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Ground-Glass Opacities on Thin-Section Helical CT: Differentiation Between Bronchioloalveolar Carcinoma and Atypical Adenomatous Hyperplasia

¹ Department of Diagnostic Radiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjyo, Kumamoto 860-8556, Japan.
² Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

Received September 4, 2007; accepted after revision October 23, 2007.

 
Address correspondence to K. Awai.

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Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
OBJECTIVE. The purpose of our study was to investigate the differentiation between bronchioloalveolar carcinoma and atypical adenomatous hyperplasia manifesting pure ground-glass opacity (GGO) based on selected features on thin-section helical CT scans.

MATERIALS AND METHODS. We evaluated 35 bronchioloalveolar carcinomas and 17 atypical adenomatous hyperplasias that were histologically confirmed and that manifested pure GGO on thin-section helical CT scans. We recorded the age, sex, and smoking history (Brinkman index) of the patients. Two board-certified radiologists measured the maximum diameter and mean attenuation value of the nodules; the measured values were averaged for each nodule. Using a 3-point scale, they visually assessed the images for consensus with respect to nodular sphericity, marginal irregularity, vascular convergence, pleural retraction, and findings of an internal air bronchogram. CT findings of atypical adenomatous hyperplasia and bronchioloalveolar carcinoma were compared using univariate and multivariate logistic regression analysis; the odds ratio was computed using the atypical adenomatous hyperplasia group as the reference group.

RESULTS. By univariate analysis, the patient age, nodular maximum diameter, mean attenuation value, and findings of an internal air bronchogram were statistically significantly associated with bronchioloalveolar carcinoma (odds ratio [OR] = 1.10 [p = 0.012], OR = 1.27 [p < 0.01], OR = 1.01 [p = 0.023], and OR = 25.30 [p < 0.001], respectively), and sphericity was significantly associated with atypical adenomatous hyperplasia (OR = 0.059, p < 0.001). By multivariate analysis, sphericity was significantly associated with atypical adenomatous hyperplasia (OR = 0.125, p = 0.042) and findings of an internal air bronchogram were associated with bronchioloalveolar carcinoma (OR = 16.10, p = 0.007).

CONCLUSION. Nodular sphericity and an internal air bronchogram were useful at thin-section helical CT performed to differentiate between bronchioloalveolar carcinoma and atypical adenomatous hyperplasia. Interobserver agreement was high for each finding.

Keywords: atypical adenomatous hyperplasia • bronchioloalveolar carcinoma • ground-glass opacity • thin-section helical CT

Introduction

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Pulmonary nodules with ground-glass opacity (GGO) [1] are frequently detected at lung cancer screening with low-dose CT; 19–38% of detected nodules manifested GGO [2, 3]. Nodules with GGO have been classified as part-solid and nonsolid GGO nodules by Henschke et al. [2], who also reported that 63% of part-solid and 18% of nonsolid nodules were malignant. Nonsolid GGO nodules, called pure GGOs, may be attributable to focal inflammation, atypical adenomatous hyperplasia, and bronchioloalveolar carcinoma [4–6]. Atypical adenomatous hyperplasia has been suggested as a possible precursor to bronchioloalveolar carcinoma [7], and both atypical adenomatous hyperplasia and bronchioloalveolar carcinoma without fibroblast proliferation exhibit a pathologic replacement growth pattern of atypical or cancer cells [7].

Yang et al. [8], who studied adenocarcinomas showing pure GGO on high-resolution CT, categorized 94% as type A or B and 6% as type C lesions on the basis of the Noguchi classification [9], a pathologic classification for small adenocarcinomas in which types A and B carry a favorable (5-year survival rate, 100%) and type C a less favorable (5-year survival rate, 75%) prognosis. Although bronchioloalveolar carcinomas with pure GGOs are encountered less frequently, they include tumors with a relatively poor prognosis. To our knowledge, there have been no reports on the differentiation between atypical adenomatous hyperplasia, bronchioloalveolar carcinomas, and adenocarcinoma. Therefore, we attempted to identify thin-section helical CT findings useful for the differentiation between atypical adenomatous hyperplasia and bronchioloalveolar carcinoma.

Materials and Methods

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All patients who underwent CT examination at our institute gave their prior informed consent for the use of their CT images in future retrospective studies. Our institutional review board approved this retrospective study and informed specific study-related consent was waived by the study subjects.

Nodule Selection
One chest radiologist with 21 years of chest CT experience reviewed the records of 451 consecutive patients suspected of harboring pulmonary nodules who underwent thin-section helical CT of the chest at our institute between January 2000 and April 2005. Most of these patients were suspected of having pulmonary nodules or manifested pulmon ary nodules on chest radiographs or chest CT scans acquired at other institutions and were referred to us for further workup. For inclusion in this study, the following criteria had to be satisfied: The pulmonary nodules were pure GGOs on high-resolution CT; to facilitate defining the nodule boundary, there was no consoli dation due to pneumonia or idiopathic pulmonary fibrosis around the nodules; and bronchioloalveolar carcinoma or atypical adeno matous hyperplasia was histo logically con firmed in specimens obtained at video-assisted thoracic surgery.

Two pathologists independently reviewed the histologic specimens and confirmed the pathologic diagnosis in consensus. On the basis of these criteria, 52 patients (35 with bronchioloalveolar carcinoma and 17 with atypical adenomatous hyperplasia) were included in the present study. Among them, 40 had a single GGO nodule, seven had two GGO nodules, three had three, and two had four 4 GGO nodules (total nodules, 71). In the 12 patients with multiple nodules, we used the largest of their histologically confirmed nodules for CT analysis to avoid statistical multiplicity [9].

The age, sex, and Brinkman index—defined as the number of cigarettes smoked per day multiplied by the number of years the subject smoked [10]—of all study subjects were recorded by one of the authors.

CT
CT scans were obtained on one of two 4-MDCT scanners (LightSpeed QX/I, GE Healthcare; or Somatom Volume Zoom, Siemens Medical Solutions). After routine helical scanning of the whole thorax (image thickness and interval, 5 mm each), thin-section helical scans with the scan range limited to approximately 5 cm, including the pulmonary nodules, were obtained. Two CT technologists with 12 and 20 years of experience reviewed the routine CT images and chose the scan range for thin-section helical scans. At the LightSpeed scan ner, the parameters for routine and thin-section helical scans were: detector collimation, 4 x 2.5 mm and 4 x 1.25 mm; helical pitch (beam pitch), 1.5 and 0.75; section thickness and interval, 5.0 and 1.25 mm; 0.8-second rotation time; 120 kVp; and 250 mA and 160–200 mA, respectively. The reconstruction algorithm for thin-section helical scans was the "bone plus" algorithm.

At the Somatom scanner, the parameters for routine and thin-section helical scans were detector collimation, 4 x 2.5 mm and 4 x 1.0 mm; helical pitch, 1.5; section thickness and interval, 5.0 and 1.0 mm; 0.5- and 0.75-second rotation time; 120 kVp; and 300 mA and 160–200 mA, respectively. The reconstruction algorithm for thin-section helical scans was the "B60s" algorithm.

The LightSpeed scanner was used in 15 of 17 atypical adenomatous hyperplasia patients and in 29 of 35 bronchioloalveolar carcinoma patients; the other patients were scan ned with the Somatom scanner. Contrast enhance ment was not performed in any of the 52 cases.

Analysis of Thin-Section Helical CT
The thin-section helical scans were reviewed by two board-certified radiologists with 10 and 9 years of chest CT experience, respectively, who specialize in body imaging and read chest CT scans on a regular basis. They were blinded to the pathologic diagnosis but were cognizant of the patient age, sex, and Brinkman index.

All images were presented in random order on PCs (Precision 5100C, Dell) with dual 3.4-GHz processors (Pentium 4, Intel) and linked to a liquid crystal color monitor with a display of 1,920 x 1,200 lines (monitor model 2405 FPW, Dell). A PACS (Dr ABLE EX; Fujitsu Ltd.) was used on the operating system (Windows XP, SP 2.0, Microsoft). On the PACS, axial, coronal, and sagit tal images of each patient were presented simul taneously. The preset window level (–600 H) and window width (1,500 H) could be changed at will; reading time was not limited. The radiologists were presented only the relevant slices that contained the nodules to be evaluated.

The radiologists independently identified the slice that showed the maximum diameter of the nodule on axial, coronal, or sagittal sections. They measured the maximum diameter of the nodule using an electronic cursor on the PACS. The measured values they obtained were averaged for each nodule. They also measured the mean attenuation value of the tumor using region-of-interest (ROI) cursors on the slices featuring the maximum lesion diameter. Attempts were made to set the ROI area as large as possible in the tumor. The measured CT attenuations were averaged for each nodule.

Using a 3-point scale, the two radiologists also visually assessed the thin-section helical CT scans for nodular sphericity, irregularity of the nodule margin, vascular convergence around the nodule, pleural retraction, and findings of an internal air bronchogram in the nodule (Table 1). Referring to previously published work [1, 3, 5, 11–13], two chest radiologists with 21 and 4 years of experience analyzing chest CT scans selected these particulars in consensus.

When the diameter of a nodule was almost the same on axial, coronal, and sagittal views, we considered the nodule to be a 3D sphere. A pleural tag was defined as a linear strand that originated at the nodule surface and terminated at the pleural surface [14]. Vascular convergence was defined as narrowing of the distance between the dichotomous branches of pulmonary vessels around the nodule [1], and internal air bronchogram was defined as branching structures with air density in the nodule [15].

The rating of all findings was such that scores of 1 and 3 represented the lowest and highest degree, respectively. If, after independent evaluation, the two readers assigned an identical score, it was adopted as the definitive score for that particular finding. If the scores assigned by the two readers did not agree, a score of 2 (undetermined) was assigned for the finding.

To learn how to measure maximum diameters and mean attenuation values, and how to score their CT findings, the radiologists trained on five cases with nodules exhibiting focal GGO; these cases were not included in the subsequent study.

Statistical Analysis
All numeric data, including the patient age, Brinkman index, and the maximum diameter and mean attenuation value of the nodules, were reported as the mean ± SD.

To determine which CT findings were useful to differentiate between bronchioloalveolar carcinoma and atypical adeno matous hyperplasia, we performed univariate and multi variate logistic regression analyses. Variables with p values less than 0.05 by univariate logistic regression analysis were chosen as the variables for multiple logistic regression analysis. In both the univariate and multivariate logistic regression analyses, we computed the odds ratio using the atypical adenomatous hyperplasia group as the reference group.

To analyze the qualitative CT findings for bronchioloalveolar carcinoma and atypical adenomatous hyperplasia, we used the Cohen kappa coefficient to assess the degree of observer agreement between the two radiologists. The scale for the kappa coefficients for interobserver agreement was < 0.20, poor; 0.21–0.40, fair; 0.41–0.60, moderate; 0.61–0.80, substantial; and 0.81–1.00, almost perfect [16, 17]. Values for p of less than 0.05 were considered to indicate statistically significant differences. Statistical analysis was performed with a statistical software package (SPSS, version 15.0).

Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
The clinical background of the 52 patients is shown in Table 2; the quantitative and qualitative results of high-resolution CT anal ysis are listed in Tables 3 and 4. All 17 patients with atypical adenomatous hyperplasia were nonsmokers. The mean Brinkman index of the 35 bronchioloalveolar carcinoma patients was 362.8; 21 of these individuals were nonsmokers. We found that 76.5% of atypical adenomatous hyperplasias and 14.3% of bronchioloalveolar carcinomas presented with almost spherical nodules. Internal air bronchograms were seen in 77.1% of bronchioloalveolar carcinomas and 11.8% of atypical adenomatous hyperplasias.

By univariate analysis, the patient age, nodular maximum diameter, mean attenuation value, and an internal air bronchogram were statistically significantly associated with bronchioloalveolar carcinoma (p = 0.012, p = 0.006, p = 0.023, and p < 0.001, respectively) (Table 5). On the other hand, sphericity was statistically significantly associated with atypical adenomatous hyperplasia (p < 0.001). By multivariate analysis, nodule sphericity was statistically associated with atypical adenomatous hyperplasia (p = 0.042) and internal air bronchogram results with bronchioloalveolar carcinoma (p = 0.007) (Table 6).

The kappa coefficients for nodule sphericity, marginal irregularity, pleural retraction, and internal air-bronchographic findings were 0.89, 0.77, 0.89, and 0.81, respectively. Representative cases are shown in Figures 1A, 1B, 1C and 2A, 2B.

View larger version (95K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A —47-year-old man with histologic diagnosis of atypical adenomatous hyperplasia. Axial (A), coronal (B), and sagittal (C) sections of high-resolution CT scan of three contiguous sections (section thickness and interval, 1.25 mm) show 11.5-mm maximum diameter nodule with focal ground-glass opacity. Mean attenuation of nodule is –380.5 H. Nodule is almost spherical on axial, coronal, and sagittal sections.

View larger version (47K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B —47-year-old man with histologic diagnosis of atypical adenomatous hyperplasia. Axial (A), coronal (B), and sagittal (C) sections of high-resolution CT scan of three contiguous sections (section thickness and interval, 1.25 mm) show 11.5-mm maximum diameter nodule with focal ground-glass opacity. Mean attenuation of nodule is –380.5 H. Nodule is almost spherical on axial, coronal, and sagittal sections.

View larger version (43K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1C —47-year-old man with histologic diagnosis of atypical adenomatous hyperplasia. Axial (A), coronal (B), and sagittal (C) sections of high-resolution CT scan of three contiguous sections (section thickness and interval, 1.25 mm) show 11.5-mm maximum diameter nodule with focal ground-glass opacity. Mean attenuation of nodule is –380.5 H. Nodule is almost spherical on axial, coronal, and sagittal sections.

View larger version (149K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A —74-year-old woman with histologic diagnosis of bronchioloalveolar carcinoma. Axial (A) and sagittal (B) sections of high-resolution CT scan (section thickness, 1.25 mm; section interval, 1.25 mm) show 18.0-mm maximum diameter nodule with focal ground-glass opacity. Mean attenuation of nodule is –399.1 H. Internal air bronchogram (arrows) is seen in nodule.

View larger version (46K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B —74-year-old woman with histologic diagnosis of bronchioloalveolar carcinoma. Axial (A) and sagittal (B) sections of high-resolution CT scan (section thickness, 1.25 mm; section interval, 1.25 mm) show 18.0-mm maximum diameter nodule with focal ground-glass opacity. Mean attenuation of nodule is –399.1 H. Internal air bronchogram (arrows) is seen in nodule.

Top Abstract Introduction Materials and Methods Results Discussion References

Pleural retraction, vascular convergence, and air bronchograms, reflective of tumor contraction, are often seen in bronchioloalveolar carcinomas [1, 11–13, 15, 19]. In general, this tumor contraction is due to the collapse or narrowing of alveolar spaces or to fibrotic areas in tumors in which cells exhibit a lepidic growth pattern [5, 11]. Because pleural retraction and vascular convergence were relatively frequent in both bronchioloalveolar carcinoma and atypical adenomatous hyperplasia (40% vs 23.5% and 48.6% vs 29.4%, respectively), these parameters are not useful for a differentiation between bronchioloalveolar carcinoma and atypical adenomatous hyperplasia. In fact, these findings were not statistically significantly associated with bronchioloalveolar carcinoma by either univariate or multivariate analysis. On the other hand, multivariate logistic analysis indicated that in bronchioloalveolar carcinoma, the odds of internal air bronchograms were 16.1. Consistent with our findings, Kuriyama et al. [15] reported that internal air bronchograms were seen in 65% of malignant tumors and 5% of benign nodules, indicating that internal air bronchograms in pure GGO are highly suggestive of bronchioloalveolar carcinoma.

Previously reported atypical adenomatous hyperplasias measured less than 10 mm. The reported diameter of atypical adenomatous hyperplasia was 7 ± 3 mm (range, 3–10 mm) [10] and 7.9 ± 2.1 mm [9]. In our study, the maximum diameter of nine of 17 (52.9%) atypical adenomatous hyperplasias and of five of 35 (14.3%) bronchioloalveolar carcinomas was less than 10 mm. Because it is not possible to rule out atypical adenomatous hyperplasia in patients with pure GGOs larger than 10 mm and bronchioloalveolar carcinoma in those whose pure GGOs are smaller than 10 mm, the size of pure GGOs is not pathognomonic.

A recent study by Kim et al. [20] showed that bronchioloalveolar carcinoma could not be differentiated from other ground-glass nodules having a different histopathologic diagnosis, such as atypical adenomatous hyperplasia, fibrosis, or organizing pneumonia. Because their study included 40 bronchioloalveolar carcinomas or adenocarcinomas and only three atypical adenomatous hyperplasias, the dearth of atypical adenomatous hyperplasias may explain the discrepancy between their results and ours.

The management of patients with pure GGOs remains controversial because the natural history of these lesions has not been elucidated. According to Nakamura et al. [21] and Nakata et al. [22], patients with pure GGO nodules are good candidates for limited lung resection. We suggest that follow-up CT studies are appropriate in these individuals because lung cancer presenting with pure GGO grows very slowly; its reported mean doubling time is 813–880 days [11, 23]. To determine the appropriate follow-up intervals in patients with pulmonary nodules, the issue of radiation exposure must be considered in addition to the growth speed of the nodules. According to Brenner [24], annual CT screening increases the 16.9% lung cancer risk of a 50-year-old woman smoker by 0.85% and the 15.8% risk of a man smoker of the same age by 0.23%. Although atypical adenomatous hyperplasia is considered a precursor of bronchioloalveolar carcinoma or adenocarcinoma [1, 25–28], there have been no reports of the progression of atypical adenomatous hyperplasia to bronchioloalveolar carcinoma or adenocarcinoma. We suggest that in patients whose high-resolution CT findings are highly suggestive of atypical adenomatous hyperplasia, the interval between CT studies should be longer than in patients whose high-resolution CT findings are suggestive of bronchioloalveolar carcinoma; however, the adequate follow-up intervals remain to be determined.

The management of patients with pure GGO is somewhat controversial. Guidelines promulgated by the Japanese Society of CT Screening [29] recommend biopsy or surgical resection for pure GGO nodules larger than 10 mm on thin-section helical CT because they have a high probability for bronchioloalveolar carcinoma. On the other hand, for pure GGO nodules smaller than 10 mm, the guidelines recommend reevaluation by thin-section helical CT 6 months after the initial CT. If on second CT examination the GGO nodule has increased in size or density, biopsy and surgical resection are recommended. If there is no change, further reevaluation by thin-section helical CT 6 months after the second CT examination is recommended. If the nodule has disappeared or decreased in size without an increase in density, reevaluation by routine low-dose CT 12 months after the second CT study is recommended.

Our study has some limitations. First, in our database, all histologically verified pure GGO nodules were either atypical adenomatous hyperplasia or bronchioloalveolar carcinoma. According to Kodama et al. [30], although most pure GGOs were bronchioloalveolar carcinoma or atypical adenomatous hyperplasia histologically, patients with lymphoproliferative disorder or focal fibrosis may also present with these lesions. Second, although two pathologists independently reviewed the histologic specimens and confirmed the patho logic diagnosis in consensus, pathologic differentiation between bronchioloalveolar carcinoma and atypical adenomatous hyperplasia may be difficult in some cases. Third, the chest CT images we examined were obtained with two different CT scanners, and we cannot rule out the possibility that this may have affected the CT attenuations.

In conclusion, at thin-section helical CT, nodular sphericity and internal air bronchograms were useful to differentiate between bronchioloalveolar carcinoma and atypical adenomatous hyperplasia that manifested pure GGO. Interobserver agree ment for these findings was high.

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