DOI: 10.1148/rg.272065061
RadioGraphics 2007;27:391-408
© RSNA, 2007
Nodular Ground-Glass Opacity at Thin-Section CT: Histologic Correlation and Evaluation of Change at Follow-up1
Chang Min Park, MD,
Jin Mo Goo, MD,
Hyun Ju Lee, MD,
Chang Hyun Lee, MD,
Eun Ju Chun, MD and
Jung-Gi Im, MD
1 From the Department of Radiology, Seoul National University College of Medicine and the Institute of Radiation Medicine, Seoul National University Medical Research Center, 28 Yeongeon-dong, Jongno-gu, Seoul 110-744, Republic of Korea. Presented as an education exhibit at the 2005 RSNA Annual Meeting. Received April 11, 2006; revision requested June 12 and received July 25; accepted August 1. All authors have no financial relationships to disclose.
Address correspondence to J.M.G. (e-mail: jmgoo{at}plaza.snu.ac.kr).
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Abstract
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The popularization of computed tomography (CT) in clinical practice and the introduction of mass screening for early lung cancer with the use of CT have increased the frequency of findings of subtle nodules or nodular ground-glass opacity. Nodular ground-glass opacity may be observed in malignancies such as bronchioloalveolar carcinoma and adenocarcinoma, as well as in their putative precursors, such as atypical adenomatous hyperplasia. Nodular ground-glass opacity also may be seen in the presence of benign conditions, including focal interstitial fibrosis, inflammation, and hemorrhage. The persistence of nodular ground-glass opacity over time may be strongly suggestive of an early-stage malignancy, especially if the lesion increases in size or includes a solid component that increases in its extent. Persistent nodular ground-glass opacity also may remain stable in size but show increased attenuation. The more extensive the solid portions of the lesion, the higher the probability of malignancy and the poorer the prognosis. An awareness of the clinical setting, in addition to familiarity with the thin-section CT features of nodular ground-glass opacity at initial and follow-up imaging over several months, can help identify malignancy and achieve an accurate diagnosis. A meticulous evaluation of those CT features, and their correlation with specific histopathologic characteristics, also may enable a more accurate prognosis in cases of neoplastic disease.
© RSNA, 2007
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LEARNING OBJECTIVES
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After reading this article and taking the test, the reader will be able to:- Describe the diseases in which nodular ground-glass opacity may be manifested at thin-section CT.
- Recognize changes in nodular ground-glass opacity at follow-up CT that allow accurate differentiation between benign and malignant lesions.
- Correlate CT findings of nodular ground-glass opacity with histopathologic characteristics to determine the disease prognosis.
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Introduction
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Ground-glass opacity is defined as hazy opacity that does not obscure underlying bronchial structures or pulmonary vessels at high-resolution computed tomography (CT) (1). Ground-glass opacity may be caused by partial airspace filling; interstitial thickening with inflammation, edema, fibrosis, or neoplastic proliferation; or interstitial thickening with partial airspace filling. Given the common use of CT in clinical practice and the introduction of CT in mass screening for early lung cancer, many faint pulmonary nodules that previously would have gone undetected at radiography are now discovered. Several investigators have reported that lesions that appear as nodular ground-glass opacity at CT might have higher malignant potential than do solid nodules. Malignancies with that CT appearance include bronchioloalveolar carcinoma and early-stage adenocarcinoma (2–9). However, nodular ground-glass opacity also may be observed in the presence of various benign conditions, including inflammatory diseases, focal hemorrhage, and fibrosis, as well as in putatively precancerous lesions such as atypical adenomatous hyperplasia (7–12).
An awareness of the significance of CT findings of nodular ground-glass opacity and of changes in that feature seen at follow-up CT might allow us to better understand disease progression and to differentiate malignancy from benignity. In this article, we discuss the significance of findings of nodular ground-glass opacity on thin-section CT images and correlate those findings with surgically confirmed pathologic diagnoses. In addition, we describe the changes that may occur over time in nodular ground-glass opacity lesions and discuss the prognostic value of a finding of nodular ground-glass opacity at thin-section CT.
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Technical Considerations
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The detection and recognition of nodular ground-glass opacity is based on a subjective assessment of lung attenuation. Therefore, CT should be performed within objective parameters that make lesion depiction reliable and reproducible. Generally, a tube current of 200–400 mA is acceptable (13,14). Low tube current may produce excessive noise that simulates ground-glass opacity or may lead to the failure to depict ground-glass opacity (14). In this context, low-dose CT probably would not be appropriate for characterizing nodular ground-glass opacity (Fig 1). Section thickness should be 1.0–1.5 mm, because with thicker sections ground-glass opacity may not be visible or the volume averaging effect may cause a solid nodule to mimic nodular ground-glass opacity (Fig 2) (10).
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Figure 1a. Pseudo-ground-glass opacity at CT in a 53-year-old man. (a) Axial low-dose CT image (5-mm-thick section) shows a nodular ground-glass opacity in the upper lobe of the left lung. No solid component is visible in the 10-mm poorly marginated lesion. (b) Thin-section CT image obtained at the level of the aortic arch depicts a well-defined oval solid nodule instead of the nodular ground-glass opacity shown in a. (c) CT image obtained with a mediastinal window setting shows a densely calcified granuloma.
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Figure 1b. Pseudo-ground-glass opacity at CT in a 53-year-old man. (a) Axial low-dose CT image (5-mm-thick section) shows a nodular ground-glass opacity in the upper lobe of the left lung. No solid component is visible in the 10-mm poorly marginated lesion. (b) Thin-section CT image obtained at the level of the aortic arch depicts a well-defined oval solid nodule instead of the nodular ground-glass opacity shown in a. (c) CT image obtained with a mediastinal window setting shows a densely calcified granuloma.
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Figure 1c. Pseudo-ground-glass opacity at CT in a 53-year-old man. (a) Axial low-dose CT image (5-mm-thick section) shows a nodular ground-glass opacity in the upper lobe of the left lung. No solid component is visible in the 10-mm poorly marginated lesion. (b) Thin-section CT image obtained at the level of the aortic arch depicts a well-defined oval solid nodule instead of the nodular ground-glass opacity shown in a. (c) CT image obtained with a mediastinal window setting shows a densely calcified granuloma.
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Figure 2a. Pseudo-ground-glass opacity at CT in a 66-year-old man. (a) Axial low-dose CT image (5-mm-thick section) obtained at the level of the left brachiocephalic vein shows a mixed ground-glass opacity lesion with a central solid component (arrow) in the upper lobe of the left lung, a finding suggestive of cancer. (b) Thin-section CT images show an irregularly shaped solid mass without nodular ground-glass opacity. (c) Coronal slab maximum intensity projection image shows a flat focus of atelectasis above the aortic arch (arrow) and no ground-glass opacity.
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Figure 2b. Pseudo-ground-glass opacity at CT in a 66-year-old man. (a) Axial low-dose CT image (5-mm-thick section) obtained at the level of the left brachiocephalic vein shows a mixed ground-glass opacity lesion with a central solid component (arrow) in the upper lobe of the left lung, a finding suggestive of cancer. (b) Thin-section CT images show an irregularly shaped solid mass without nodular ground-glass opacity. (c) Coronal slab maximum intensity projection image shows a flat focus of atelectasis above the aortic arch (arrow) and no ground-glass opacity.
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Figure 2c. Pseudo-ground-glass opacity at CT in a 66-year-old man. (a) Axial low-dose CT image (5-mm-thick section) obtained at the level of the left brachiocephalic vein shows a mixed ground-glass opacity lesion with a central solid component (arrow) in the upper lobe of the left lung, a finding suggestive of cancer. (b) Thin-section CT images show an irregularly shaped solid mass without nodular ground-glass opacity. (c) Coronal slab maximum intensity projection image shows a flat focus of atelectasis above the aortic arch (arrow) and no ground-glass opacity.
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Despite its potential clinical significance, nodular ground-glass opacity might be missed at low-dose screening CT because the lesion appears faint. According to a study conducted by Li et al (15), 69% of lung cancers missed by radiologists at screening CT were nodules with ground-glass opacity. Although thin-section CT has been recommended as the next step when nodular ground-glass opacity is detected at low-dose screening CT, differentiation of malignant nodules from benign ones is difficult. However, recently developed computerized schemes (16,17) may help in the detection and characterization of nodular ground-glass opacity.
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Significance of Nodular Ground-Glass Opacity
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It is often difficult to identify the specific cause of nodular ground-glass opacity because this CT feature may be found in the presence of various pathologic entities, including a neoplasm, inflammation, focal hemorrhage, and focal interstitial fibrosis (2–12). The clinical setting and change in the CT appearance of the lesion over time may enable an accurate diagnosis; most benign conditions resolve spontaneously or after appropriate treatment over weeks or months, and patients have characteristic clinical findings and symptoms (10). In contrast, malignant neoplasms are persistent, and their size and attenuation may increase over several months or years; in addition, patients often have no clinical symptoms (2–4,6–9, 11,12).
Several investigators have reported that persistent nodular ground-glass opacity could be a sign of early-stage adenocarcinoma or its precursor (4–9). Nakata et al (4) reported that all findings of persistent nodular ground-glass opacity in their study were due to neoplasms, which were proved at pathologic analysis to be bronchioloalveolar carcinoma (53.5%), adenocarcinoma with mixed bronchioloalveolar carcinoma components (25.6%), and atypical adenomatous hyperplasia (20.9%). The malignancy rate of nodular ground-glass opacity lesions was 93% when the lesion contained a solid component within a nodular ground-glass opacity. Henschke et al (6) reported similar results based on their Early Lung Cancer Action Project data; 44 (19%) of 233 positive results were lesions with nodular ground-glass opacity, and 15 (34%) of the 44 lesions were malignant. Malignancy rates among findings of nodular ground-glass opacity were 63% and 18% for lesions with and without a solid component, respectively, much higher than the malignancy rate for solid nodules (6).
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Neoplastic Diseases and Precursors
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Neoplastic diseases and putative precursors that have a replacement growth pattern—that is, atypical adenomatous hyperplasia, localized bronchioloalveolar carcinoma, and adenocarcinoma—should be suspected when a nodular ground-glass opacity persists on follow-up CT images. Replacement growth or lepidic growth of a tumor involves replacement of the cuboidal or columnar cells lining the alveolar wall, without invasion of the stroma. The underlying lung parenchyma serves as a framework along which cancer cells replace normal cells.
Atypical adenomatous hyperplasia is a peripheral focal lesion produced by the proliferation of atypical cuboidal or columnar epithelial cells along the alveoli and respiratory bronchioles (18). Several authors have reported that atypical adenomatous hyperplasia may be a precancerous lesion or a putative precursor of well-differentiated adenocarcinoma of the lung (19,20). This hypothesis is supported by epidemiologic, morphometric, cytofluorometric, and genetic evidence (21). Atypical adenomatous hyperplasia occurs in 2.8% of the general population and in 6.6% of the population at the age of 60 years or older (22). Moreover, it occurs much more frequently in patients with pulmonary adenocarcinoma, among whom the reported incidence ranges from 10% to 23.2% (22–24). Atypical adenomatous hyperplasia has been described as a round or oval lesion without a solid component. The lesion appears as a nodular ground-glass opacity on thin-section CT images (Fig 3a), without marginal spiculation, pleural retraction, or vascular convergence (2–4,8,12). Ground-glass opacity is thought to represent the replacement growth pattern of atypical adenomatous hyperplasia (Fig 3b), a lesion that is usually smaller than are localized bronchioloalveolar carcinoma and adenocarcinoma (2–4,8). Nakata et al (4) believed that the size of a persistent nodular ground-glass opacity might be a criterion for differentiation between atypical adenomatous hyperplasia and carcinoma. However, differentiation between atypical adenomatous hyperplasia and bronchioloalveolar carcinoma is generally difficult because they share many CT features and may occur concurrently (Fig 4) (12).
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Figure 3a. Atypical adenomatous hyperplasia in a 53-year-old woman. (a) Thin-section CT image of the right lung shows an 11-mm well-defined nodular ground-glass opacity without a solid component in the lower lobe. (b) Photomicrograph (original magnification, x100; hematoxylin-eosin stain) shows thickened alveolar walls lined by an intermittent single layer of atypical cuboidal pneumocytes.
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Figure 3b. Atypical adenomatous hyperplasia in a 53-year-old woman. (a) Thin-section CT image of the right lung shows an 11-mm well-defined nodular ground-glass opacity without a solid component in the lower lobe. (b) Photomicrograph (original magnification, x100; hematoxylin-eosin stain) shows thickened alveolar walls lined by an intermittent single layer of atypical cuboidal pneumocytes.
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Figure 4a. Concurrent atypical adenomatous hyperplasia and adenocarcinoma in a 71-year-old woman. (a) Thin-section CT image at the level of the carina shows an 18-mm-diameter mixed nodular ground-glass opacity with a solid component in the upper lobe of the right lung and a 10-mm pure nodular ground-glass opacity in the lower lobe of the left lung. (b) Photomicrograph of a resected specimen (original magnification, x40; hematoxylin-eosin stain) from a superior segment of the lower lobe of the left lung shows atypical epithelial cell proliferation along thickened alveolar septa, findings suggestive of atypical adenomatous hyperplasia. (c) Photomicrograph of a histologic slice (original magnification, x40; hematoxylin-eosin stain) from the right upper lobectomy specimen shows adenocarcinoma, with carcinoma of the bronchioloalveolar subtype at the periphery of the lesion.
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Figure 4b. Concurrent atypical adenomatous hyperplasia and adenocarcinoma in a 71-year-old woman. (a) Thin-section CT image at the level of the carina shows an 18-mm-diameter mixed nodular ground-glass opacity with a solid component in the upper lobe of the right lung and a 10-mm pure nodular ground-glass opacity in the lower lobe of the left lung. (b) Photomicrograph of a resected specimen (original magnification, x40; hematoxylin-eosin stain) from a superior segment of the lower lobe of the left lung shows atypical epithelial cell proliferation along thickened alveolar septa, findings suggestive of atypical adenomatous hyperplasia. (c) Photomicrograph of a histologic slice (original magnification, x40; hematoxylin-eosin stain) from the right upper lobectomy specimen shows adenocarcinoma, with carcinoma of the bronchioloalveolar subtype at the periphery of the lesion.
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Figure 4c. Concurrent atypical adenomatous hyperplasia and adenocarcinoma in a 71-year-old woman. (a) Thin-section CT image at the level of the carina shows an 18-mm-diameter mixed nodular ground-glass opacity with a solid component in the upper lobe of the right lung and a 10-mm pure nodular ground-glass opacity in the lower lobe of the left lung. (b) Photomicrograph of a resected specimen (original magnification, x40; hematoxylin-eosin stain) from a superior segment of the lower lobe of the left lung shows atypical epithelial cell proliferation along thickened alveolar septa, findings suggestive of atypical adenomatous hyperplasia. (c) Photomicrograph of a histologic slice (original magnification, x40; hematoxylin-eosin stain) from the right upper lobectomy specimen shows adenocarcinoma, with carcinoma of the bronchioloalveolar subtype at the periphery of the lesion.
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According to the revised definition from the World Health Organization Histologic Classification of Tumors, bronchioloalveolar carcinoma is a non-invasive adenocarcinoma with a pure replacement growth pattern, without stromal, vascular, or pleural invasion, although it may involve multiple foci produced through aerogenous spread or metastasis (25). The incidence of bronchioloalveolar carcinoma was reported to be 5.2% in non–small cell lung cancer in a population-based study (26). Localized bronchioloalveolar carcinoma is the most common type and accounts for 48.3% of cases (26). It usually is discovered incidentally in asymptomatic individuals and is associated with a much better prognosis than are other subtypes of adenocarcinoma (25). Its characteristic CT appearance is a round nodular ground-glass opacity in a peripheral region of the lung. The lesion may or may not include a solid component (Figs 5a, 6a) (27,28). The appearance of ground-glass opacity has been considered to reflect the replacement growth pattern of bronchioloalveolar carcinoma (Fig 5b). Solid components are associated with areas of collapsed alveoli or fibroblastic proliferation in localized bronchioloalveolar carcinoma (Fig 6b), and the volume of solid components usually depends on the stage of disease progression (27). Investigators have reported that the solid components in advanced-stage lesions are significantly larger than those in lesions at earlier stages (27,28).
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Figure 5a. Localized bronchioloalveolar carcinoma in a 63-year-old woman. (a) Thin-section CT image obtained at the level of the right upper anterior segmental bronchus shows a 10-mm well-defined nodular ground-glass opacity without a solid component in the lower lobe of the right lung. Note the presence of pulmonary vessels in the lesion. (b) Photomicrograph of a histologic specimen (original magnification, x100; hematoxylin-eosin stain) shows replacement of the alveolar lining by neoplastic columnar epithelium, without evidence of stromal invasion.
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Figure 5b. Localized bronchioloalveolar carcinoma in a 63-year-old woman. (a) Thin-section CT image obtained at the level of the right upper anterior segmental bronchus shows a 10-mm well-defined nodular ground-glass opacity without a solid component in the lower lobe of the right lung. Note the presence of pulmonary vessels in the lesion. (b) Photomicrograph of a histologic specimen (original magnification, x100; hematoxylin-eosin stain) shows replacement of the alveolar lining by neoplastic columnar epithelium, without evidence of stromal invasion.
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Figure 6a. Localized bronchioloalveolar carcinoma in a 49-year-old woman. (a) Thin-section CT image obtained at the level of the right bronchus intermedius shows a 14-mm well-defined nodular ground-glass opacity with a solid component (arrow) in the lower lobe of the right lung, abutting the vertebral body. (b) Photomicrograph of a histologic specimen (original magnification, x40; hematoxylin-eosin stain) shows replacement-type tumor cell growth, as well as foci of fibroblastic proliferation and alveolar collapse (arrowheads).
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Figure 6b. Localized bronchioloalveolar carcinoma in a 49-year-old woman. (a) Thin-section CT image obtained at the level of the right bronchus intermedius shows a 14-mm well-defined nodular ground-glass opacity with a solid component (arrow) in the lower lobe of the right lung, abutting the vertebral body. (b) Photomicrograph of a histologic specimen (original magnification, x40; hematoxylin-eosin stain) shows replacement-type tumor cell growth, as well as foci of fibroblastic proliferation and alveolar collapse (arrowheads).
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Small peripheral adenocarcinoma is the most common pathologic type of lung cancer and is detected with increasing frequency (29,30). The appearance of ground-glass opacity in a case of adenocarcinoma may be related to the presence of bronchioloalveolar carcinoma components within the mass (7). According to Lee et al (7), all adenocarcinomas that appeared as areas of ground-glass opacity on thin-section CT images were found to contain bronchioloalveolar carcinoma as a component (Fig 7). In general, tumors with a large component of ground-glass opacity are likely to be localized bronchioloalveolar carcinomas (31). In theory, adenocarcinoma should contain a nonaerogenous component that is depicted as a solid portion on thin-section CT images, but some adenocarcinomas may be manifested as pure ground-glass opacity (Fig 8). The failure to depict a solid portion within the nodular ground-glass opacity is believed to be caused by inadequate spatial resolution (7,8).
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Figure 7a. Adenocarcinoma with mixed acinar and bronchioloalveolar carcinoma in a 50-year-old woman. (a) Thin-section CT image obtained at the level of the aortic arch shows a 28-mm well-defined mixed ground-glass opacity lesion with peripheral ground-glass opacity in the upper lobe of the left lung. The mass abuts the pleura. (b) Photomicrograph of a histologic specimen (original magnification, x40; hematoxylin-eosin stain) shows a replacement-type growth pattern characteristic of bronchioloalveolar carcinoma in the periphery of the tumor.
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Figure 7b. Adenocarcinoma with mixed acinar and bronchioloalveolar carcinoma in a 50-year-old woman. (a) Thin-section CT image obtained at the level of the aortic arch shows a 28-mm well-defined mixed ground-glass opacity lesion with peripheral ground-glass opacity in the upper lobe of the left lung. The mass abuts the pleura. (b) Photomicrograph of a histologic specimen (original magnification, x40; hematoxylin-eosin stain) shows a replacement-type growth pattern characteristic of bronchioloalveolar carcinoma in the periphery of the tumor.
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Figure 8a. Adenocarcinoma in a 56-year-old man. (a) Thin-section CT image obtained at the level of the aortopulmonary window shows a 14-mm nodular ground-glass opacity with no solid component in the upper lobe of the right lung. (b) Photomicrograph of a histologic specimen (original magnification, x40; hematoxylin-eosin stain) shows adenocarcinoma with dense sclerosis.
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Figure 8b. Adenocarcinoma in a 56-year-old man. (a) Thin-section CT image obtained at the level of the aortopulmonary window shows a 14-mm nodular ground-glass opacity with no solid component in the upper lobe of the right lung. (b) Photomicrograph of a histologic specimen (original magnification, x40; hematoxylin-eosin stain) shows adenocarcinoma with dense sclerosis.
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Other Diseases
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Focal Interstitial Fibrosis
Focal interstitial fibrosis recently was recognized in excised specimens from lesions that appeared as nodular ground-glass opacity at CT, and it is the main entity among benign nonneoplastic diseases that is manifested as persistent nodular ground-glass opacity (Fig 9a) (2,8). Focal interstitial fibrosis does not change remarkably over a considerable period of time and often shares the imaging features of neoplastic ground-glass opacity lesions (2,8,11). This entity was recognized only recently because of an increase in the number of biopsies performed for diagnosis of ground-glass opacity lesions. At histopathologic analysis, tissue specimens from focal interstitial fibrosis show interstitial septal thickening with fibroblast proliferation and with preservation of the intraalveolar airspace (Fig 9b, 9c) (11). The pathogenesis of focal interstitial fibrosis is still unknown (11). Focal interstitial fibrosis has been described as a sharply demarcated nodular ground-glass opacity with a maximal diameter of less than 2 cm on thin-section CT images (2,8,11). Solid components may be related to the presence of fibrotic foci and alveolar collapse (8). Takashima et al (2) reported that in most cases focal interstitial fibro-sis appeared with a concave margin and a polygonal shape, important features that help differentiate it from malignancies. However, in another study, focal interstitial fibrosis in most cases appeared as a round or oval nodular ground-glass opacity without solid components (32). Nakajima et al (8) reported that focal interstitial fibrosis does not show indentation or spiculation, which are features of malignancy. However, focal interstitial fibrosis shares many CT features with neoplastic diseases in which there is a replacement growth pattern, and its differentiation from a neoplasm is often extremely difficult.
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Figure 9a. Focal interstitial fibrosis in a 40-year-old woman. (a) Thin-section CT image at the level of the superior segmental bronchus shows a 25-mm well-defined nodular ground-glass opacity with no solid component in the lower lobe of the left lung. (b) Photomicrograph of a histologic specimen (original magnification, x40; hematoxylin-eosin stain) shows the lesion (arrow) with alveolar septal thickening and fibrosis and with intraalveolar infiltration by inflammatory cells. (c) High-power photomicrograph (original magnification, x200; hematoxylin-eosin stain) shows fibrosis of the alveolar wall, with intraalveolar lymphocytes and denuded pneumocytes (arrows).
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Figure 9b. Focal interstitial fibrosis in a 40-year-old woman. (a) Thin-section CT image at the level of the superior segmental bronchus shows a 25-mm well-defined nodular ground-glass opacity with no solid component in the lower lobe of the left lung. (b) Photomicrograph of a histologic specimen (original magnification, x40; hematoxylin-eosin stain) shows the lesion (arrow) with alveolar septal thickening and fibrosis and with intraalveolar infiltration by inflammatory cells. (c) High-power photomicrograph (original magnification, x200; hematoxylin-eosin stain) shows fibrosis of the alveolar wall, with intraalveolar lymphocytes and denuded pneumocytes (arrows).
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Figure 9c. Focal interstitial fibrosis in a 40-year-old woman. (a) Thin-section CT image at the level of the superior segmental bronchus shows a 25-mm well-defined nodular ground-glass opacity with no solid component in the lower lobe of the left lung. (b) Photomicrograph of a histologic specimen (original magnification, x40; hematoxylin-eosin stain) shows the lesion (arrow) with alveolar septal thickening and fibrosis and with intraalveolar infiltration by inflammatory cells. (c) High-power photomicrograph (original magnification, x200; hematoxylin-eosin stain) shows fibrosis of the alveolar wall, with intraalveolar lymphocytes and denuded pneumocytes (arrows).
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Aspergillosis
Infectious conditions such as aspergillosis may be manifested at thin-section CT as areas of nodular ground-glass opacity, an appearance caused by hemorrhage or inflammatory cell infiltration (10) (Fig 10a). The clinicopathologic features and radiologic manifestations of aspergillosis depend on patient immunity, the presence of structural lung disease, and the virulence of the fungal species involved (33–35).
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Figure 10a. Aspergillosis in a 52-year-old woman with a chronic cough. (a) Thin-section CT image at the level of the main pulmonary artery shows a 23-mm poorly defined nodular ground-glass opacity in the upper lobe of the left lung. The lesion includes several peripheral solid portions (arrows) and a subtle ground-glass opacity (arrowhead). (b) Photomicrograph of a histologic specimen (original magnification, x100; hematoxylin-eosin stain) shows an aspergillus colony (arrows) and a surrounding area of intraalveolar hemorrhage (arrowheads). (c) High-power photomicrograph (original magnification, x1000; hematoxylin-eosin stain) shows fungal hyphae.
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Figure 10b. Aspergillosis in a 52-year-old woman with a chronic cough. (a) Thin-section CT image at the level of the main pulmonary artery shows a 23-mm poorly defined nodular ground-glass opacity in the upper lobe of the left lung. The lesion includes several peripheral solid portions (arrows) and a subtle ground-glass opacity (arrowhead). (b) Photomicrograph of a histologic specimen (original magnification, x100; hematoxylin-eosin stain) shows an aspergillus colony (arrows) and a surrounding area of intraalveolar hemorrhage (arrowheads). (c) High-power photomicrograph (original magnification, x1000; hematoxylin-eosin stain) shows fungal hyphae.
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Figure 10c. Aspergillosis in a 52-year-old woman with a chronic cough. (a) Thin-section CT image at the level of the main pulmonary artery shows a 23-mm poorly defined nodular ground-glass opacity in the upper lobe of the left lung. The lesion includes several peripheral solid portions (arrows) and a subtle ground-glass opacity (arrowhead). (b) Photomicrograph of a histologic specimen (original magnification, x100; hematoxylin-eosin stain) shows an aspergillus colony (arrows) and a surrounding area of intraalveolar hemorrhage (arrowheads). (c) High-power photomicrograph (original magnification, x1000; hematoxylin-eosin stain) shows fungal hyphae.
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Won et al (36), in a study of patients with invasive pulmonary aspergillosis, found segmental consolidation or a nodule with surrounding ground-glass opacity (a CT halo sign) on thin-section CT images. The surrounding region of ground-glass opacity represents alveolar hemorrhage related to infarction (Fig 10b) (37). Pinto (38) reported that the frequency of the CT halo sign ranged from 96% on day 0 to 19% on day 14 after disease onset. These CT findings may be early indicators of invasive aspergillosis in severely neutropenic febrile patients in whom antibiotic medications are ineffective.
Eosinophilic Pneumonia
Eosinophilic lung disease may occur in various conditions, including parasitic infection, idiopathic pulmonary fibrosis, sarcoidosis, collagen vascular disease, hypereosinophilic syndrome, and drug reactions (39). Simple eosinophilic pneumonia (Loeffler syndrome) and idiopathic hypereosinophilic syndrome have been reported to produce nodular ground-glass opacity on thin-section CT images (Fig 11) (40). Histologically, ground-glass opacity represents intraalveolar exudates and fibrotic change with eosinophilic infiltration in the interstitium (41). In lesions with a central solid component, the solid portion corresponds histologically to a neutrophilic abscess (41).
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Figure 11a. Eosinophilic pneumonia in a 36-year-old man with peripheral blood eosinophilia. (a) Thin-section CT image at the level of the aortic arch shows an ill-defined area of nodular ground-glass opacity in the upper lobe of the right lung. (b) Thin-section CT image at the level of the upper lobar bronchus in the left lung shows a similar nodular ground-glass opacity.
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Figure 11b. Eosinophilic pneumonia in a 36-year-old man with peripheral blood eosinophilia. (a) Thin-section CT image at the level of the aortic arch shows an ill-defined area of nodular ground-glass opacity in the upper lobe of the right lung. (b) Thin-section CT image at the level of the upper lobar bronchus in the left lung shows a similar nodular ground-glass opacity.
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Bronchiolitis Obliterans with Organizing Pneumonia
Bronchiolitis obliterans with organizing pneumonia is an idiopathic disease that produces polypoid granulation tissue in bronchioles and alveolar ducts, with variable degrees of interstitial and airspace infiltration by mononuclear cells and foamy macrophages (42). The most common CT finding in patients with this disease is bilateral ground-glass opacity or consolidation with a peribronchovascular distribution, a feature that may be manifested as one or more nodules or masses within which an air bronchogram is visible (43, 44). Kim et al (44) reported that CT images of six of 31 patients with bronchiolitis obliterans with organizing pneumonia showed nodular ground-glass opacity (Fig 12). Kim and colleagues also described the reverse halo sign (central nodular ground-glass opacity surrounded by a ring-shaped lesion with higher attenuation), a finding that might be specific for bronchiolitis obliterans with organizing pneumonia (44).
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Figure 12. Bronchiolitis obliterans with organizing pneumonia in a 46-year-old woman. Axial CT image at the level of the aortic arch shows multiple bilateral areas of ill-defined nodular ground-glass opacity, some of which contain solid components (arrows).
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Thoracic Endometriosis
Thoracic endometriosis, or catamenial syndrome, may produce an appearance of nodular ground-glass opacity on thin-section CT images (Fig 13). This disease group includes four well-recognized clinical entities: catamenial pneumothorax, catamenial hemothorax, catamenial hemoptysis, and lung nodules (45). Most patients report the monthly recurrence of hemoptysis, pneumothorax, or hemothorax during the menstrual period, and most have a history of pregnancy or obstetric-gynecologic surgery (45). These clinical symptoms and signs are believed to be due to the presence of ectopic endometrial tissue in the lung (46). Clinical suspicion and recognition of the temporal relationship between symptoms and menstruation help establish the diagnosis.
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Figure 13. Catamenial hemoptysis syndrome in a 24-year-old woman with recurrent monthly hemoptysis during menstruation. Axial CT image at the level of the diaphragmatic dome shows multiple areas of ill-defined nodular ground-glass opacity (arrows), features representative of bleeding. The patient underwent a bronchoscopic examination, and endometrial tissue was found at bronchial lavage.
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Focal Traumatic Lung Injury
Traumatic lung injury may be manifested as nodular ground-glass opacity at CT during subsequent disease progression. When Kazerooni and colleagues performed 141 CT studies in 40 patients within 1 month after transbronchial biopsy, they found nine solid nodules with areas of ground-glass opacity on CT images (47). The pseudonodules were considered to result from focal hemorrhage and parenchymal contusion. Similar features may be observed on lung CT images obtained in patients who have undergone a transthoracic lung biopsy, where central areas of solid high attenuation may be depicted within foci of ground-glass opacity (Fig 14).
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Figure 14a. Pseudonodule in a 56-year-old woman who underwent a previous percutaneous lung biopsy. (a) Thin-section CT image obtained at the level of the aortic arch shows a 9-mm well-defined nodular ground-glass opacity (arrow) in the right upper lobe. (b) Axial image obtained during CT-guided percutaneous transthoracic biopsy with the patient in the supine position shows the biopsy needle (arrow), which has been inserted near the nodule. (c) Axial CT image, obtained after the biopsy, shows a poorly defined pseudonodule represented by ground-glass opacity (arrow) along the biopsy tract. The pathologic diagnosis, obtained after a wedge resection, was focal interstitial fibrosis.
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Figure 14b. Pseudonodule in a 56-year-old woman who underwent a previous percutaneous lung biopsy. (a) Thin-section CT image obtained at the level of the aortic arch shows a 9-mm well-defined nodular ground-glass opacity (arrow) in the right upper lobe. (b) Axial image obtained during CT-guided percutaneous transthoracic biopsy with the patient in the supine position shows the biopsy needle (arrow), which has been inserted near the nodule. (c) Axial CT image, obtained after the biopsy, shows a poorly defined pseudonodule represented by ground-glass opacity (arrow) along the biopsy tract. The pathologic diagnosis, obtained after a wedge resection, was focal interstitial fibrosis.
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Figure 14c. Pseudonodule in a 56-year-old woman who underwent a previous percutaneous lung biopsy. (a) Thin-section CT image obtained at the level of the aortic arch shows a 9-mm well-defined nodular ground-glass opacity (arrow) in the right upper lobe. (b) Axial image obtained during CT-guided percutaneous transthoracic biopsy with the patient in the supine position shows the biopsy needle (arrow), which has been inserted near the nodule. (c) Axial CT image, obtained after the biopsy, shows a poorly defined pseudonodule represented by ground-glass opacity (arrow) along the biopsy tract. The pathologic diagnosis, obtained after a wedge resection, was focal interstitial fibrosis.
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Less Common Diseases
Pulmonary cryptococcus infection may be represented by solitary or multiple pulmonary nodules with or without peripheral ground-glass opacity (48), as well as by solitary foci of nodular ground-glass opacity on thin-section CT images (49). In addition, hemorrhagic components of lesions that occur in Wegener granulomatosis, Henoch-Schönlein purpura, and other forms of vasculitis may be manifested as areas of nodular ground-glass opacity (10).
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Changes in Lesions at Follow-up CT
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Li et al (3) reported that the margin characteristics and the sizes of foci of nodular ground-glass opacity were not helpful for differentiating between benign and malignant lesions. Instead, they identified benign lesions on the basis of the apparent resolution of nodular ground-glass opacity at short-term follow-up CT; benign lesions, except focal interstitial fibrosis, resolved partially or completely within 3 months after initial CT. Benign lesions that are due to inflammation, focal hemorrhage, or edema might resolve spontaneously or after appropriate therapy with antibiotics or steroids (Fig 15) (10).
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Figure 15a. Resolution of nodular ground-glass opacity over time helps determine the benignity of a lesion in a 50-year-old man. (a) Initial thin-section CT image at the level of the inferior pulmonary vein shows a 12-mm poorly defined nodular ground-glass opacity in the right lower lobe. (b) Follow-up CT image obtained approximately 2 months later shows that the lesion in a has resolved.
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Figure 15b. Resolution of nodular ground-glass opacity over time helps determine the benignity of a lesion in a 50-year-old man. (a) Initial thin-section CT image at the level of the inferior pulmonary vein shows a 12-mm poorly defined nodular ground-glass opacity in the right lower lobe. (b) Follow-up CT image obtained approximately 2 months later shows that the lesion in a has resolved.
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In contrast, lesions that are represented by nodular ground-glass opacity at CT and are caused by neoplasms or focal interstitial fibrosis persist and do not decrease in size or resolve, even over a lengthy period (Fig 16) (3,4,7).
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Figure 16a. Persistent nodular ground-glass opacity in a 69-year-old man. (a) Thin-section CT image obtained at the level of the left brachiocephalic vein shows a 14-mm poorly defined round nodular ground-glass opacity in the upper lobe of the left lung. (b) Follow-up thin-section CT image obtained 4 months later shows the persistence and stable appearance of the lesion. The pathologic diagnosis, obtained after a wedge resection, was focal interstitial fibrosis.
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Figure 16b. Persistent nodular ground-glass opacity in a 69-year-old man. (a) Thin-section CT image obtained at the level of the left brachiocephalic vein shows a 14-mm poorly defined round nodular ground-glass opacity in the upper lobe of the left lung. (b) Follow-up thin-section CT image obtained 4 months later shows the persistence and stable appearance of the lesion. The pathologic diagnosis, obtained after a wedge resection, was focal interstitial fibrosis.
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According to Lee et al (7), lesions depicted at CT as pure nodular ground-glass opacity that remained stable throughout a variable follow-up period were diagnosed histopathologically as focal interstitial fibrosis, atypical adenomatous hyperplasia, localized bronchioloalveolar carcinoma, and adenocarcinoma. Lee and colleagues also reported the growth of lesions in three patients over the follow-up period. In all three cases, the lesions were represented at CT as mixed nodular ground-glass opacity and were confirmed histologically to be adenocarcinomas (Fig 17) (7). Kakinuma et al (50) reported eight cases with findings of pure nodular ground-glass opacity that changed over a 6-month period (ie, increased in size, decreased in size and developed a solid component, or remained stable in size and increased in attenuation). When localized bronchioloalveolar carcinoma increases in size and progresses to more advanced disease, alveolar collapse and fibroblastic proliferation appear in the tumor, and the foci of fibrosis increase in extent (9,20). Several investigators have reported that an air bronchogram, a pleural tag, and spiculation also may be seen at CT in localized bronchioloalveolar carcinoma and adenocarcinoma (27,31,51). With regard to neoplastic disease, it is widely accepted that the time it takes for a tumor to double in size is much longer for tumors with a homogeneous appearance of nodular ground-glass opacity than for those with mixed nodular ground-glass opacity and solid components or with a homogeneous solid appearance (51,52). Hasegawa et al (52) categorized tumors by using high-resolution CT findings of ground-glass opacity, ground-glass opacity with central solid components, or a solid appearance; the mean volume doubling times for lesions with those characteristics were 813 days, 457 days, and 149 days, respectively (52).
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Figure 17a. Persistent nodular ground-glass opacity in an 80-year-old man with adenocarcinoma. (a) Initial thick-section CT image obtained at the level of the right inferior pulmonary vein shows a subtle nodule (arrow) in the middle lobe of the right lung. (b) Follow-up CT image obtained 12 months later shows an increase in the lesion size and an additional subtle internal solid component (arrow). (c) Follow-up thin-section CT image obtained at 16 months shows an increase in the size of the solid component within the lesion (arrow). Adenocarcinoma was found at histopathologic analysis of an excised specimen.
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Figure 17b. Persistent nodular ground-glass opacity in an 80-year-old man with adenocarcinoma. (a) Initial thick-section CT image obtained at the level of the right inferior pulmonary vein shows a subtle nodule (arrow) in the middle lobe of the right lung. (b) Follow-up CT image obtained 12 months later shows an increase in the lesion size and an additional subtle internal solid component (arrow). (c) Follow-up thin-section CT image obtained at 16 months shows an increase in the size of the solid component within the lesion (arrow). Adenocarcinoma was found at histopathologic analysis of an excised specimen.
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Figure 17c. Persistent nodular ground-glass opacity in an 80-year-old man with adenocarcinoma. (a) Initial thick-section CT image obtained at the level of the right inferior pulmonary vein shows a subtle nodule (arrow) in the middle lobe of the right lung. (b) Follow-up CT image obtained 12 months later shows an increase in the lesion size and an additional subtle internal solid component (arrow). (c) Follow-up thin-section CT image obtained at 16 months shows an increase in the size of the solid component within the lesion (arrow). Adenocarcinoma was found at histopathologic analysis of an excised specimen.
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Focal interstitial fibrosis may persist over a significant follow-up period, and it is unclear how long it may take for the lesions to decrease in size or to disappear. More long-term follow-up data are required to resolve these questions.
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Value of CT Features for Prognosis of Neoplastic Disease
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Several investigators have suggested that the internal features of small adenocarcinomas (pure ground-glass opacity, mixed ground-glass opacity, or solid nodule) are closely related to the disease prognosis and that these features might be more important prognostic factors than are conventional considerations such as lesion size (8,9,27,28,53). In several studies, patients with a tumor with a larger ground-glass opacity component were found to have a much better prognosis than those with a tumor with a larger solid component; long-term survival rates were found to be extraordinarily good (up to 100%) for such patients (54–56). That is, atypical adenomatous hyperplasia and localized bronchioloalveolar carcinoma usually are manifested by pure ground-glass opacity, whereas more advanced adenocarcinomas may include a larger solid component within the region of ground-glass opacity. Noguchi et al (9) classified small peripheral adenocarcinomas of the lung into six subtypes (types A–F). Type A, B, and C tumors showed a replacement growth pattern along the alveolar lining cells (9). Patients with type A and B tumors showed no evidence of lymph node metastases and had a 5-year survival rate of 100% (9). Suzuki et al (57) reported that none of their 69 patients with lung cancer with a CT appearance of nodular ground-glass opacity had lymph node metastases and that all patients survived with a median follow-up time of 35 months. Aoki et al (53) reported less frequent lymph node metastasis and vascular invasion, with a better prognosis, among patients with adenocarcinoma that included a ground-glass opacity component of more than 50% of the lesion volume than among those in whom ground-glass opacity accounted for less than 50% of the lesion volume. When a nodular ground-glass opacity lesion with a predominant solid portion is accompanied by CT features such as spiculations, pleural retraction, or bronchovascular bundle thickening, the lesion is highly likely to be an advanced adenocarcinoma (27). Moreover, such lesions were associated with higher probabilities of lymph node metastasis and vascular invasion (53).
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Conclusions
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Persistent findings of nodular ground-glass opacity at CT may be strongly suggestive of a neoplastic condition such as atypical adenomatous hyperplasia, bronchioloalveolar carcinoma, or adenocarcinoma, and the probability of malignancy is much higher when the lesion contains a solid component. Observations of temporal changes in a lesion may be useful for differentiating a malignant neoplasm from benign disease. In addition, a meticulous evaluation of the CT features of nodular ground-glass opacity in cases of neoplastic disease often helps in assessing the disease prognosis.
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C. M. Park, J. M. Goo, T. J. Kim, H. J. Lee, K. W. Lee, C. H. Lee, Y. T. Kim, K. G. Kim, H. Y. Lee, E.-A. Park, et al.
Pulmonary Nodular Ground-Glass Opacities in Patients With Extrapulmonary Cancers: What is Their Clinical Significance and How Can We Determine Whether They Are Malignant or Benign Lesions?
Chest,
June 1, 2008;
133(6):
1402 - 1409.
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Abstract
LEARNING OBJECTIVES
