


It may be most prudent to use the CT lung nodule enhancement

technique for nodules
with a diameter of 2.0 cm or less. S
maller

nodules have a higher likelihood of benignity
(
49
), result in

more difficulty in obtaining biopsy specimens successfully (
50
),

and are
less likely to contain substantial regions of necrosis

(
40
).


The CT lung nodule enhancement technique may be clinically useful

in the evaluation of
radiologically indeterminate lung nodules.

Absence of significant enhancement is
strongly predictive of

benignity.







Footnotes



Nothin
g in this publication implies that the Mayo Foundation

endorses the products of
GE Medical Systems or Bracco Diagnostics.


Author contributions: Guarantor of integrity of entire study,

S.J.S.; study concepts and
design, S.J.S.; definition of intellectual

c
ontent, S.J.S.; literature research, S.J.S.; clinical
studies,

all authors; data acquisition, all authors; data analysis, S.J.S.,

A.L.W.; statistical
analysis, S.J.S., A.L.W.; manuscript preparation,

editing, and review, all authors.







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U. Tateishi, M. Kusumoto, Y. Akiyama, F. Kishi, M. Nishimura, and N.
Moriyama

Role of Contrast
-
Enhanced Dyn
amic CT in the Diagnosis of Active
Tuberculoma

Chest, October

1,

2002; 122(4): 1280
-

1284.

[Abstract]

[Full

Text]

[PDF]










Y. Ohno, H. Hatabu, D. Takenaka, S. Adachi, M. Kono, and K. Sugimura

Solitar
y Pulmonary Nodules: Potential Role of Dynamic MR
Imaging in Management

Initial Experience

Radiology, August

1,

2002; 224(2): 503
-

511.

[Abstract]

[Full Text]

[PDF]










A. K. Buck, H. Schi
rrmeister, M. Hetzel, M. von der Heide, G. Halter, G.
Glatting, T. Mattfeldt, F. Liewald, S. N. Reske, and B. Neumaier

3
-
Deoxy
-
3
-
[18F]Fluorothymidine
-
Positron Emission Tomography
for Noninvasive Assessment of Proliferation in Pulmonary Nodules

Cancer Res.,

June

1,

2002; 62(12): 3331
-

3334.

[Abstract]

[Full Text]

[PDF]










S. Diederich, D. Wormanns, M. Semik, M. Thomas, H. Lenzen, N. Roos,
and W. Heindel

Screening for Early Lung Cancer

with Low
-
Dose Spiral CT:
Prevalence in 817 Asymptomatic Smokers

Radiology, March

1,

2002; 222(3): 773
-

781.

[Abstract]

[Full Text]

[PDF]










K. A. Miles, M. R. Griffiths, and M. A. Fuentes

Standar
dized Perfusion Value: Universal CT Contrast
Enhancement Scale that Correlates with FDG PET in Lung Nodules

Radiology, August

1,

2001; 220(2): 548
-

553.

[Abstract]

[Full Text]

[PDF]









Thoracic Imaging

Lung Nodule Enhancement at CT: Multicenter Study
1


Stephen J. Swensen, MD, Robert W. Viggiano, MD, David E. Midthun, MD, Nestor
L. Müller, MD, Andrew Sherrick,
MD, Keiji Yamashita, MD, David P. Naidich,
MD, Edward F. Patz, MD, Thomas E. Hartman, MD, John R. Muhm, MD and Amy
L. Weaver, MS

1

From the Dept of Diagnostic Radiology (S.J.S., T.E.H.) and Div of Pulmonary and Critical Care Medicine
and Internal Medicine

(D.E.M.), Mayo Clinic and Mayo Foundation, 200 First St SW, Rochester, MN
55905; Div of Pulmonary Medicine (R.W.V.), Dept of Diagnostic Radiology (J.R.M.), and Section of
Biostatistics (A.L.W.), Mayo Clinic Scottsdale, Ariz;
Dept of Diagnostic Radiology,
Vancouver
General Hospital, British Columbia, Canada (N.L.M.)
; Dept of Diagnostic Radiology,
Memorial Medical Center, Springfield, Ill (A.S.); Dept of Diagnostic Radiology, Shiga Health Insurance
Hospital, Otsu, Japan (K.Y.); Dept of Diagnostic Radiology,
New York University Medical Center, NY
(D.P.N.); Dept of Diagnostic Radiology, Duke University Medical Center, Durham, NC (E.F.P.).
Supported in part by grants from GE Medical Systems, Bracco Diagnostics, and the Mayo Foundation.
Recd Sept 22, 1998; revisi
on reqd Nov 10; final revision recd Apr 15, 1999; accepted Apr 22.
Address
reprint requests to

S.J.S.

PURPOSE:

To test the hypothesis that absence of statistically

significant lung nodule
enhancement (
15 HU) at computed tomography

(CT) is strongly predictive of benignity.


MATERIALS AND METHODS:

Five hundred fifty lung nodules were

studied. Of
these, 356 met all entrance criteria and had a diagnosis.

On nonenhanced, thin
-
sec
tion CT
scans, the nodules were solid,

5

40 mm in diameter, relatively spherical, homogeneous,

and without calcification or fat. All patients were examined

with 3
-
mm
-
collimation CT
before and after intravenous injection

of contrast material. CT scans throu
gh the nodule
were obtained

at 1, 2, 3, and 4 minutes after the onset of injection. Peak

net nodule
enhancement and time
-
attenuation curves were analyzed.

Seven centers participated.


RESULTS:

The prevalence of malignancy was 48% (171 of 356 nodules).

Mali
gnant
neoplasms enhanced (median, 38.1 HU; range, 14.0

165.3

HU) significantly more than
granulomas and benign neoplasms

(median, 10.0 HU; range,
-
20.0 to 96.0 HU;
P

< .001).
With

15 HU as the threshold, the sensitivity was 98% (167 of 171

malignant nodule
s), the
specificity was 58% (107 of 185 benign

nodules), and the accuracy was 77% (274 of 356
nodules).


CONCLUSION:

Absence of significant lung nodule enhancement (
15

HU) a
t CT is
strongly predictive of benignity.


Index terms:

Lung, CT, 60.12112, 60.12115 • Lung, nodule, 60.281 • Lung neoplasms,
CT, 60.12112, 60.12115 • Lung neoplasms, diagnosis, 60.30