The Computer Aided Diagnosis (CAD) Research Laboratory at the University of Michigan is developing algorithms to detect and characterize lung nodules in CT images. One of the distinguishing features of many benign pulmonary nodules is the presence of a significant amount of calcifications with central, diffuse, laminated, or popcornlike patterns.1
Calcium salts are accumulated by dead or dying benign nodules because as the cells die, the proteins are denatured, exposing “groups capable of binding phosphates which in turn serve as sites for the deposition of calcium in the form of phosphates, carbonates, or oxalates.”2
Since calcium absorbs x rays more than most other tissue components, it can often be readily detected in CT images. The pixel values (CT numbers) of a CT image are directly related to the relative x-ray attenuation of the tissues. Ideally, the CT number of a tissue should depend only upon the composition of the tissue. Unfortunately, this is not the case. Many other factors affect the CT numbers including x-ray beam hardening, x-ray scatter, partial volume, and reconstruction kernel effects. These factors cause errors in the CT numbers, which can reduce the conspicuity of calcifications in pulmonary nodules.
One way to counter these effects is to relate the CT numbers in a patient scan to those in an anthropomorphic phantom. Zerhouni et al.3,4
developed such a phantom for pulmonary nodules and employed it in studies with considerable success. The reference phantom became a commercial product marketed by Computerized Imaging Reference Systems, Inc. (CIRS) of Norfolk, VA. It consists of three x-ray tissue-equivalent transaxial sections that simulate the anatomy of the thorax in the upper, middle, and lower levels. These sections simulate small patients. The reference phantom includes sets of fat-equivalent rings that can be added to the outside of the sections so as to simulate medium- and large-size patients. There are also three different size inserts for simulating the liver, spleen, and diaphragm. In addition, there is a set of 15 reference nodules. These reference nodules are cylinders or rods of various diameters that are made of epoxy resins. A certain amount of calcium carbonate (CaCO3
) was mixed in the resin to produce a desired threshold CT number for distinguishing benign from malignant nodules. The amount of CaCO3
was experimentally determined on a Pfizer/AS&E 500 CT scanner. In the initial research phantom,3
the desired threshold was set at 164 HU for the 1 cm diameter rod. This value was determined from earlier patient studies.5
Later, to add a margin of safety (to reduce the number of false benign diagnoses and account for overestimates of the CT numbers of small nodules by the Pfizer/AS&E scanner and CT number variability for other scanners), the composition was adjusted to produce a representative CT number (=average of ten highest pixel values) of 264 HU for the 1 cm reference nodules when scanned in the center of the lung in the thorax section phantom using the Pfizer/AS&E scanner.4
The CT numbers of the reference nodules did vary considerably with the size of the nodule and the type of scanner. For example, the CT numbers of the 6, 8, 10, and 20 mm diameter cylindrical reference nodules measured on a Pfizer/AS&E 500 scanner were 310, 284, 264, and 190 HU, respectively, and the corresponding values on a GE 9800 scanner were 74, 83, 97, and 145 HU.4
The threshold that was decided upon for the commercial product was a representative CT number of 185 HU.6
The amount of CaCO3
was reduced from that in the 264 HU reference nodules “in order to increase the percentage of calcified nodules diagnosed as benign with the reference phantom.”6
The reference phantom CT method may be summarized as follows. First, the patient is scanned. Next, the patient’s images are examined for suspicious nodules. When a slice containing a suspicious nodule is found, a reference phantom section that best matches this slice (including appropriate fat rings and liver, spleen, and diaphragm inserts where applicable) is selected. Next, a reference nodule of about the same size as the suspicious patient nodule is positioned at about the same location in the lung region of the phantom. Finally, the phantom is scanned using the same x-ray technique factors as were used for the patient.
The criteria employed for classifying patient nodules as probably benign included (1) having smooth or lobulated borders in the CT image, (2) having CT numbers greater than the CT number of the corresponding scanned reference phantom nodule with the further requirement that these high CT numbers be in a benign pattern (i.e., central, laminated or diffuse), and if the high pixel values were centrally located, they had to represent at least 10% of the cross-sectional area, and (3) the benign pattern had to be present in at least two slices through the nodule.4,6
Researchers have had mixed results with the commercial phantom. Khan et al.7
compared the accuracy of the classification of calcified and noncalcified solitary pulmonary nodules obtained with standard CT (10 mm slice thickness), thin-section CT (1.5 mm slice thickness), and reference phantom CT. The latter utilized the thin-section CT images of the patient and corresponding thin-section CT images of an appropriate reference thorax section phantom. That phantom contained a cylindrical reference nodule, the size and lung location of which were determined from the CT images of the patient. Khan et al.
found that the reference phantom technique of Zerhouni et al.
improved sensitivity by 22% compared with thin-section CT, which was the next best method. On the other hand, in a different study, Swensen et al.
found that 10 of 85 cases that were diagnosed as benign by comparison with the reference phantom were later shown to be malignant. This represented a much higher mis-diagnosis rate than in other studies, and Swensen et al.
cautioned that even if the reference phantom indicated a high probability of benignity, those nodules should be considered indeterminate and should be closely followed up.
Today, thoracic scans are conventionally performed using multi-detector CT in helical mode, technologies that did not exist when the reference phantom was developed. Also, the new scanners employ high-frequency generators with kVp and mA feedback loops that make the exposures and therefore the reconstructions more reproducible. However, to our knowledge, CT scanner manufacturers still have not addressed the CT number inaccuracy issue. For our CAD application, our long-term goal is to compensate for variations in the CT numbers of the nodules with position in the lung field and with the size of the nodules by employing a modified reference phantom to determine CT number versus calcium concentration calibration curves throughout the lung fields. The curves will be used to convert the CT numbers of the voxels in the patient lung nodules to calcium concentrations, the values and distributions of which in turn will be employed as CAD features. The commercial reference phantom was modified for our studies by increasing the phantom thickness to account for the longer scan lengths associated with helical scanning with pitches greater than 1. Also, spherical rather than cylindrical reference nodules were employed in order to better simulate the shape of patient nodules and the associated partial volume effects on the estimation of the CT numbers.
It should be noted that the spherical reference nodules that were employed in our studies were uniform mixtures of CaCO3
in water-equivalent plastic. Therefore, they simulated “solid” solitary pulmonary nodules and are representative of only one of the three classes of nodules that are detected at screening. These classes include ground glass opacity, focal ground glass opacity with a solid central component, and solid nodules.8
Nevertheless, the CT-number-to-CaCO3
-concentration conversion relations that are derived with the reference nodules can be utilized to characterize entire nodules as well as regions-of-interest within the nodules in terms of calcium content. The calcium content should be less susceptible to factors that cause CT number variability such as differences in patient body size, nodule position within the lung, CT scanning parameters, CT scanner x-ray beam filtration, etc.
The purpose of the present study was to (1) develop the modified reference thorax phantom and nodules, (2) determine the uniformity of the CT numbers of the reference nodule samples and the dependence of the CT numbers on the sizes and calcium concentrations of the nodules, (3) determine the effect of the lung/air cavity on the measured CT numbers of the nodules, and (4) determine the reproducibility and dependence of the measured CT numbers of the reference nodules on their sizes, calcium concentrations, and positions within the thorax phantom for several multi-detector helical CT scanning protocols.