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Original Research |
1 Department of Radiology and Center for Imaging Science, Samsung Medical
Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong,
Kangnam-Ku, Seoul 135-710, Korea.
2 Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul 135-710, Korea.
Received December 1, 2005;
accepted after revision March 25, 2006.
Presented at the 2005 annual meeting of the Radiological Society of North
America, Chicago, IL.
Abstract
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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MATERIALS AND METHODS. One hundred forty-three patients with stage
T1 NSCLC underwent both helical dynamic CT and integrated PET/CT followed by
surgical nodal staging. In helical dynamic CT, patients were regarded to have
stage N2 disease when a nodule showed a peak enhancement 
110 H or a net
enhancement 60 H. In integrated PET/CT, nodes were regarded as positive
for malignancy when they showed 3 3.5 in maximum standardized
uptake value with a discrete margin and more 18F-FDG uptake than
mediastinal structures. Sensitivities, specificities, and accuracies for
mediastinal nodal metastasis detection were compared for helical dynamic CT
and integrated PET/CT using the McNemar test.
RESULTS. Of the 143 patients, 34 (24%) had positive mediastinal nodes. The sensitivity, specificity, and accuracy for mediastinal nodal metastasis prediction on helical dynamic CT were 65% (22 of 34 patients), 89% (97 of 109), and 83% (119 of 143), respectively, whereas those on integrated PET/CT were 56% (19 of 34), 100% (109 of 109), and 90% (128 of 143). The p values were 0.664, < 0.001, and 0.015.
CONCLUSION. In stage T1 NSCLC, contrast-enhanced helical dynamic CT better predicts, but not significantly so, mediastinal nodal metastasis than PET/CT, whereas PET/CT shows perfect specificity and higher accuracy than helical dynamic CT.
Keywords: chest • CT • lung neoplasms • mediastinal lymph nodes • PET/CT • staging
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As for the mediastinoscopic evaluation of lymph nodes, initial studies raise questions concerning routine mediastinoscopy in patients with stage T1 NSCLC because of the low prevalence of mediastinal nodal metastases and the substantial morbidity and mortality associated with the invasiveness of the procedure. However, several recent studies have reported relatively high frequencies of mediastinal lymph node metastases in stage T1 NSCLC, ranging from 16% to 21%, by complete nodal sampling using either mediastinoscopy or thoracotomy [2-4]. Therefore, the accurate detection of mediastinal nodal metastasis in stage T1 NSCLC helps with decision making concerning staging procedures (mediastinoscopy) and treatment options (surgery vs neoadjuvant chemoradiation therapy).
In the CT diagnosis of mediastinal nodal metastasis, lymph nodes have been evaluated classically using the size criterion of 10 mm in short-axis diameter, which is based on statistical data regarding the normal size range of mediastinal lymph nodes [5, 6]. However, the results of mediastinal nodal metastasis prediction in NSCLC by CT diagnosis are unsatisfactory and show a sensitivity of 41-54% and a specificity of 43-97% [4, 7, 8]. Moreover, in stage T1 lung cancer, CT has a sensitivity of only 27-41% [4, 9].
The likelihood of metastasis increases as the number of intratumoral microvessels increases in lung cancer. Because mean peak attenuation values of helical dynamic CT reflect microvessel densities in lung cancer and are significantly higher in vascular endothelial growth factor (VEGF)-positive lung cancer, the likelihood of metastasis is probably increased in lung cancers that show strong enhancement on helical dynamic CT [9, 10]. Shim et al. [9] suggested that the probability of mediastinal nodal metastasis is high in strongly enhancing malignant lung nodules with 3 110 H of peak enhancement or 3 60 H of net enhancement on helical dynamic CT in stage T1 NSCLC. With these cutoff vales for nodule enhancement of 3 110 H of peak enhancement or 60 H of net enhancement for mediastinal nodal metastases, helical dynamic CT enabled mediastinal nodal metastasis prediction with sensitivity of 62-77%, specificity of 70-76%, and accuracy of 71-74%.
PET with 18F-FDG as a radiotracer has recently been reported to be more effective at detecting tumor involvement in mediastinal and hilar lymph nodes than CT [11, 12]. FDG PET has an advantage in functional imaging because it reflects tissue hypermetabolism but is limited in anatomic detail because of its poor resolution. On the other hand, integrated PET/CT, by combining morphologic CT and functional PET data, provides satisfactory spatial resolution and anatomic and metabolic information. Moreover, integrated PET/CT scanners have shown promising initial oncologic imaging results [13, 14]. However, in stage T1 NSCLC, integrated PET/CT still has a low sensitivity of 47%, although it has 100% positive predictive value and a high negative predictive value [15].
Although helical dynamic CT and integrated PET/CT have been the most reliable techniques in the prediction of mediastinal nodal metastasis in stage T1 NSCLC until now [9, 15], the diagnostic efficacies of these two techniques have not been directly compared. Therefore, the purpose of our study is to compare the diagnostic accuracies of helical dynamic CT and integrated PET/CT for the prediction of mediastinal nodal metastasis in patients with stage T1 NSCLC.
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At our institution, integrated PET/CT is usually recommended for cancer staging before surgery in patients with proven lung cancer or for tissue characterization in patients with clinically indeterminate pulmonary nodules or masses. Twelve patients were excluded from analysis because they had a positive PET scan or brain MRI indicating extrathoracic metastases. Nine patients with pathologically proven positive nodes on cervical mediastinoscopy were also excluded because they had received concurrent neoadjuvant chemoradiation therapy before curative resection in another hospital. The remaining 143 patients (82 men and 61 women; age range, 31-72 years; mean age, 60 years) underwent surgical nodal staging. Eleven of the 143 patients underwent mediastinoscopy only, and the remaining 132 patients underwent lobectomy or pneumonectomy plus lymph node dissection. None had evidence of distant metastasis at the time of surgery.
Helical Dynamic CT Image Acquisition
Helical dynamic CT was performed using a 4-MDCT scanner (LightSpeed QX/i,
GE Healthcare) or a 16-MDCT scanner (LightSpeed Ultra or Ultra16, GE
Healthcare). Before the IV injection of contrast medium, a series of 13 images
was obtained through a nodule for 30 mm along the z-axis with 2.5-mm
collimation at 120 kVp, 90 mA, 0.8-second gantry rotation time, and 3.75 mm/s
table speed over 8 seconds. Thereafter, an additional six series of images
were obtained at 30, 60, 90, and 120 seconds and 5 and 15 minutes after IV
injection of contrast medium (iomeprol [Iomeron 300, Bracco]) at 3 mL/s, total
of 120 mL, using a power injector (Envision CT, Medrad) and using the same
parameters as for the initial unenhanced series (a total series of seven
images at 0, 30, 60, 90, and 120 seconds and at 5 and 15 minutes).
Image data were reconstructed with a thickness of 2.5 mm using a standard algorithm. Immediately after the dynamic study at 120 seconds, helical CT (125 mA, 120 kVp, 5-mm collimation, and 15 mm/s table speed) scans were obtained from the lung apices to the level of the middle pole of both kidneys for tumor staging. All thin-section and dynamic CT image data were directly interfaced with our PACS system (PathSpeed, GE Healthcare), which displayed all image data on monitors (four monitors, 1,536 x 2,048 image matrices, 8-foot bit viewable gray scale, and 60-foot-lambert luminescence). Both mediastinal (window width, 400 H; window level, 20 H) and lung (window width, 1,500 H; window level, -700 H) window images were viewed on these monitors.
Integrated PET/CT Acquisition
All 143 patients underwent an integrated FDG PET/CT study within 7 days of
helical dynamic CT (mean, 3.2 days; median, 2 days), and all patients fasted
for at least 6 hours before the integrated PET/CT examination, although oral
hydration with glucose-free water was allowed. After we tested each patient's
peripheral blood to ensure a normal blood glucose level, each patient received
an IV injection of 370 MBq (10 mCi) of FDG and then rested for approximately
45 minutes before undergoing imaging. Image acquisition was performed using an
integrated PET/CT device (Discovery LS, GE Healthcare) consisting of an
Advance NXi PET scanner and an 8-MDCT LightSpeed Plus CT scanner. The axes of
both systems were mechanically aligned so that shifting the examination table
by 68 cm moved the patient from the CT gantry into the PET gantry. The
resulting PET and CT images were then coregistered.
CT was performed from the head to the pelvic floor using a standardized protocol involving 140 kV, 80 mA, tube-rotation time of 0.5 second per rotation, pitch of 6, and section thickness of 5 mm, which matched the PET section thickness. Patients were in normal shallow respiration during the CT scan acquisition. No contrast material was administered. Immediately after CT, PET was performed in the identical axial field of view. The acquisition time for PET was 5 minutes per table position. CT data were resized from a 512 x 512 matrix to a 128 x 128 matrix to match the PET data so that the images could be fused and CT transmission maps generated. PET image data sets were reconstructed iteratively using the ordered subsets expectation maximization algorithm and by segmented attenuation correction (two iterations, 28 subsets) using the CT data. Coregistered images were displayed using eNTEGRA software (GE Healthcare).
Helical Dynamic CT Image Evaluation
We measured nodule attenuation values in the same area on the selected
image for each cluster on each occasion (from unenhanced images to the
15-minute images). A circular region of interest (ROI) was placed over a
nodule, and an ROI covering about one half of the diameter of the nodule at
its equator was examined. Calcified, cavitary, or necrotic areas were avoided;
thus ROIs were designed to be as large as possible without overlapping such
areas. Two radiologists, with 4 years and 8 years of chest CT experience,
independently measured attenuation values. All measurements were made at the
time of CT examination. The radiologists were unaware of the patient
information such as age and clinical history. Two measurements were obtained
for each nodule at each imaging phase by each observer.
Mean attenuation values were recorded by each observer and then, by
averaging attenuation values by the two observers, the extent of nodule
enhancement was analyzed by calculating peak enhancement and net enhancement
(wash-in of contrast medium). Peak enhancement attenuation was defined as the
maximum attenuation value of a nodule over the entire time course of the
dynamic study. Net enhancement attenuation was calculated by subtracting the
unenhanced attenuation value from the peak enhancement attenuation value. If a
patient had a pulmonary nodule with an 110 H peak enhancement or an
60 H net enhancement, the mediastinal nodes were considered metastatic
[9].
We also measured the short-axis diameter of each mediastinal nodal group according to the lymph node map definition for lung cancer staging proposed by Mountain and Dresler [16]: group 1, highest mediastinal (1R, right; 1L, left); group 2, upper paratracheal (2R, right; 2L, left); group 3, prevascular or retrotracheal; group 4, lower paratracheal (4R, right; 4L, left); group 5, subaortic (aortopulmonary window); group 6, paraaortic (ascending aorta or phrenic); group 7, subcarinal; group 8, paraesophageal; and group 9, pulmonary ligament (9R, right; 9L, left).
Nodal groups with a lymph node of 10 mm in the short-axis diameter on
CT scans were considered metastatic on a per lymph node basis
[6]. Nodes containing nodular
or laminated calcification were regarded as benign irrespective of size.
Integrated PET/CT Image Analysis
Integrated PET/CT data sets were evaluated prospectively by one chest
radiologist with 16 years of chest CT interpretation experience and 2 years of
integrated PET/CT interpretation experience and one nuclear medicine physician
with 12 years of PET interpretation experience who were blinded to clinical
and pathologic results. Decisions on findings were reached by consensus. Nodal
stations were evaluated by allocating them to nine groups according to the
lymph node map definition for lung cancer staging proposed by Mountain and
Dresler [16] as previously
described. Mediastinal nodes with increased glucose uptake satisfying both
qualitative (greater than that of the surrounding tissue) and quantitative (a
maximum standardized uptake value [SUV] adjusted for patient body weight of
3.5 with a distinct margin) criteria were considered positive.
By receiver operating characteristic (ROC) curve analysis using different maximum SUV threshold cutoffs, we decided that an SUV of 3.5 was optimum for differentiating benign and malignant nodules on our machines [14, 17]. Mediastinal nodes were divided into four categories according to the integrated PET/CT results: positive uptake without calcification or high attenuation, positive uptake with calcification or high attenuation, negative uptake with calcification or high attenuation, and negative uptake without calcification or high attenuation. Calcification was regarded as present when it was nodular or laminated in pattern and > 200 H. A high-attenuation lymph node was defined as a node that appeared visually to have a higher attenuation than mediastinal vascular structures or had an attenuation of > 70 H by ROI-based measurement. Even if glucose uptake was high (higher than background activity or > 3.5 in SUV), calcified lymph nodes and lymph nodes with a higher attenuation (> 70 H) than surrounding great vessels on CT images on integrated PET/CT were regarded as benign [14].
Surgical-Pathologic Correlation
Surgical staging included mediastinoscopic nodal sampling alone in 11
patients and thoracotomy and lymph node dissection in 132. The surgical
staging was performed by one of two experienced thoracic surgeons (one with 17
years of experience and the other with 12). In 11 patients, only
mediastinoscopic nodal staging results were available because curative
resection was deferred in favor of neoadjuvant concurrent chemoradiation
therapy due to the presence of positive nodes. During mediastinoscopy,
American Thoracic Society (ATS) lymph node stations
[16] of 2R, 4R, 2L, 4L, and 7
were routinely sampled, and during thoracotomy all encountered lymph nodes
were removed from the ATS lymph nodal stations of 10R, 9, 8, 7, 4R, 3, and 2R
in tumors of the right lung and from areas 10L, 9, 8, 7, 6, 5, and 4L of the
left lung. When necessary, station 1 (highest mediastinal) or 2L (when tumors
were located in the left lung) nodes were also evaluated during
mediastinoscopy or thoracotomy.
A lung pathologist with 10 years of experience described lymph nodes (location and number) according to the surgeons' labeling of dissected lymph nodes [16]. The pathologist then evaluated the nodes for the presence or absence of tumor as numbered in the surgical field and recorded the presence or absence of tumor in the nodes. Specimens were stained with H and E and examined by light microscopy.
Data and Statistical Analysis
Statistical analyses were performed using commercially available software
(SAS version 8.2, SAS Institute). Agreement between the two observers in terms
of nodule measured attenuation values was analyzed by calculating intraclass
correlation coefficients. The Student's t test and the Mann-Whitney
test were used to analyze statistical differences in the extents of
enhancement of pulmonary nodules on helical dynamic CT and SUVs on integrated
PET/CT between those with or without mediastinal nodal metastasis. A
p value of < 0.05 was regarded as significant.
Diagnostic characteristics—that is, sensitivity, specificity,
accuracy, and positive and negative predictive values—were calculated by
considering the peak and net enhancements of nodules (lymph node metastasis
with peak enhancement of 110 H or net enhancement of 60 H) on
helical dynamic CT and by considering maximum SUVs from integrated PET/CT on a
per-patient basis. Likewise, diagnostic characteristics on a per-nodal basis
were also calculated by measuring short-axis diameter on helical dynamic CT
and considering SUVs obtained on integrated PET/CT for each mediastinal lymph
node group.
The McNemar test was used to compare helical dynamic CT and integrated PET/CT with respect to sensitivity, specificity, and accuracy. A p value of < 0.05 was regarded as significant.
In patients with pathologically proven positive mediastinal nodal metastasis, helical dynamic CT and integrated PET/CT results concerning the detection of mediastinal nodal metastases were compared. In false-negative cases on integrated PET/CT for the diagnosis of mediastinal nodal metastasis, the size and CT attenuation values of nodes were reviewed to identify the relationship between FDG uptake of nodes on PET and size or morphology on CT correlated with the pathologic results of the nodes.
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Tumor characteristics are summarized in Table 1, which shows the extent of enhancement on helical dynamic CT and SUVs on integrated PET/CT. Net enhancements on helical dynamic CT (p = 0.049, Student's t test) and SUVs on integrated PET/CT (p = 0.043, Mann-Whitney test) were significantly higher in patients with lymph node metastasis in the mediastinum. Good interobserver agreement was obtained between the two observers in terms of measured nodule attenuation values (intraclass correlation coefficient = 0.863-0.902, p < 0.0001) on helical dynamic CT.
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Efficacy of Helical Dynamic CT and Integrated PET/CT in Diagnosing Mediastinal Nodal Metastasis
When applying the diagnostic criteria for the presence of mediastinal nodal
metastasis fulfilling pulmonary nodule enhancement of either 110 H of
peak enhancement or 60 H of net enhancement, the sensitivity,
specificity, and accuracy for a prediction of mediastinal nodal metastasis
were 65%, 89%, and 83%, respectively, on a per-patient basis on helical
dynamic CT. The results for integrated PET/CT were as follows: sensitivity,
56%; specificity, 100%; and accuracy, 90%
(Table 2). The sensitivity of
helical dynamic CT was higher than that of integrated PET/CT, although the
difference was not statistically significant (p = 0.664). The
specificity and accuracy of integrated PET/CT were significantly higher than
those of helical dynamic CT (p <0.001, p = 0.015,
respectively).
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In the evaluation of nodal stations by applying the criterion for
mediastinal nodal metastasis of 10 mm in the short-axis diameter on
helical dynamic CT, sensitivity, specificity, and accuracy for the diagnosis
of mediastinal nodal metastasis were 42%, 99%, and 92%, respectively, on a
per-nodal basis. Those for integrated PET/CT were as follows: sensitivity,
44%; specificity, 99%; and accuracy, 93%
(Table 3). The sensitivities,
specificities, and accuracies of helical dynamic CT and integrated PET/CT were
not significantly different from each other (p =0.727 
1.000).
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Comparison of Nodal Metastasis Prediction Results Between Helical Dynamic CT and Integrated PET/CT in Positive Cases
Of the 34 NSCLC patients with proven mediastinal nodal metastasis, nodal
metastasis was detected concordantly in 10 patients by both helical dynamic CT
and integrated PET/CT (Fig. 1A,
1B,
1C,
1D). However, it was not
detected by helical dynamic CT or integrated PET/CT in three patients. In the
remaining 21 patients, helical dynamic CT and integrated PET/CT results were
discordant; helical dynamic CT was positive in 12 patients (Fig.
2A,
2B,
2C,
2D,
2E,
2F) and integrated PET/CT in
nine patients (Fig. 3A,
3B,
3C,
3D). Therefore, mediastinal
nodal metastasis was suggested by either technique—helical dynamic CT or
integrated PET/CT—in 31 of the 34 (91%) patients with proven
disease.
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Efforts have been made to identify CT findings that indicate a propensity
to metastasize based on analyses of morphologic characteristics such as size
or the marginal characteristics of primary tumors
[14,
18-21].
However, results have been unsatisfactory and controversial, especially in
solid NSCLC nodules. Shim et al.
[9] suggested that the extent
of nodule enhancement is related to a propensity toward mediastinal or hilar
nodal metastasis, not tumor size, marginal characteristics, or the presence of
necrosis or bronchovascular thickening, which showed no correlation with
mediastinal or hilar nodal metastasis. They reported that stage T1 lung
cancers showing high peak enhancement or net enhancement on dynamic CT have a
high likelihood of mediastinal nodal metastasis, with a sensitivity of 62%,
specificity of 76%, and accuracy of 74% after applying a cutoff value of
110 H of peak enhancement and a sensitivity of 77%, specificity of 70%, and
accuracy of 71% after applying a cutoff value of 60 H of net
enhancement.
As was found by meta-analysis, PET is more sensitive than CT for detecting small metastatic nodes, with sensitivity in the range of 79-84% and specificity of 89-91% for mediastinal nodal metastasis [22-24]. With the introduction of the coregistration of morphologic CT and functional PET (integrated PET/CT) data, the overall efficacy of PET/CT in predicting the presence of nodal metastasis (regardless of T staging) has improved to 81-84% accuracy [14, 25]. Shim et al. [14] reported that for the depiction of malignant nodes, including mediastinal and hilar nodal groups regardless of T staging, the sensitivity, specificity, and accuracy of CT were 70%, 69%, and 69%, respectively, whereas those of PET/CT were 85%, 84%, and 84% (p = 0.25, p < 0.001, and p < 0.001). However, according to a study by Kim et al. [15], the sensitivity, specificity, and accuracy of integrated PET/CT for mediastinal nodal staging were 42%, 100%, and 94%, respectively, in stage T1 NSCLC [15]. PET/CT is still limited in the detection of metastatic nodes when the nodes are microscopic in diameter [25, 26]. Our false-negative cases on integrated PET/CT for the prediction of mediastinal nodal metastasis support this limitation of integrated PET/CT and also disclose false-negative results for small lymph nodes. In 12 of 15 false-negative cases in which there was no significant FDG uptake on PET, there were visible lymph nodes in the mediastinum, but they were small, with an average short-axis diameter of 5.5 mm.
In our study, the sensitivity of helical dynamic CT was found to be higher than that of integrated PET/CT for predicting mediastinal nodal metastasis. However, the accuracy of helical dynamic CT is lower than that of integrated PET/CT because of the 100% specificity of integrated PET/CT. In terms of sensitivity for detecting mediastinal nodal metastasis, only three (9%) of 34 patients with proven mediastinal nodal metastasis were not shown to have mediastinal nodal metastasis on either helical dynamic CT or integrated PET/CT. Each of the remaining false-negative cases, nine on helical dynamic CT and 12 on integrated PET/CT, was properly suggested to have mediastinal nodal metastasis by the other technique.
Although integrated PET/CT is currently the best technique available for an
imaging diagnosis of nodal staging in NSCLC, its sensitivity is not high for
the detection of mediastinal nodal metastasis in stage T1 NSCLC. On the other
hand, our study showed up to 24% (34 of 143 patients) prevalence for
mediastinal nodal metastasis in stage T1 lung cancer. Consequently, the need
for routine mediastinoscopic lymph node biopsy has increased despite its high
cost and associated risks. We suggest that mediastinoscopic biopsy of
mediastinal lymph nodes should be recommended in patients with highly
enhancing NSCLC with 110 H of peak enhancement or 60 H of net
enhancement, even when the results of integrated PET/CT are negative for
mediastinal lymph node metastasis.
Our study may have a selection bias because it was not designed prospectively. However, in our hospital we perform helical dynamic CT for every solitary pulmonary nodule detected on chest radiography that appears solid on thin-section CT. Integrated PET/CT was performed on all stage T1 NSCLC patients and on all patients with an indeterminate-nature nodule on helical dynamic CT or nodule biopsy. We did not obtain respiration-gated PET/CT images; thus, motion-induced registration and FDG uptake quantification errors might have contributed to an incomplete mediastinal nodal characterization evaluation.
In conclusion, our evaluation of the extent of nodule enhancement on helical dynamic CT in stage T1 NSCLC shows better (although not statistically significant) sensitivity for the prediction of mediastinal nodal metastasis on a per-patient basis than PET/CT, whereas PET/CT was found to have perfect specificity and positive predictive values. Therefore, mediastinoscopy may be omitted and direct neoadjuvant therapy given to patients with positive nodal metastasis results on PET/CT. Mediastinoscopy may be recommended in patients with malignant lung nodules showing high enhancement on helical dynamic CT even though PET/CT does not suggest the presence of mediastinal nodal metastasis.
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