Original Research
Cardiopulmonary Imaging
November 23, 2012

Can Low-Dose Unenhanced Chest CT Be Used for Follow-Up of Lung Nodules?

Abstract

OBJECTIVE. The purpose of this study is to establish the difference in lung nodule volume between standard-dose contrast-enhanced and low-dose unenhanced CT.
SUBJECTS AND METHODS. Twenty patients with known pulmonary metastases underwent three CT examinations on 1 day: two unenhanced low-dose (120 kVp and 30 mAs) and a standard-dose (120–140 kVp and 75–200 mAs) contrast-enhanced chest CT examinations. For nodules < 1000 mm3, nodule volume was quantified using dedicated software from the CT manufacturer. Wilcoxon’s signed rank tests were used for analysis of nodules ≤ 200 mm3 and > 200 mm3 (approximately diameter of 8 mm).
RESULTS. One hundred one nodules (n = 69 ≤ 200 mm3) were analyzed in 15 of these subjects. Measured volume of nodules ≤ 200 mm3 was systematically lower on both low-dose unenhanced CT examinations when compared with standard-dose contrast-enhanced CT (differences, 13.7% and 15.5%, respectively; p < 0.0001), but nodule volume was not different between low-dose CT (median difference, 1.0%; p = 0.10). Nodule volume was not systematically different between the protocols for nodules > 200 mm3 (p > 0.30).
CONCLUSION. For lung nodules ≤ 200 mm3 (approximately 8 mm) the measured volume on low-dose unenhanced CT is significantly lower when compared with standard-dose contrast-enhanced CT. This effect is likely due to contrast administration rather than other imaging parameters, which should be taken into account in the follow-up of lung nodules because growth can remain undetected or doubling time underestimated.
Lung nodules of unknown etiology detected by CT are a common problem in clinical practice. It is essential to differentiate malignant from benign. Unfortunately, only a few nodule characteristics, such as full or popcorn calcification, fat density, nodule size < 4 mm, and typical perifissural location signify a generally benign etiology [14]. However, if none of these characteristics is present, the absence of growth for 24 months or a volume doubling time more than 600 days is commonly used to define benignity for solid lung nodules [4]. Follow-up guidelines have been published for incidentally discovered nodules up to 8 mm [4, 5]. In these guidelines, the average diameter of the nodule on an axial CT slice is used as size measurement. For dose-saving purposes, the Fleischner Society has recommended follow-up of incidentally detected solitary lung nodules with low-dose unenhanced CT [5]. Sensitivity of chest CT for the detection of pulmonary nodules has been reported to be similar for low-dose and conventional-dose CT [68].
Recently there has been increased interest in volumetric measurement of lung nodules instead of diameter measurements [9], but understanding the potential sources of error and variation in these measurements is essential to evaluate growth. We noted that in our own practice, measured nodule volume seemed to be dependent on the use of IV contrast material in combination with the applied radiation dose. Although interobserver [1012] and interexamination variation [13, 14] and impact of radiation dose [1517] in measurement of pulmonary nodules have been reported, knowledge is limited regarding the effect of both contrast enhancement and dose effects on the size of pulmonary nodules.
The aim of the current study was to compare volumes of lung nodules measured on a routine clinical CT (contrast-enhanced standard radiation dose) with low-dose unenhanced CT in 20 subjects with known pulmonary metastases.

Subjects and Methods

Subjects

The study protocol was approved by the ethical committee and patients provided written informed consent. Twenty patients who were known to have lung metastases on previous imaging studies underwent three CT examinations on the same day: first, low-dose unenhanced chest CT, then a second low-dose unenhanced chest CT, and the planned standard-dose contrast-enhanced chest CT. Patient characteristics were described previously [14].

CT Protocol

Volumetric breath-hold instruction inspiration CT was obtained on commercially available 16-MDCT or 64-MDCT systems (Mx8000 IDT, Brilliance 16P, or Brilliance 64, Philips Healthcare). Collimation was 16 × 0.75 mm or 64 × 0.625 mm, and axial images were reconstructed with slice thickness of 1.0 mm at 0.7-mm increments from lung bases to lung apices for all CT studies, irrespective of applied collimation or radiation dose. The low-dose protocol was unenhanced and images were acquired with 120 kVp and 30 mAs (volume CT dose index [CTDIvol] = 2.2 mGy). The protocol used a standard IV contrast injection (60–185 mL depending on the indication and body weight), with 120–140 kVp and 75–200 mAs depending on body weight (CTDIvol = 5.5–20 mGy).
TABLE 1: Characteristics of Study Population
TABLE 2: Absolute and Relative Differences in Lung Nodule Volume

Volumetry Protocol

One of two thoracic radiologists with 9 and 8 years of experience in chest CT inspected the CT studies for lung nodules. Only noncalcified nodules between 15 mm3 (approximately 3 mm in diameter) and 1000 mm3 (approximately 18 mm in diameter) that could be matched between the three CT studies were included in the current analysis. Nodule volumes were measured on a portable CT workstation (IntelliSpace, Philips Healthcare) using software from the manufacturer. This software only requests the observer to click with the mouse within the nodule, and further segmentation and quantification is fully automated. For some nodules, minor manual adjustments had to be made (mostly because the nodule was attached to a blood vessel), but for the majority of nodules, the segmentation by the program was judged acceptable without adjustment. Nodule shape (round vs lobulated or irregular) was judged visually by one of the observers to assess the impact of shape on differences in measured nodule volume between the two protocols.
All nodules were first detected on the contrast-enhanced CT, followed by the two low-dose CT studies. Nodules in the low-dose studies were identified with knowledge of findings on the contrast-enhanced study. The nodules were matched by using the combination of section number, lung segment, and distance to the pleura.

Data Analysis

The statistical hypothesis of this study was to test the null hypothesis that there is no difference between the volumes from the enhanced standard CT dosing versus the volumes from the unenhanced low dose protocol. Although normality was not tested, nodule size was not normally distributed visually. Nodule volumes were first compared between the three CT studies graphically using modified Bland-Altman plots [18]. Subsequently, the Friedman test was used, and, in cases of significant results, post hoc analysis with Wilcoxon signed rank tests was conducted with a Bonferroni correction applied, resulting in a significance level set at p < 0.017. Data were analyzed for all nodules and separately for nodules ≤ 200 mm3 and ≤ 200 mm3, where 200 mm3 corresponds to approximately 8 mm in diameter. For both large and small nodules separately, we tested whether nodule volume differences were different between round and nonround (lobular or irregular) nodules with a Mann-Whitney U test.

Results

Subjects

In five of the 20 subjects, lung metastases were no longer visible after treatment of the cancer. In the other 15 subjects, 101 nodules were quantified. Of these nodules, 69 were smaller than 200 mm3 and 32 were larger than 200 mm3. Further characteristics of the 15 subjects with nodules and the nodule characteristics are provided in Table 1.

Nodule Volumes in Different Chest CT Protocols

On the low-dose CT, nodule volumes were 7.4% and 9.8% smaller when compared with standard CT, but between the two low-dose CT examinations, nodule volumes did not differ significantly (Table 2). The difference between low-dose CT and standard CT could mainly be attributed to nodules ≤ 200 mm3, which were 13.7% and 15.5% smaller on the low-dose CT (p < 0.001), whereas nodules > 200 mm3 were 1.4% and 1.9% smaller, a difference that did not reach significance. These differences between the three protocols are further illustrated in Figures 1A, 1B, and 1C. The shape of nodules was not related to the difference in measured nodule volume for small (p > 0.45) or large nodules (p > 0.39).

Discussion

With the increasing use of CT, the number of incidentally detected small lung nodules has increased considerably. To distinguish malignant nodules from the vast majority of benign lesions, sequential follow-up CT studies are recommended [4, 5]. However, to reduce radiation and contrast agent risk, for follow-up, low-dose unenhanced CT is recommended, although initially the pulmonary nodule is often detected on standard-dose contrast-enhanced CT performed for other purposes. Although several hospitals use unenhanced chest CT for most diagnostic purposes, others use mostly contrast-enhanced chest CT, as is routine in our hospital.
Fig. 1A Graphs plot mean nodule volume in mm3on x-axis against difference in nodule volume between two protocols divided by mean nodule volume expressed as percentage on y-axis. Vertical dotted line is at nodule volume of 200 mm3, which corresponds to diameter of approximately 8 mm. Dotted lines represent 95% CI.
A, Bland-Altman plots show difference between standard and initial low-dose examination (A), difference between standard and repeat low-dose examination (B), and difference between two low-dose CT examinations (C).
Fig. 1B Graphs plot mean nodule volume in mm3on x-axis against difference in nodule volume between two protocols divided by mean nodule volume expressed as percentage on y-axis. Vertical dotted line is at nodule volume of 200 mm3, which corresponds to diameter of approximately 8 mm. Dotted lines represent 95% CI.
B, Bland-Altman plots show difference between standard and initial low-dose examination (A), difference between standard and repeat low-dose examination (B), and difference between two low-dose CT examinations (C).
Fig. 1C Graphs plot mean nodule volume in mm3on x-axis against difference in nodule volume between two protocols divided by mean nodule volume expressed as percentage on y-axis. Vertical dotted line is at nodule volume of 200 mm3, which corresponds to diameter of approximately 8 mm. Dotted lines represent 95% CI.
C, Bland-Altman plots show difference between standard and initial low-dose examination (A), difference between standard and repeat low-dose examination (B), and difference between two low-dose CT examinations (C).
We report that especially for pulmonary nodules ≤ 200 mm3 (corresponding to a diameter of 8 mm), that comprise the majority of incidentally detected pulmonary nodules, measurement variation between both protocols can be substantial and growth of a (malignant) nodule can be missed or the growth rate can be underestimated. Our study shows that for these relatively small nodules, low-dose unenhanced CT significantly underestimates the volume by about 15% when compared with a standard-dose contrast-enhanced CT.
The implication of a 15% lower volume could be as follows: Let us assume a malignant nodule of 100 mm3 (approximately 5.8 mm) with a volume doubling time of 300 days. This nodule is detected on a baseline standard-dose contrast-enhanced CT study. When this nodule is followed up after 100 days with standard-dose contrast-enhanced CT, the newly measured volume would be 126 mm3, a significant increase of 26% and a malignant growth rate (doubling time, 300 days). However, when this nodule is followed up with low-dose unenhanced CT, the new volume would be only 107 mm3, a nonsignificant increase of 7% and a benign growth rate with a doubling time of 969 days. On a 1-year follow-up low-dose unenhanced CT study, this nodule would have increased significantly (48% increase), with a malignant doubling time of 374 days, but a delay in diagnosis would have occurred. As illustrated, when low-dose follow-up CT is used, there is a serious risk of missing relevant growth of a nodule. Possible solutions for this problem are to follow-up nodules with the same CT protocol as the baseline CT instead of changing to low-dose protocols, obtain a low-dose baseline CT scan as soon as possible after the clinical study when follow-up is warranted, or downsize the nodule volume on the baseline scan by a certain factor (or upsize the follow-up volume).
Regarding the mechanism of the difference in volume, we speculate that the change in nodule volume is an effect of contrast enhancement. Recently, Christe et al. [17] showed that nodule measured on low-dose CT was not significantly different from the size measured on standard dose (300 mAs) images. Other studies reported that the same holds true for nodule volume measurements [15, 16]. Therefore, the variation in measured volume will be due mainly to the effect of contrast enhancement (on average, 25 HU for nodules in our study), and most likely the smaller volumes are an effect of lack of contrast medium. Apparently, the increased nodule density caused by the contrast uptake alters the edge detection of our software, leading to larger nodules.
Our study has several limitations. First, our nodules are most likely to be metastases and, although it is unlikely that underestimation is different for benign nodules or primary tumors, we cannot rule this out. Second, we used the software of one manufacturer, and results may be different for other software packages. Third, we applied an arbitrary cutoff corresponding to 200 mm3; however, this shows that there is a difference in systematic relative error for smaller and larger nodules.
In conclusion, we have shown that the volume of fairly small lung nodules is significantly smaller on low-dose unenhanced chest CT when compared with standard-dose contrast-enhanced chest CT when analyzed with commercially available image analysis software. This has important implication for the introduction of volumetry in the clinical setting because malignant growth may remain undetected when low-dose unenhanced CT is used for follow-up of detected nodules in clinical practice when the prior CT was contrast enhanced.

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Information & Authors

Information

Published In

American Journal of Roentgenology
Pages: 777 - 780
PubMed: 22997367

History

Submitted: July 26, 2011
Accepted: February 8, 2012

Keywords

  1. CT
  2. dose
  3. pulmonary nodule
  4. volumetry

Authors

Affiliations

Pim A. de Jong
Department of Radiology, University Medical Centre Utrecht, HP E.01.132, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Tim Leiner
Department of Radiology, University Medical Centre Utrecht, HP E.01.132, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Jan-Willem J. Lammers
Department of Pulmonology, University Medical Centre Utrecht, Utrecht, The Netherlands.
Hester A. Gietema
Department of Radiology, University Medical Centre Utrecht, HP E.01.132, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Notes

Address correspondence to P. A. de Jong ([email protected]).

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