CT Screening for Lung Cancer: Frequency and Significance of Part-Solid and Nonsolid Nodules

Claudia I. Henschke 1 David F. Yankelevitz 1 Rosna Mirtcheva 1 Georgeann McGuinness 2 Dorothy McCauley 1 0lli S. Miettinen 3 for the ELCAP Group Received June 19, 2001; accepted after revision November 20, 2001. 1 Department of Radiology, New York Presbyterian Hospital Weill Cornell Medical Center, 525 E. 68th St., New York, NY 10021. Address correspondence to C. I. Henschke. 2 Department of Radiology, New York University Medical Center, 550 First Ave., New York, NY 10016. 3 Department of Medicine, New York Presbyterian Hopital Weill Cornell Medical Center, New York, NY 10021. AJR 2002;178:1053 1057 0361 803X/02/1785 1053 American Roentgen Ray Society CT Screening for Lung Cancer: Frequency and Significance of Part-Solid and Nonsolid Nodules OBJECTIVE. In the Early Lung Cancer Action Project (ELCAP), we found not only solid but also part-solid and nonsolid nodules in patients at both baseline and repeat CT screening for lung cancer. We report the frequency and significance of part-solid and nonsolid nodules in comparison with solid nodules. MATERIALS AND METHODS. We reviewed all instances of a positive finding in patients at baseline (from one to six noncalcified nodules) and annual repeat screenings (from one to six newly detected noncalcified nodules with interim growth) to classify each of the nodules as solid, part-solid, or nonsolid. We defined a solid nodule as a nodule that completely obscures the entire lung parenchyma within it. Part-solid nodules are those having sections that are solid in this sense, and nonsolid nodules are those with no solid parts. Chi-square statistics were used to test for differences in the malignancy rates. RESULTS. Among the 233 instances of positive results at baseline screening, 44 (19%) involved a part-solid or nonsolid largest nodule (16 part-solid and 28 nonsolid). Among these 44 cases of positive findings, malignancy was diagnosed in 15 (34%) as opposed to a 7% malignancy rate for solid nodules (p = 0.000001). The malignancy rate for part-solid nodules was 63% (10/16), and the rate for nonsolid nodules was 18% (5/28). Even after standardizing for nodule size, the malignancy rate was significantly higher for part-solid nodules than for either solid ones (p = 0.004) or nonsolid ones (p = 0.03). The malignancy type in the part-solid or nonsolid nodules was predominantly bronchioloalveolar carcinoma or adenocarcinoma with bronchioloalveolar features, contrasting with other subtypes of adenocarcinoma found in the solid nodules (p = 0.0001). At annual repeat screenings, only 30 instances of positive test results have been obtained; seven of these involved part-solid or nonsolid nodules. CONCLUSION. In CT screening for lung cancer, the detected nodule commonly is either only part-solid or nonsolid, but such a nodule is more likely to be malignant than a solid one, even when nodule size is taken into account. We initiated our Early Lung Cancer Action Project (ELCAP) in 1992 to assess the usefulness of a regimen of CT screening for lung cancer, and we have reported the frequency of a positive result of the screening test and of the diagnosis of malignancy at both baseline and annual repeat screenings [1, 2]. A positive finding on the screening test was defined as detection of between one and six noncalcified nodules at baseline screening; and at repeat screening, detection of between one and six new noncalcified nodules showing growth since the previous screening. All focal nonlinear densities were counted as representing nodules, and we classified a nodule as noncalcified if it failed to meet our criteria for a benign noncalcified nodule [1, 2]. Among these noncalcified nodules, we found solid nodules, which we defined as nodules that completely obscure the lung parenchyma within them. We also found nodules that did not completely obscure the entire lung parenchyma within them, commonly called ground-glass opacities [3 8]. We wanted to use the data from a CT screening program to address the frequency of occurrence of these different types of nodule and the frequency with which they represent malignancy. We also wanted to introduce a different terminology for ground-glass opacities because we believe that this term is not appropriate in the context of CT screening for lung cancer. The term ground-glass was introduced to describe and is still applied to not only focal abnormalities but diffuse ones AJR:178, May 2002 1053

Henschke et al. as well, so that, for our purposes, the adjective focal needs to be added. We also prefer to use the anatomic term nodule rather than opacity because the former is in line with other anatomic terms generally used in chest radiology, such as bronchi and blood vessels. Accordingly, in this article, we distinguish between solid and subsolid nodules. The former was defined as a nodule that completely obscures the entire lung parenchyma within it whereas the latter does not. A subsolid nodule can be further classified as either part-solid (in the case of a nodule with patches of parenchyma that are completely obscured) or nonsolid (in the case of a nodule with no such areas). Materials and Methods This study was based on the ELCAP experience with persons undergoing baseline and annual repeat CT screening for lung cancer [1, 2]. Among the 233 instances of positive findings on baseline CT scans, 159 of the findings involved only a single noncalcified nodule, 43 of the positive findings involved two noncalcified nodules, 16 positive findings involved three such nodules, seven positive findings involved four nodules, six positive findings involved five nodules, and two involved six nodules. Among the 30 instances of a positive finding on annual repeat CT scans, 28 involved a solitary nodule of the relevant type, one involved two nodules, and the remaining finding involved three nodules. We reviewed all these instances of positive finding, classifying each nodule as to its type solid, part-solid, or nonsolid on the basis of the nodule s appearance on the high-resolution CT scans obtained after the identification of the nodule on lowdose CT. The high-resolution CT scans of the nodules were obtained with a targeted field of view (9.6 cm), 1-mm collimation with overlapping 0.5-mm reconstructions, and high-spatial-frequency algorithm. A nodule was classified as part-solid if it contained patches that completely obscured the lung parenchyma (Figs. 1 and 2) or had spiculations (Fig. 3). A nodule was classified as nonsolid if none of the lung parenchyma within it was totally obscured (Figs. 4 and 5). In making the distinction between a partsolid and a nonsolid nodule, we did not regard blood vessels as solid components despite their solid appearance (Fig. 5). Figure 6 shows a solid nodule for comparison. Chi-square statistics with one degree of freedom were used for comparisons of the frequency of malignancy among the three types of nodule. The sizeadjusted frequencies were obtained by deriving mutually standardized rates with the weighting proportional to comparative information. Results Among the 233 positive findings on the baseline CT scans, 189 (81%) involved only solid nodules, 40 (17%) involved only partsolid or nonsolid nodules, and four (2%) involved a combination of both part-solid and nonsolid nodules. The distribution of the positive findings by size of the (solitary or otherwise) largest nodule is shown in Table 1, grouped by nodule type. The median diameter of the largest nodule was 3 mm for the solid nodules, 10 mm for the part-solid nodules, and 7 mm for the nonsolid nodules. As this table indicates, part-solid nodules were less common than nonsolid ones. The largest nodule was part-solid in 16 instances and nonsolid in 28 instances. Fig. 1. High-resolution CT scan shows part-solid nodule with central cystic space in 72-year-old man. Final pathologic diagnosis was adenocarcinoma. The prevalence of malignancy by the size and type of the largest nodule is shown in Table 2. The prevalence of malignancy increased markedly as the size of the largest nodule increased and was distinctly higher among the part-solid and nonsolid nodules combined (15/44, 34%) than among solid nodules (14/189, 7%; p = 0.000001). After adjustment for the differing size distributions, the prevalence still was somewhat higher for the part-solid and nonsolid nodules combined than for solid ones (p = 0.04). Among the mutually standardized rates for all three types of nodules, the malignancy Fig. 2. High-resolution CT scan shows part-solid nodule detected on baseline CT in 71-year-old woman. Solid components are centrally located and surrounded by nonsolid component. Air bronchograms are seen in solid component. Final pathologic diagnosis was adenocarcinoma. Fig. 3. High-resolution CT scan reveals part-solid nodule with spiculations and pleural tag that proved to be adenocarcinoma in 75-year-old woman. 1054 AJR:178, May 2002

CT Screening for Lung Cancer Fig. 4. High-resolution CT scan depicts nonsolid nodule that proved to be adenocarcinoma with bronchioloalveolar features in 76-year-old woman. Fig. 6. Magnification of high-resolution CT scan reveals solid nodule found to be adenocarcinoma in 62-year-old man. Fig. 5. Magnification of high-resolution CT scan shows nonsolid nodule that has not yet been biopsied in 68- year-old man. No solid components other than blood vessels are seen. Blood vessels (top arrow), bronchus (middle arrow), and cyst or area of emphysema (bottom arrow) can be identified. rate for the part-solid nodules was significantly higher than the rates for either solid nodules (p = 0.004) or nonsolid ones (p = 0.03). When adjusting the malignancy rate of solid nodules to the distribution of the nonsolid ones, the results were identical. Table 3 gives the distribution of malignancy type by solid and subsolid nodule type. Among the malignancies associated with subsolid nodules, we found a preponderance of bronchioloalveolar carcinoma or adenocarcinoma with bronchioloalveolar features, which are quite different entities from the malignancies associated with the solid nodules (p = 0.0001). Among the 30 positive findings on annual repeat CT scans were no instances of partsolid nodules, seven findings of nonsolid nodules only, and 23 findings of solid ones only. The prevalence of diagnosed malignancy in these cases was seven of 23 solid nodules and one of seven nonsolid nodules. These numbers are too small for further scrutiny. Discussion Nodules that are not considered solid because they do not completely obscure the en- AJR:178, May 2002 1055

Henschke et al. tire parenchyma we called subsolid nodules. These nodules can be further subdivided into part-solid and nonsolid nodules. They are a topic peculiar to CT of the chest, and their importance in CT-based screening for lung cancer has not been fully appreciated. Nevertheless, every effort was made in the ELCAP to identify them, and they indeed were fully included in the classification of the initial test finding as positive or negative. The present results indicate that the frequency of these subsolid nodules (in relation to that of solid nodules) in CT-based screening for lung cancer is appreciable (detected on approximately 20% of baseline screenings), a topic we believe has not been discussed in previous literature. With the finer CT collimation made possible by advancements in technology, the relative frequency of detection of the part-solid and, especially, the nonsolid nodule will be even higher. A more notable finding in our study, however, has to do with the significance of these nodules: overall, the frequency of malignancy in them was much higher than in solid nodules, in the part-solid nodules in particular. To the best of our knowledge, no previous literature exists on malignancy rates in subsolid nodules. In addition, the distribution by malignancy type was strikingly different in the subsolid nodules as compared with the solid ones. The malignancies in subsolid nodules were typically bronchioloalveolar carcinomas or adenocarcinomas with bronchioloalveolar features, whereas in solid ones the malignancies were typically other subtypes of adenocarcinoma. This comparison also has not been addressed in the literature. Although there may be suspicion that bronchioloalveolar carcinoma represents overdiagnosis of lung cancer that is, that it progresses so slowly as to be inconsequential the natural history of three of our patients who were clinically diagnosed as being in stage IA at the time of detection suggests otherwise. Two patients progressed to stage IV adenocarcinoma during the 4 years that elapsed before attempted surgical resection, whereas the third patient remained in stage IA for 2 years before undergoing resection. In the most notable report on the course of bronchioloalveolar carcinoma, Hill [9] noted that in all 46 patients with unresected clinically stage I bronchioloalveolar carcinomas, the disease progressed to a more advanced stage, typically within 2 years. Once the disease was beyond stage I, death TABLE 1 Distribution of Positive Findings at Baseline Screening by Size and Type of Largest Nodule Size (in mm) of Largest Nodule (% of Nodule Group) 2 5 6 10 11 20 21 45 Total Solid 127 (67) 49 (26) 11 (6) 2 (1) 189 (100) Partially solid 2 (12) 6 (38) 6 (38) 2 (12) 16 (100) Nonsolid 7 (25) 15 (53) 5 (18) 1 (4) 28 (100) Total 136 (58) 70 (30) 22 (10) 5 (2) 233 (100) Note. Percentages for part-solid and nonsolid nodules have been rounded to total 100%. TABLE 2 Frequency of Malignancy Found at Baseline Screening by Size and Type of Largest Nodule a Diameter (in mm) of Largest Nodule Totals 2 5 6 10 11 20 21 45 Crude Standarized b Solid 1/127 (1) 7/49 (14) 4/11 (36) 2/2 (100) 14/189 (7) 32% Partially solid 0/2 (0) 2/6 (33) 6/6 (100) 2/2 (100) 10/16 (63) 63% Nonsolid 0/7 (0) 5/15 (33) 0/5 (0) 0/1 (0) 5/28 (18) 13% Total 1/136 (1) 14/70 (20) 10/22 (45) 4/5 (80) 29/233 (12) Note. Numbers in parentheses are percentages. a Of 29 diagnosed malignancies, all but one were associated with nodules that were solitary or the largest. b Standarized for size using part-solid nodules as standard (because they were smallest group). TABLE 3 Distribution of Malignancy by Type of Largest Nodule Malignancy Type Subsolid Solid Bronchioloalveolar 4 0 carcinoma Adenocarcinoma with 6 0 bronchioloalveolar features Other adenocarcinomas 5 8 Other carcinomas 0 6 Total 15 14 typically occurred within 3 years. The progression was slow in only five of these 46 patients, but the disease in these patients, too, progressed to an advanced stage. Results of more recent studies have also suggested this progression on the basis of cytologic and histologic evidence and studies of monoclonality and molecular markers [10 14]. Therefore, because subsolid nodules are a topic of greater importance than previously presumed in the context of CT screening for lung cancer, these nodules need to be studied in greater detail. Work is needed on the quantification of the extent of the solid component and of the rates of growth of the solid and nonsolid components, and then on the significance of these determinations. The radiologic pathologic correlation of these subsolid nodules and information on potential biomarkers need further elucidation. On the basis of our experience and that of others [3 14], we think that the solid component is caused by lack of aeration in the alveoli, perhaps because the alveoli are being compressed or are otherwise being inadequately oxygenated. To the extent that a nodule is not solid, it presumably owes its cloudy appearance to partially aerated alveoli or thickened alveolar walls. For further research, pooling of data is necessary to adequately determine the natural history of malignancies diagnosed in these subsolid nodules and in their more detailed subtypes. References 1. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99 105 2. Henschke CI, Naidich DP, Yankelevitz DF, et al. Early Lung Cancer Action Project: preliminary findings on annual repeat screening. Cancer 2001;92:153 159 3. Miller RR. Bronchioloalveolar cell adenomas. Am J 1056 AJR:178, May 2002

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