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Thoracic Imaging |
1 From the Department of Radiology, St Marianna University School of Medicine, 2–16-1 Sugao, Miyamae-Ku, Kawasaki City, Kanagawa 216-8511, Japan. Received April 13, 2004; revision requested June 1; revision received July 3; accepted July 17. Address correspondence to S.M. (e-mail: shinma@d9.dion.ne.jp).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: The authors’ institutional review board required neither its approval nor patient informed consent for this retrospective study. The authors retrospectively reviewed 2-mm-thick CT images of 41 nodules (21 malignant, 20 benign) in 41 patients with emphysema (age range, 58–88 years; mean, 71.9 years) and 40 nodules (20 malignant, 20 benign) in 40 patients without emphysema (age range, 50–85 years; mean, 69.2 years). Two radiologists who were unaware of the diagnosis independently evaluated the shape and margin of the nodule, recorded the presence of ground-glass opacities and air bronchograms, and classified nodules into two diagnostic categories: malignant and benign. Final decisions were reached by consensus. For quantitative assessment of the nodules, the fractal dimensions of the nodule interfaces and circularity of the nodule shape were calculated with an image-processing program, and the percentage of the nodule surrounded by emphysema was obtained. Statistical comparisons were made with a 
2 or Fisher exact test and the Mann-Whitney U test.
RESULTS: In patients with emphysema, there were no significant differences in fractal dimension, circularity, or frequency of lobulation or spiculation between malignant and benign nodules. Of the 41 nodules in patients with emphysema, 26 (63%) were correctly diagnosed. Thirteen benign nodules (65%) were diagnosed as malignant in patients with emphysema. Of the 40 nodules in nonemphysematous lungs, 37 (93%) were correctly diagnosed. The mean percentage of emphysema around the nodule was greater for misdiagnosed nodules than for correctly diagnosed nodules (P = .003).
CONCLUSION: Malignant and benign nodules associated with emphysema exhibited considerably more overlap in CT features than did nodules in nonemphysematous lungs.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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The CT appearances of peripheral solitary lung cancer have been well described in numerous previous reports (12–19), but not the CT findings in lung cancer with coexisting lung disease. A few studies have assessed CT findings of lung cancer associated with previous lung diseases, such as pulmonary fibrosis (20,21). Although the association of lung cancer with pulmonary emphysema and bullae has been well documented (1–7,22–26), to our knowledge, the CT appearances of lung cancer associated with pulmonary emphysema or bulla have not previously been assessed in detail.
Emphysema is defined anatomically as abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis (27). Reflecting these pathologic conditions, pneumonia in the presence of emphysema has an unusual appearance called "Swiss-cheese pattern" (28,29). It has also been reported that emphysema can influence the appearance and distribution of pulmonary edema (30). Preexisting emphysema can influence the radiographic appearance of various lung diseases. Thus, we hypothesized that the extent of emphysema around a peripheral lung nodule might affect its CT features. The purpose of this study was to analyze retrospectively the CT features of peripheral noncalcified solitary pulmonary nodules in patients with and those without emphysema.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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One radiologist (S.M.; 12 years of experience with chest CT) reviewed the medical records and CT images of all patients with pulmonary emphysema who underwent CT in our institution between January 2000 and May 2003. Fifty-four patients had a peripheral solitary noncalcified pulmonary nodule that was smaller than 3 cm in largest diameter and located in an area of emphysema and had no hilar or mediastinal lymphadenopathy or extrapulmonary neoplasms. We excluded four patients whose emphysema was present only around the nodule and nine patients in whom the nodule was not diagnosed. The final study population included 41 patients with a peripheral solitary nodule associated with emphysema (40 men, one woman; age range, 58–88 years; mean age, 71.9 years; 38 current or former smokers, three lifetime nonsmokers). Of the 41 nodules, 21 were malignant and 20 were benign. All patients had emphysema in both lungs, and all nodules were located in an area of emphysema.
All 21 patients with malignant nodules had been given a definitive final diagnosis based on one of the following: (a) transbronchial lung biopsy (n = 4), (b) CT-guided needle biopsy (n = 3), or (c) surgery (n = 14). LVRS was not performed in any patient. The malignant nodules comprised 16 adenocarcinomas and five squamous cell carcinomas.
Nine nodules were diagnosed as benign because of negative results (no evidence of malignant cells) at transbronchial lung biopsy (n = 6) or CT-guided needle biopsy (n = 3), and these nodules decreased substantially in size or resolved within 6 months of CT follow-up. The remaining 11 benign nodules were diagnosed as benign because of either radiologic evidence of lack of growth during a follow-up of at least 2 years (n = 3) or substantial decrease in nodule size or resolution of the nodule during 6 months of follow-up (n = 8). The malignant nodules were located in the upper lobe in 12 patients, the middle lobe in one, and the lower lobe in eight. The benign nodules were located in the upper lobe in 15 patients and in the lower lobe in five.
The same radiologist (S.M.) reviewed the medical records and CT images of 171 patients who had a peripheral solitary noncalcified nodule smaller than 3 cm in largest diameter, had no hilar or mediastinal lymphadenopathy or extrapulmonary neoplasms, and underwent CT between January 2000 and May 2003. Of those 171 patients, 52 had no obvious coexisting lung disease. From among these 52 patients, the radiologist (S.M.) randomly selected 40 (39 men, one woman; age range, 50–85 years; mean age, 69.2 years; 28 current or former smokers, 12 lifetime nonsmokers)—20 patients with a malignant nodule and 20 with a benign nodule. All 20 malignant nodules had a definitive final diagnosis based on one of the following: (a) transbronchial lung biopsy (n = 3); (b) CT-guided needle biopsy (n = 1); or (c) surgery (n = 16). These nodules comprised 14 adenocarcinomas, five squamous cell carcinomas, and one small cell carcinoma.
Two of the 20 benign nodules were diagnosed because of negative results of transbronchial lung biopsy; the nodules decreased substantially in size or resolved within 6 months of radiographic follow-up. The other 18 nodules were diagnosed as benign because there was radiologic evidence of lack of growth during a follow-up of at least 2 years (n = 4) or because the nodule decreased substantially in size or resolved within 6 months (n = 14). The malignant nodules were located in the upper lobe in eight patients, the middle lobe in four, and the lower lobe in eight. The benign nodules were located in the upper lobe in 12 patients and in the lower lobe in eight.
CT Scanning
Eleven patients with emphysema and 13 patients without emphysema had been scanned with a multi–detector row spiral CT scanner (Aquillion or Asteion; Toshiba Medical, Tokyo, Japan) within one breath hold at deep inspiration. The scans were obtained with four detector rows, a 2-mm section thickness, and a table feed of 12–16 mm per 0.5–0.75-second scanner rotation (ie, pitch 6–8). Scanning was performed at 120 kV and 200–250 mAs, with a 512 x 512 matrix. The raw data were retrospectively reconstructed with a section thickness of 8 mm and an additional section thickness of 2 mm, with 2–5-mm intervals, and with use of a lung algorithm. A section interval of 10 mm was reconstructed for evaluation of emphysema.
Thirty patients with emphysema and 27 without emphysema had been scanned with a single–detector row helical CT scanner. Helical CT scans (X-Vigor; Toshiba Medical, Tokyo, Japan) were obtained throughout the entire thorax with 8- or 10-mm collimation. Scanning parameters for helical CT were 120 kVp, 180–220 mAs, and 1-second scanning time. Additional thin sections through nodules were obtained with 2-mm collimation, at 2–5-mm intervals, and with a lung algorithm. All CT images were photographed at identical window settings (window width, 1500 HU; window level, –600 HU) on laser film.
Contrast material (iopamidol, Iopamiron 300, Nihon Schering, Osaka, Japan; or iohexol, Omnipaque 300, Daiichi Pharmaceutical, Tokyo, Japan) was intravenously administered before scanning to 11 of the 41 patients with emphysema and to 25 of the 40 patients without emphysema.
Evaluation of CT Findings
Nodule.—All thin-section CT images were reviewed independently by two chest radiologists who had not initially selected the nodules for this study (Y.K. and K.Y., who had 19 and 10 years of experience with chest CT, respectively). They were unaware of the final diagnosis, and final decisions on the findings were reached by consensus. CT analysis included the maximum size, shape, and margin of the nodule and the presence or absence of ground-glass opacity and internal low attenuation such as air bronchogram or cavitation. All nodules were measured from a transverse section that included the greatest diameter of the lesion. The shape of the lesion was categorized as round or oval, polygonal, or irregular. The border was classified as well defined if the nodule was sharply and distinctly separated from surrounding lung parenchyma. The presence of lobulation or spiculation was also recorded. To analyze the combination of CT findings, one point was given for each of the following: the presence of an ill-defined border, lobulation, spiculation, air bronchogram, and ground-glass opacity. The total score was obtained for each nodule.
We analyzed the nodule interfaces with fractal analysis. Fractal analysis is a mathematical method that can be used to quantify texture on digital images and that provides physical measurements related to the complexity of an object (31). Thin-section CT images were transferred to a personal computer, and fractal analysis was performed with a semiautomatic image-processing program (Image J, version 1.3 [public-domain Java image-processing program inspired by NIH Image for the Macintosh]). For calculation of fractal dimensions, binary images of nodules were obtained. Regions of interest with a matrix size of 64 x 64 or 128 x 128 were selected manually over the nodule interfaces on thin-section CT images by one radiologist (S.M.). Fractal dimension was calculated automatically with a box-counting method.
We also determined the circularity (C) of each nodule to analyze the deviation from circular form with the same image-processing program, according to the following formula: C = 4
(A/P2), where A is the area and P is the perimeter. A circularity value of 1.0 indicates a perfect circle. Values approach 0.0 as a polygon becomes increasingly elongated. To calculate the fractal dimension and circularity, we used the section in which the largest diameter of the nodule was depicted. All measurements were performed three times, and the mean values were recorded.
Emphysema.—To assess emphysema throughout the lung, the grade of emphysema was evaluated visually on CT scans throughout the lung by one radiologist (S.M.) and was scored as follows: grade 1, more normal lung than emphysema (emphysema, <30%); grade 2, even distribution of emphysema and normal lung (emphysema, 30%–60%); and grade 3, more emphysema than normal lung (emphysema, >60%). Next, to evaluate the degree of emphysema around the nodules, the observers subjectively and visually quantified the percentage of low-attenuating area, which reflected emphysema along the circumference of the nodule. A value of 100% around a nodule indicated that the nodule was completely surrounded by emphysema. The percentage of emphysema around a nodule approaches 0 as the nodule becomes completely surrounded by normal lung parenchyma. The section in which the largest diameter of the nodule was depicted was used for this semiquantitative analysis.
Two radiologists (Y.K. and K.Y.) independently classified nodules into one of two diagnostic categories: malignant and benign. Final decisions were reached by consensus. These decisions were mainly based on the characteristic CT findings of malignant and benign pulmonary nodules. It is highly probable that a nodule with a lobulated contour and an irregular or spiculated margin is malignant (14,15,18,19) and also highly probable that an oval or polygonal nodule with smooth, well-defined margins is benign (13,15,18). When a nodule had CT features of both malignancy and benignity, it was diagnosed as malignant. In addition, all nodules were divided into two groups to assess the accuracy of the CT diagnosis: correctly diagnosed and misdiagnosed nodules.
Statistical Analysis
Comparisons of the frequencies of various CT findings and shapes between malignant and benign nodules in patients with emphysema and in patients without emphysema were evaluated with the 2 or Fisher exact test when table cells had expected values below five. Comparisons of the frequencies of various CT findings of malignant nodules and benign nodules between patients with emphysema and those without were also evaluated by using the 2 or Fisher exact test when table cells had expected values below five.
The Mann-Whitney U test was used to compare the mean total score of the CT findings, fractal dimension, circularity, and percentage of emphysema around the nodule between (a) benign and malignant nodules in patients with emphysema and in those without; (b) in all malignant nodules and all benign nodules between patients with emphysema and those without; (c) between nodules with a high probability of being malignant and those with a high probability of being benign; and (d) between correctly diagnosed and misdiagnosed nodules.
The mean size and mean grade of emphysema were also compared between malignant and benign nodules and between correctly diagnosed and misdiagnosed nodules with the Mann-Whitney U test. All statistical analyses were performed with StatView 5.0 software (SAS Institute, Cary, NC). Data are expressed as means ± standard deviations. For all statistical analyses, P values less than .05 were considered to indicate a significant difference.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Comparison of Nodules: Patients with Emphysema versus Those Without
In all patients with malignant nodules, the frequency of lobulation was significantly greater in patients without emphysema (P = .043). There was no significant difference in the frequencies of well-defined borders, spiculation, internal low-attenuating areas, or ground-glass opacity between patients with emphysema and those without (P = .399, P = .159, P = .52, and P = .197, respectively). In all patients with benign nodules, the frequency of spiculation was significantly greater in patients with emphysema (P = .003). The frequency of well-defined borders was significantly greater in patients without emphysema (P = .041). There was no significant difference between patients with emphysema and those without in the frequencies of lobulation, internal low-attenuating areas, and ground-glass opacity (P = .408, P = .273, and P > .999, respectively).
Irregularly shaped benign nodules were more frequent in patients with (65%) than in patients without (20%) emphysema (P = .01) (Table 2). Round or oval benign nodules were less frequent in patients with (5%) than in those without (35%) emphysema (P = .044).
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Malignant versus Benign Diagnosis
Of the 41 nodules in patients with emphysema, 32 (78%) were classified as malignant, and nine (22%) were classified as benign (Table 4). The mean scores for CT findings and fractal dimensions were significantly greater in nodules diagnosed as malignant than in those diagnosed as benign (P < .001 for both). There were no significant differences according to diagnosis in the mean percentage of emphysema around the nodule or in circularity (P = .813 and P = .313, respectively).
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Correctly Diagnosed versus Misdiagnosed Nodules
There was no significant difference in mean fractal dimensions or circularity between correctly diagnosed and misdiagnosed nodules in patients with emphysema (P = .372 and P = .645, respectively) (Table 5). The mean percentage of emphysema around the nodule in patients with emphysema was 37.5% ± 19.2 for correctly diagnosed nodules and 56.7% ± 14.1 for misdiagnosed nodules. The mean percentage of emphysema around the nodule was greater for misdiagnosed nodules than for correctly diagnosed nodules (P = .003). In patients without emphysema, there were no significant differences in fractal dimensions or circularity between correctly diagnosed and misdiagnosed nodules (P = .804 and P = .264, respectively).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Numerous studies involving CT have been conducted to improve differentiation between malignant and benign solitary pulmonary nodules (12–18). Most of those studies have been based on morphologic analyses and nodule size. Internal and edge characteristics of solitary pulmonary nodules do give some indication of the probability of malignancy, but we found that malignant nodules in patients with emphysema had lower frequencies of lobulation and spiculation than those previously reported for malignant nodules in the general population. Zwirewich et al (14) reported that in patients with normal lung, spiculation was significantly more frequent among malignant nodules than among benign nodules. In the patients with emphysema in our study, however, there was no significant difference in the frequency of spiculation between malignant and benign nodules.
We also found that the frequencies of well-defined border and lobulation significantly differed between malignant and benign nodules in patients with normal lung parenchyma, although there was considerable overlap in both well-defined margins (13) and lobulation (14) between benign and malignant nodules. We found no significant differences in these edge characteristics between malignant and benign nodules in patients with emphysema. Internal low-attenuating areas and ground-glass opacities have been found more frequently in malignant than in benign nodules in previous studies (14,17). We found similar results in patients without emphysema, although the differences were not significant. In patients with emphysema, we found no significant differences between malignant and benign nodules in the frequencies of internal low-attenuating areas and ground-glass opacities.
Moreover, we found no significant differences in fractal dimension or circularity between malignant and benign nodules associated with emphysema. Kido et al (32) reported that fractal dimensions reflected characteristics of the interfaces of small peripheral pulmonary nodules and could be used to distinguish between benign and malignant pulmonary nodules. In our study, in patients with normal lung parenchyma, the mean fractal dimension and circularity differed significantly between malignant and benign nodules. Because we assessed solitary pulmonary nodules without calcification, typical benign nodules were not included in this study. Our exclusion of calcified benign nodules may have affected our results for patients with emphysema, but the differences in edge characteristics and fractal dimension between malignant and benign nodules in patients without emphysema were similar to previous findings.
Furuya et al (15) analyzed margin characteristics of pulmonary nodules at thin-section CT and found that 80% of the polygonal nodules were the result of inflammatory change and 20% represented primary lung cancer. Pathologically, fibrosis in the tumor and emphysema were most frequent in neoplasms with tentacle or polygonal shapes, so Furuya et al speculated that fibrosis in the tumor and emphysema may be important factors in the appearance of polygonal nodules with malignancy. When the surrounding parenchyma is emphysematous, the extension of tumor cells along its interstitium may sometimes produce a concave or rough spiculated margin. Li et al (33) analyzed lung cancers missed with CT screening and concluded that lesions were missed on 16 of 39 CT scans owing to interpretation error. These lesions mimicked benign nodules and were associated with underlying lung disease, such as tuberculosis, emphysema, or lung fibrosis.
Conversely, benign nodules associated with emphysema may resemble malignancies. In our study, 65% of benign nodules (13 of 20) were misdiagnosed in patients with emphysema. Gierada et al (34) reported that pseudomasses in patients with severe bullous emphysema most likely result from compression of the lung by adjacent large bullae. The CT features of focal organizing pneumonia have been reported; in some instances, it is difficult to differentiate focal organizing pneumonia from bronchogenic carcinoma even with CT (35). In our study, although we included patients for whom histologic diagnosis had not been made, spiculation was found in 77% of misdiagnosed benign nodules. Benign nodules are more likely to exhibit CT characteristics of malignant nodules, such as spiculation, in patients with preexisting emphysema.
Patients considered eligible for LVRS are at high risk of developing lung cancer. Hazelrigg et al (3) identified at least one pulmonary nodule in 111 (39.5%) of 281 patients undergoing LVRS and found 17 malignant nodules among 78 resected nodules. McKenna et al (1) found nodules, including 11 non–small cell lung cancers and 42 benign lung masses, in 51 (16%) of 325 patients selected for LVRS. These reports suggest the importance of preoperative detection and accurate diagnosis of lung cancer in candidates for LVRS. However, our results show that accurate diagnosis of nodules associated with emphysema is difficult on the basis of CT findings.
Our study had several limitations. First, there were few pathologic diagnoses of the benign nodules, because most patients were treated without surgery or underwent additional follow-up. Moreover, some nodules were diagnosed as benign because they decreased substantially in size within 6 months, but later follow-up has not been performed. Second, the CT appearance of malignant nodules varies subtly with histologic type (14,15). Our sample numbers were too small to permit evaluation of CT features according to histologic type. In addition, metastatic lung tumors were not included in our study because no patient was found to have a solitary metastatic lung tumor and emphysema. Third, emphysema in the circumference of the cancer is a secondary characteristic of lung cancer. We excluded cases in which the only emphysema was in the circumference of the nodule. Fourth, we did not analyze the degree of contrast material enhancement of pulmonary nodules. Results of several studies have shown that postcontrast nodule enhancement of less than 15 HU is a highly reliable indicator of benignity in solitary pulmonary nodules (36,37). In our study, however, dynamic CT was not performed in any patient.
In conclusion, we found that emphysema around the nodule was related to the CT appearance and diagnosis of noncalcified solitary pulmonary nodules, and malignant and benign nodules associated with emphysema exhibited considerably more overlap in CT appearance than did nodules in patients without emphysema. This made it more difficult to distinguish accurately between benign and malignant nodules in patients with emphysema. CT findings cannot be used to reliably discriminate between malignant and benign nodules associated with severe emphysema.
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FOOTNOTES |
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Authors stated no financial relationship to disclose.
Author contributions: Guarantor of integrity of entire study, S.M.; study concepts and design, S.M.; literature research, S.M.; clinical studies, S.M., Y.K., K.Y.; data acquisition, S.M.; data analysis/interpretation, S.M., Y.K., K.Y.; statistical analysis, S.M., Y.K., H.N.; manuscript preparation, S.M., Y.K.; manuscript definition of intellectual content, revision/review, and final version approval, all authors; manuscript editing, S.M., Y.K., Y.N.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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