DOI: 10.1148/rg.246045018
RadioGraphics 2004;24:1617-1636
© RSNA, 2004
T1 Non–Small Cell Lung Cancer: Imaging and Histopathologic Findings and Their Prognostic Implications1
Kyung Soo Lee, MD,
Yeon Joo Jeong, MD,
Joungho Han, MD,
Byung-Tae Kim, MD,
Hojoong Kim, MD and
O Jung Kwon, MD
1 From the Department of Radiology and Center for Imaging Science (K.S.L., Y.J.J.), the Department of Diagnostic Pathology (J.H.), the Department of Nuclear Medicine (B.T.K.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine (H.K., O.J.K.), Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135–710, Korea. Presented as an education exhibit at the 2003 RSNA scientific assembly. Received February 13, 2004; revision requested March 26; final revision received April 19; accepted April 19. Supported in part by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (00-PJ1-PG1-CY03–0001). All authors have no financial relationships to disclose. Address correspondence to K.S.L. (e-mail: melon2@samsung.co.kr).
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Abstract
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About 5% of T1 non–small cell lung cancers (ie, lung cancers less than 3 cm in diameter), mostly focal nodular bronchioloalveolar carcinomas and carcinoid tumors, demonstrate no uptake at fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and appear to be indolent in growth; consequently, they are associated with long-term patient survival. About 21% of T1 lung cancers show mediastinal nodal metastasis at the time of diagnosis and about 24% show extrathoracic metastasis, mostly brain metastasis, either at the time of diagnosis or at 1-year follow-up. T1 lung cancers with a large ground-glass attenuation component (50% of tumor volume) at thin-section computed tomography (CT) have a good prognosis with less likelihood of mediastinal nodal or extrathoracic metastasis. On the other hand, solid cancer lesions, especially those with a spiculated margin or with bronchovascular bundle thickening in the surrounding lung, more frequently demonstrate local vessel invasion, lymph node metastasis, and extrathoracic metastasis. In these tumors, work-up for extrathoracic metastases (including whole-body FDG PET or brain magnetic resonance imaging and mediastinoscopy for mediastinal nodes) may be needed, even when CT demonstrates no enlarged nodes in the mediastinum.
© RSNA, 2004
Index Terms: Lung neoplasms, 60.321 • Lung neoplasms, CT, 60.1211 • Lung neoplasms, diagnosis • Lung neoplasms, PET, 60.12163 • Lung neoplasms, screening, 60.1211, 60.12163 • Lung neoplasms, staging
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LEARNING OBJECTIVES FOR TEST 3
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After reading this article and taking the test, the reader will be able to:
- Describe the CT and FDG PET findings in T1 lung cancer.
- Correlate these imaging findings with their prognostic implications.
- Discuss the frequency of occurrence of mediastinal nodal and extrathoracic metastasis in T1 lung cancer.
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Introduction
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Patients with peripheral lung cancer less than 3 cm in diameter (T1 lung cancer) without nodal or distant metastasis, designated as stage IA (T1 N0 M0) with the TNM staging system, have a 5-year postoperative survival rate of over 50% (1,2). Initial studies suggested a low prevalence of nodal metastases in T1 lung cancer. However, several recent studies have reported a relatively high prevalence of mediastinal lymph node metastases (3,4). Seely et al (5) reviewed the computed tomographic (CT) and surgical findings in 104 patients with T1 cancer lesions and found that 21%of the patients had nodal metastases at complete nodal sampling performed with either mediastinoscopy or thoracotomy. The reported prevalence of extrathoracic metastases in T1 lung cancer differs widely (0%–24%) because of a lack of uniformity in patient selection or in the methods used to assess the presence of metastases (6–8). Recently, Jung et al (8) found that 24% of patients with T1 lung cancer had extrathoracic metastases either at the time of diagnosis (13%) or at 1-year follow-up (11%). Because small T1 peripheral lung cancers are associated with mediastinal nodal or extrathoracic metastasis, it is important to be able to determine from imaging studies which tumors are likely to metastasize. Awareness of the metastatic potential of small T1 peripheral lung cancers may allow the categorization of such tumors regarding metastatic work-up, which may include preoperative mediastinoscopy and imaging studies for extrathoracic metastasis. In this article, we discuss and illustrate the thin-section CT and fluorine-18 fluorodeoxyglucose (FDG) positron emission tomographic (PET) findings in T1 non–small cell lung cancer. We also discuss the correlation of CT findings with prognosis and survival, the correlation between tumor size and survival, and extrathoracic metastasis of T1 lung cancer.
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Peripheral Adenocarcinoma: Correlation of Thin-Section CT Findings with Prognosis and Survival
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Adenocarcinoma of the lung is the most common histopathologic type of lung cancer, and its prevalence is reported to be increasing (9,10). In addition, reports have shown that screening with low-dose CT can improve the detection of lung cancer, especially of adenocarcinoma, at an earlier and potentially more curable stage (Fig 1) (11,12). Because adenocarcinoma of the lung is composed of a histopathologically heterogeneous group of tumors, it is difficult to predict the prognosis in cases of surgically resectable peripheral lung adenocarcinoma (13). However, several recent studies have suggested that the extent of the BAC component in a small peripheral adenocarcinoma reflects the clinicopathologic and prognostic characteristics of the tumor. As the BAC component within a tumor increases in extent, the adenocarcinoma shows a better prognosis (14–16).
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Figure 1a. T1 N0 bronchioloalveolar carcinoma (BAC) in a 53-year-old man. (a) Initial transaxial thin-section (1-mm collimation, 170 mA) CT scan (lung window) obtained at the level of the bronchus intermedius shows a small nodular area of ground-glass attenuation in the right upper lobe (arrow). (b) Follow-up CT scan (5-mm collimation, 50 mA) obtained 48 months later shows increased nodule size (arrow). The lobectomy specimen showed BAC without nodal metastasis.
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Figure 1b. T1 N0 bronchioloalveolar carcinoma (BAC) in a 53-year-old man. (a) Initial transaxial thin-section (1-mm collimation, 170 mA) CT scan (lung window) obtained at the level of the bronchus intermedius shows a small nodular area of ground-glass attenuation in the right upper lobe (arrow). (b) Follow-up CT scan (5-mm collimation, 50 mA) obtained 48 months later shows increased nodule size (arrow). The lobectomy specimen showed BAC without nodal metastasis.
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Noguchi et al (14) proposed a new histopathologic classification system for adenocarcinoma of the lung based on tumor growth patterns (Table). They suggested that patients with adenocarcinomas with (a) a growth pattern involving replacement of alveolar lining cells (lepidic growth, characteristic of BAC), (b) no active fibroblastic proliferation (types A and B), and (c) no lymph node metastasis have an excellent outcome after surgical resection (Figs 2, 3). These tumors can be regarded as in situ carcinoma, whereas type C tumors (BAC with active fibroblastic proliferation) (Fig 4) represent an advanced stage of types A and B. Patients with Noguchi type C–F tumors (Figs 4–7) have a high risk of micrometastasis to hilar and mediastinal lymph nodes, whereas those with Noguchi type A and B tumors have no nodal metastasis. Therefore, lobectomy and lymph node dissection are necessary for Noguchi type C–F adenocarcinomas, whereas extensive lymph node dissection may not be required for type A and B adenocarcinomas (limited surgery or video-assisted thoracoscopic surgery may be enough for these tumors).
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Figure 2a. Noguchi type A adenocarcinoma (localized BAC) in a 63-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the apical segmental bronchus of the right upper lobe shows a 10-mm nodular area of ground-glass attenuation (arrow). (b) Low-power photomicrograph (original magnification, x4; hematoxylin-eosin [H-E] stain) of a surgical specimen shows tumor cells growing along the alveolar walls (lepidic growth) (arrows), which appeared as nodular ground-glass attenuation at CT. The alveolar walls are mildly thickened. The surgical specimens showed no hilar or mediastinal nodal metastasis, and no recurrence was seen at postoperative follow-up.
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Figure 2b. Noguchi type A adenocarcinoma (localized BAC) in a 63-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the apical segmental bronchus of the right upper lobe shows a 10-mm nodular area of ground-glass attenuation (arrow). (b) Low-power photomicrograph (original magnification, x4; hematoxylin-eosin [H-E] stain) of a surgical specimen shows tumor cells growing along the alveolar walls (lepidic growth) (arrows), which appeared as nodular ground-glass attenuation at CT. The alveolar walls are mildly thickened. The surgical specimens showed no hilar or mediastinal nodal metastasis, and no recurrence was seen at postoperative follow-up.
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Figure 3a. Noguchi type B adenocarcinoma (localized BAC with foci of alveolar collapse) in a 48-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the aortic arch shows a 20-mm nodular area of ground-glass attenuation in the left upper lobe. Note that the lesion has a solid component (arrow). (b) Low-power photomicrograph (original magnification, x12; H-E stain) of a surgical specimen shows thickening of the alveolar walls with tumor cell replacement (lepidic growth). Note the foci of alveolar collapse (arrows). At CT, the foci of lepidic growth appeared as areas of ground-glass attenuation, whereas the foci of alveolar collapse corresponded to the solid component of the lesion. The surgical specimens showed no hilar or mediastinal nodal metastasis, and no recurrence was seen at postoperative follow-up.
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Figure 3b. Noguchi type B adenocarcinoma (localized BAC with foci of alveolar collapse) in a 48-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the aortic arch shows a 20-mm nodular area of ground-glass attenuation in the left upper lobe. Note that the lesion has a solid component (arrow). (b) Low-power photomicrograph (original magnification, x12; H-E stain) of a surgical specimen shows thickening of the alveolar walls with tumor cell replacement (lepidic growth). Note the foci of alveolar collapse (arrows). At CT, the foci of lepidic growth appeared as areas of ground-glass attenuation, whereas the foci of alveolar collapse corresponded to the solid component of the lesion. The surgical specimens showed no hilar or mediastinal nodal metastasis, and no recurrence was seen at postoperative follow-up.
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Figure 4a. Noguchi type C adenocarcinoma (localized BAC with active fibroblastic proliferation) in a 52-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the left main bronchus shows a 13-mm nodule in the superior segment of the left lower lobe. Note the areas of ground-glass attenuation in the periphery of the nodule (arrow). (b) Low-power photomicrograph (original magnification, x12; H-E stain) of a surgical specimen shows tumor consisting of foci of lepidic growth (spread of neoplastic cells on airspace surface with preservation of underlying lung architecture) (arrows), along with fibrosis and alveolar collapse (arrowheads). At CT, the latter findings appeared as hyperattenuating nodules, whereas the foci of lepidic growth appeared as areas of ground-glass attenuation. The surgical specimens showed no hilar or mediastinal nodal metastasis, but intrapulmonary recurrence was seen at postoperative follow-up.
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Figure 4b. Noguchi type C adenocarcinoma (localized BAC with active fibroblastic proliferation) in a 52-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the left main bronchus shows a 13-mm nodule in the superior segment of the left lower lobe. Note the areas of ground-glass attenuation in the periphery of the nodule (arrow). (b) Low-power photomicrograph (original magnification, x12; H-E stain) of a surgical specimen shows tumor consisting of foci of lepidic growth (spread of neoplastic cells on airspace surface with preservation of underlying lung architecture) (arrows), along with fibrosis and alveolar collapse (arrowheads). At CT, the latter findings appeared as hyperattenuating nodules, whereas the foci of lepidic growth appeared as areas of ground-glass attenuation. The surgical specimens showed no hilar or mediastinal nodal metastasis, but intrapulmonary recurrence was seen at postoperative follow-up.
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Figure 5a. Noguchi type D adenocarcinoma (poorly differentiated adenocarcinoma) in a 62-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the left main bronchus shows a 21-mm nodule with a spiculated margin in the left upper lobe. (b) Low-power photomicrograph (original magnification, x12; H-E stain) of a surgical specimen shows a poorly differentiated solid adenocarcinoma with a well-defined margin (arrows). The surgical specimens showed no hilar or mediastinal nodal metastasis, and no recurrence was seen at postoperative follow-up.
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Figure 5b. Noguchi type D adenocarcinoma (poorly differentiated adenocarcinoma) in a 62-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the left main bronchus shows a 21-mm nodule with a spiculated margin in the left upper lobe. (b) Low-power photomicrograph (original magnification, x12; H-E stain) of a surgical specimen shows a poorly differentiated solid adenocarcinoma with a well-defined margin (arrows). The surgical specimens showed no hilar or mediastinal nodal metastasis, and no recurrence was seen at postoperative follow-up.
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Figure 6a. Noguchi type E adenocarcinoma (tubular adenocarcinoma) in a 53-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the bronchus intermedius shows a 22-mm nodule with a spiculated margin in the right upper lobe straddling the right minor fissure (arrows). (b) Low-power photomicrograph (original magnification, x12; H-E stain) of a surgical specimen shows a lobulated solid mass with no acinar structure. The surgical specimens showed no hilar or mediastinal nodal metastasis, but brain metastasis was seen at follow-up magnetic resonance (MR) imaging performed 2 years after surgery.
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Figure 6b. Noguchi type E adenocarcinoma (tubular adenocarcinoma) in a 53-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the bronchus intermedius shows a 22-mm nodule with a spiculated margin in the right upper lobe straddling the right minor fissure (arrows). (b) Low-power photomicrograph (original magnification, x12; H-E stain) of a surgical specimen shows a lobulated solid mass with no acinar structure. The surgical specimens showed no hilar or mediastinal nodal metastasis, but brain metastasis was seen at follow-up magnetic resonance (MR) imaging performed 2 years after surgery.
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Figure 7a. Noguchi type F adenocarcinoma (papillary adenocarcinoma with compressive and destructive growth) in a 48-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the basal segmental arteries shows a 25-mm lobulated nodule in the left lower lobe. (b) Low-power photomicrograph (original magnification, x12; H-E stain) of a surgical specimen shows papillary carcinoma composed of branching true papillae. The surgical specimens showed hilar nodal metastasis, and intrapulmonary recurrence was seen at postoperative follow-up.
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Figure 7b. Noguchi type F adenocarcinoma (papillary adenocarcinoma with compressive and destructive growth) in a 48-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the basal segmental arteries shows a 25-mm lobulated nodule in the left lower lobe. (b) Low-power photomicrograph (original magnification, x12; H-E stain) of a surgical specimen shows papillary carcinoma composed of branching true papillae. The surgical specimens showed hilar nodal metastasis, and intrapulmonary recurrence was seen at postoperative follow-up.
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Localized BAC may appear as an area of ground-glass attenuation (Fig 8), as a mixed area of ground-glass attenuation and more solid components, or as a nodule (17,18). Kuriyama et al (19) suggested that the percentage of ground-glass attenuation in localized BAC is larger than that in other adenocarcinomas. Aoki et al (20) reported that adenocarcinoma appearing as localized ground-glass attenuation demonstrates slow growth. In addition, Jung et al (8) suggested that the prevalence of extrathoracic metastasis is significantly lower in a small peripheral lung cancer with ground-glass attenuation than in such a lesion without ground-glass attenuation.
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Figure 8a. BAC in a 45-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the basal segmental bronchi shows a 13-mm nodular area of ground-glass attenuation in the right lower lobe (arrow). (b) High-power photomicrograph (original magnification, x100; H-E stain) shows the spread of neoplastic cells (lepidic growth).
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Figure 8b. BAC in a 45-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the basal segmental bronchi shows a 13-mm nodular area of ground-glass attenuation in the right lower lobe (arrow). (b) High-power photomicrograph (original magnification, x100; H-E stain) shows the spread of neoplastic cells (lepidic growth).
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Kim et al (21) correlated the thin-section CT findings in peripheral small adenocarcinoma of the lung in 224 patients with histopathologic subtypes (Noguchi types A–F) and investigated whether any CT findings can help predict tumor prognosis. Of the 224 patients, 132 had BAC and 92 had other adenocarcinomas. The extent of ground-glass attenuation was greater in BACs (29% ± 31.6, mean ± standard deviation) than in other adenocarcinomas (8% ± 13.3) (P < .001) and was significantly greater in patients without recurrence (P = .020), nodal metastases (P = .017), or distant metastases (P = .007). The authors concluded that the extent of ground-glass attenuation within a nodule is greater in BACs than in other adenocarcinomas, and that a greater extent of ground-glass attenuation correlates with improved prognosis.
Aoki et al (22) evaluated the prognostic importance of preoperative thin-section CT findings in peripheral lung adenocarcinoma by retrospectively analyzing the margin characteristics of nodules and the extent of ground-glass attenuation within the nodules. Regional lymph node metastasis and vessel invasion were examined histopathologically in surgical specimens, and survival curves were calculated according to the Kaplan-Meier method. The prevalence of lymph node metastasis (4% [one of 24 patients]) and of vessel invasion (13% [three of 24]) in adenocarcinomas with ground-glass attenuation components accounting for more than 50% of tumor volume was significantly lower than that in tumors with ground-glass attenuation components accounting for less than 10% of tumor volume (lymph node metastasis, P < .05; vessel invasion, P < .01). Patients with tumors in which ground-glass attenuation components accounted for more than 50% of tumor volume had a significantly better prognosis than those with tumors in which these components accounted for less than 10% (P < .05). All 17 adenocarcinomas smaller than 2 cm in which ground-glass attenuation components accounted for more than 50% of tumor volume were free of lymph node metastasis and vessel invasion, and all these patients remain alive and without recurrence 10 years later. Coarse spiculation (Fig 9) and thickening of bronchovascular bundles around the tumors (Fig 10) were observed more frequently in tumors with lymph node metastasis or vessel invasion than in those without these entities (P < .01). Aoki et al (22) concluded that thin-section CT findings in peripheral lung adenocarcinomas correlated with histologic prognostic factors.
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Figure 9a. T1 N2 adenocarcinoma in a 40-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the azygos arch shows a 25-mm nodule with a lobulated and spiculated margin in the anterior segment of the right upper lobe. Mediastinoscopy revealed microscopic lymph node metastases in the right lower paratracheal nodes. (b) Low-power photomicrograph (original magnification, x4; H-E stain) of a surgical specimen shows spiculated adenocarcinoma with bronchovascular invasion (arrows).
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Figure 9b. T1 N2 adenocarcinoma in a 40-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the azygos arch shows a 25-mm nodule with a lobulated and spiculated margin in the anterior segment of the right upper lobe. Mediastinoscopy revealed microscopic lymph node metastases in the right lower paratracheal nodes. (b) Low-power photomicrograph (original magnification, x4; H-E stain) of a surgical specimen shows spiculated adenocarcinoma with bronchovascular invasion (arrows).
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Figure 10a. T1 adenocarcinoma with vascular invasion in a 66-year-old man. (a, b) Transaxial thin-section CT scans (lung window) obtained at the levels of the main bronchi (a) and right upper lobar bronchus (b) show a 20-mm nodule with a lobulated margin and thickened bronchovascular bundles in the right upper lobe (arrow). (c) Low-power photomicrograph (original magnification, x4; H-E stain) shows tumor invasion of adjacent bronchovascular bundles (arrows).
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Figure 10b. T1 adenocarcinoma with vascular invasion in a 66-year-old man. (a, b) Transaxial thin-section CT scans (lung window) obtained at the levels of the main bronchi (a) and right upper lobar bronchus (b) show a 20-mm nodule with a lobulated margin and thickened bronchovascular bundles in the right upper lobe (arrow). (c) Low-power photomicrograph (original magnification, x4; H-E stain) shows tumor invasion of adjacent bronchovascular bundles (arrows).
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Figure 10c. T1 adenocarcinoma with vascular invasion in a 66-year-old man. (a, b) Transaxial thin-section CT scans (lung window) obtained at the levels of the main bronchi (a) and right upper lobar bronchus (b) show a 20-mm nodule with a lobulated margin and thickened bronchovascular bundles in the right upper lobe (arrow). (c) Low-power photomicrograph (original magnification, x4; H-E stain) shows tumor invasion of adjacent bronchovascular bundles (arrows).
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Focal ground-glass attenuation has been detected increasingly with low-dose helical CT in lung cancer screening. Although focal ground-glass attenuation suggests an in situ neoplastic lesion in the peripheral lung, the management of these lesions remains controversial.
Nakata et al (23) evaluated the pathologic and radiologic characteristics of findings of ground-glass attenuation. Their study involved 43 patients with persistent (mean, 3.7 months) areas of ground-glass attenuation less than 2 cm in diameter. The histologic diagnoses included BAC (n = 23), mixed subtype adenocarcinoma (n = 11), and atypical adenomatous hyperplasia (n = 9). None of the 34 patients with carcinoma had lymph node metastasis. CT findings of ground-glass attenuation with solid lesion components were strongly associated with adenocarcinoma (malignancy rate, 93%). The authors concluded that ground-glass attenuation (Fig 11) that persists after several months of observation is an indication of early adenocarcinoma or its precursors. In particular, lesions over 1 cm in diameter or ground-glass attenuation with solid components (semisolid lesion) are significant signs of malignancy.
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Figure 11a. Atypical adenomatous hyperplasia in a 44-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) shows an 8-mm focal nodular area of ground-glass attenuation in the right upper lobe (arrow). The nodule did not change in size over a follow-up period of 12 months. (b) High-power photomicrograph (original magnification, x100; H-E stain) shows atypical epithelial cell proliferation along thickened alveolar septa (arrows), findings that indicate atypical adenomatous hyperplasia.
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Figure 11b. Atypical adenomatous hyperplasia in a 44-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) shows an 8-mm focal nodular area of ground-glass attenuation in the right upper lobe (arrow). The nodule did not change in size over a follow-up period of 12 months. (b) High-power photomicrograph (original magnification, x100; H-E stain) shows atypical epithelial cell proliferation along thickened alveolar septa (arrows), findings that indicate atypical adenomatous hyperplasia.
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Correlation between Tumor Size and Survival in Patients with T1 Non–Small Cell Lung Cancer
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The premise of lung cancer screening is that tumor size is an important determinant of stage distribution and improved survival, and that smaller stage I tumors appear to result in lower mortality rates. However, in a study of the relationship between tumor size and survival in patients with stage IA non–small cell carcinoma, Patz et al (24) found no significant correlation. Their study confirms that all patients with stage IA non–small cell lung cancer should be included in the same TNM classification. Unfortunately, these findings serve as a warning that improved small nodule detection with screening CT may not lead to a significant improvement in lung cancer mortality rates. In a similar study of the relationship between tumor size and stage distribution, Heyneman et al (25) were unable to find a statistically significant correlation between the size of primary lung cancers and disease stage at the time of presentation (Fig 12).
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Figure 12a. T1 squamous cell carcinoma with extrathoracic metastases in a 64-year-old man. (a) Conventional (7-mm collimation) CT scan (lung window) obtained at the level of the liver dome shows a small, 10-mm nodule in the right lower lobe (arrow). Note the areas of ground-glass attenuation and irregular linear areas of hyperattenuation in the surrounding lung, findings that suggest underlying pulmonary fibrosis. (b) CT scan obtained at the level of the right portal vein shows a small metastatic nodule in the liver (arrowhead) and metastatic lymphadenopathy in the left gastric area (arrow).
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Figure 12b. T1 squamous cell carcinoma with extrathoracic metastases in a 64-year-old man. (a) Conventional (7-mm collimation) CT scan (lung window) obtained at the level of the liver dome shows a small, 10-mm nodule in the right lower lobe (arrow). Note the areas of ground-glass attenuation and irregular linear areas of hyperattenuation in the surrounding lung, findings that suggest underlying pulmonary fibrosis. (b) CT scan obtained at the level of the right portal vein shows a small metastatic nodule in the liver (arrowhead) and metastatic lymphadenopathy in the left gastric area (arrow).
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However, Port et al (26) found 5-year disease-specific survival rates of 81.4% (95% confidence interval, 73.3%–89.4%) for patients with tumors less than 2 cm in diameter and 63.4% (95% confidence interval, 49.6%–77.1%) for patients with tumors over 2 cm. They concluded that tumor size in stage IA is an important predictor of survival and that further substaging should be considered. Similar results have been reported by other investigators. Martini et al (27) also found that tumor size affected the survival rate of patients with stage IA tumors: The survival rate for patients with lesions less than 1 cm in diameter was significantly greater than that for patients with tumors between 1 and 3 cm. Padilla et al (28) found a statistically significant survival advantage for patients with tumors less than 2 cm.
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Small T1 Lung Cancer: Evaluation with FDG PET and Dynamic CT
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FDG PET is a noninvasive diagnostic technique that makes use of metabolic differences between benign and malignant tissues. Increased glucose metabolism in malignant tissue may be related to multiple factors, such as the proliferation rate and the number of viable cancer cells (Fig 13). However, FDG PET is not uniformly specific or sensitive, especially when the abnormality is small. Localized BACs (Fig 14) and carcinoid tumors (Fig 15) show less FDG uptake than do other non–small cell lung cancers (29,30). FDG PET yields false-negative results in about 5% of all T1 lung cancers but in only 3% of T1 lung cancers greater than 5 mm in diameter. The long-term survival of patients with a negative PET scan for lung cancer suggests that these tumors behave indolently. Moreover, a management decision to follow up such lesions with conventional imaging to determine interval growth may be justified (30).
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Figure 13a. Adenocarcinoma in a 35-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (mediastinal window) obtained at the level of the left main bronchus shows a 15-mm nodule in the left upper lobe (arrow). (b) FDG PET scan demonstrates a focus of high glucose uptake (arrowhead).
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Figure 13b. Adenocarcinoma in a 35-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (mediastinal window) obtained at the level of the left main bronchus shows a 15-mm nodule in the left upper lobe (arrow). (b) FDG PET scan demonstrates a focus of high glucose uptake (arrowhead).
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Figure 14a. BAC in a 36-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the aortic arch show a 15-mm nodular area of ground-glass attenuation with a lobulated margin in the left upper lobe. Note also the dark bubble within the lesion (arrow). (b) On an FDG PET scan, the lesion demonstrates little glucose uptake (arrowhead) compared with other non-small cell lung cancers (not shown).
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Figure 14b. BAC in a 36-year-old woman. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the aortic arch show a 15-mm nodular area of ground-glass attenuation with a lobulated margin in the left upper lobe. Note also the dark bubble within the lesion (arrow). (b) On an FDG PET scan, the lesion demonstrates little glucose uptake (arrowhead) compared with other non-small cell lung cancers (not shown).
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Figure 15a. Endobronchial carcinoid tumor in a 54-year-old woman. (a) Transaxial contrast material-enhanced CT scan (2.5-mm collimation) obtained at the level of the lingular segmental bronchus shows a round, 21-mm endobronchial nodule in the bronchus intermedius (arrow) with attendant distal obstructive atelectasis in the right lower lobe. The nodule demonstrates strong enhancement (40 HU). Note also the calcific attenuation within the lesion (arrowhead). (b) FDG PET scan demonstrates little glucose uptake at the nodule site (arrow).
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Figure 15b. Endobronchial carcinoid tumor in a 54-year-old woman. (a) Transaxial contrast material-enhanced CT scan (2.5-mm collimation) obtained at the level of the lingular segmental bronchus shows a round, 21-mm endobronchial nodule in the bronchus intermedius (arrow) with attendant distal obstructive atelectasis in the right lower lobe. The nodule demonstrates strong enhancement (40 HU). Note also the calcific attenuation within the lesion (arrowhead). (b) FDG PET scan demonstrates little glucose uptake at the nodule site (arrow).
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Angiogenesis is a complex process that may determine the growth and metastasis of a malignant tumor. Vascular endothelial growth factor (VEGF) is known as a vascular permeability factor and plays a crucial role in tumor angiogenesis. Microvessel density measurements following immunohistochemical staining have been used to measure angiogenic activity. VEGF expression is significantly associated with the microvessel density of non–small cell lung cancers, especially adenocarcinomas of the lung (31,32).
Dynamic CT of pulmonary nodules provides quantitative information regarding blood flow patterns and is a useful diagnostic method for distinguishing between benign and malignant nodules. The peak attenuation value of tumors at dynamic CT reflects intralesional microvessel densities (Figs 16, 17), especially in adenocarcinoma of the lung. Moreover, the peak attenuation value may be an index for VEGF–related tumor angiogenesis (33). In addition, peak attenuation and relative flow at dynamic CT correlate with the standardized uptake value at FDG PET for lung cancer and serve as an index for blood pooling, which may be related to increased glucose metabolism in lung cancer (34).
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Figure 16a. Squamous cell carcinoma with ipsilateral hilar lymph node metastasis in a 75-year-old man. (a) Transaxial CT scan (2.5-mm collimation, mediastinal window) obtained at the level of the left atrium shows an 18-mm nodule in the right lower lobe (bottom arrowhead), along with ipsilateral hilar lymph node enlargement (top arrowhead). (b) Low-power photomicrograph (original magnification, x40; avidin-biotin complex method) obtained after immunostaining for VEGF shows strong cytoplasmic positive staining (arrows). (c) High-power photomicrograph (original magnification, x100; avidin-biotin complex method) obtained after immunostaining for microvessel density with CD 31 shows numerous stromal microvessels (arrows). (d) Serial CT scans obtained at 30-second intervals at similar levels after power injection of 120 mL of 30% iodinated contrast material (injection rate, 3 mL/sec) allow a dynamic enhancement study of the nodule. Peak attenuation of the nodule was 121 HU, net enhancement (peak minus precontrast attenuation) was 68 HU, and time to peak enhancement was 60 seconds (very strong and rapid enhancement). Scale at left is in Hounsfield units.
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Figure 16b. Squamous cell carcinoma with ipsilateral hilar lymph node metastasis in a 75-year-old man. (a) Transaxial CT scan (2.5-mm collimation, mediastinal window) obtained at the level of the left atrium shows an 18-mm nodule in the right lower lobe (bottom arrowhead), along with ipsilateral hilar lymph node enlargement (top arrowhead). (b) Low-power photomicrograph (original magnification, x40; avidin-biotin complex method) obtained after immunostaining for VEGF shows strong cytoplasmic positive staining (arrows). (c) High-power photomicrograph (original magnification, x100; avidin-biotin complex method) obtained after immunostaining for microvessel density with CD 31 shows numerous stromal microvessels (arrows). (d) Serial CT scans obtained at 30-second intervals at similar levels after power injection of 120 mL of 30% iodinated contrast material (injection rate, 3 mL/sec) allow a dynamic enhancement study of the nodule. Peak attenuation of the nodule was 121 HU, net enhancement (peak minus precontrast attenuation) was 68 HU, and time to peak enhancement was 60 seconds (very strong and rapid enhancement). Scale at left is in Hounsfield units.
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Figure 16c. Squamous cell carcinoma with ipsilateral hilar lymph node metastasis in a 75-year-old man. (a) Transaxial CT scan (2.5-mm collimation, mediastinal window) obtained at the level of the left atrium shows an 18-mm nodule in the right lower lobe (bottom arrowhead), along with ipsilateral hilar lymph node enlargement (top arrowhead). (b) Low-power photomicrograph (original magnification, x40; avidin-biotin complex method) obtained after immunostaining for VEGF shows strong cytoplasmic positive staining (arrows). (c) High-power photomicrograph (original magnification, x100; avidin-biotin complex method) obtained after immunostaining for microvessel density with CD 31 shows numerous stromal microvessels (arrows). (d) Serial CT scans obtained at 30-second intervals at similar levels after power injection of 120 mL of 30% iodinated contrast material (injection rate, 3 mL/sec) allow a dynamic enhancement study of the nodule. Peak attenuation of the nodule was 121 HU, net enhancement (peak minus precontrast attenuation) was 68 HU, and time to peak enhancement was 60 seconds (very strong and rapid enhancement). Scale at left is in Hounsfield units.
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Figure 16d. Squamous cell carcinoma with ipsilateral hilar lymph node metastasis in a 75-year-old man. (a) Transaxial CT scan (2.5-mm collimation, mediastinal window) obtained at the level of the left atrium shows an 18-mm nodule in the right lower lobe (bottom arrowhead), along with ipsilateral hilar lymph node enlargement (top arrowhead). (b) Low-power photomicrograph (original magnification, x40; avidin-biotin complex method) obtained after immunostaining for VEGF shows strong cytoplasmic positive staining (arrows). (c) High-power photomicrograph (original magnification, x100; avidin-biotin complex method) obtained after immunostaining for microvessel density with CD 31 shows numerous stromal microvessels (arrows). (d) Serial CT scans obtained at 30-second intervals at similar levels after power injection of 120 mL of 30% iodinated contrast material (injection rate, 3 mL/sec) allow a dynamic enhancement study of the nodule. Peak attenuation of the nodule was 121 HU, net enhancement (peak minus precontrast attenuation) was 68 HU, and time to peak enhancement was 60 seconds (very strong and rapid enhancement). Scale at left is in Hounsfield units.
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Figure 17a. Adenocarcinoma with no mediastinal or hilar lymph node metastasis in a 66-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the right upper lobar bronchus shows a 14-mm nodule with a lobulated margin in the right upper lobe. (b) Low-power photomicrograph (original magnification, x12; avidin-biotin complex method) obtained after immunostaining for VEGF shows weak cytoplasmic positive staining. (c) High-power photomicrograph (original magnification, x100; avidin-biotin complex method) obtained after immunostaining for microvessel density with CD 31 shows few stromal microvessels, a finding that suggests low vascularity. (d) On a dynamic enhancement study consisting of CT scans obtained with the same parameters as those in Figure 16d, the nodule had a peak enhancement of 84 HU, a net enhancement of 38 HU, and a time to peak enhancement of 80 seconds (moderate enhancement). Scale at left is in Hounsfield units. On an FDG PET scan (not shown), the nodule demonstrated less glucose uptake than other non-small cell lung cancers.
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Figure 17b. Adenocarcinoma with no mediastinal or hilar lymph node metastasis in a 66-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the right upper lobar bronchus shows a 14-mm nodule with a lobulated margin in the right upper lobe. (b) Low-power photomicrograph (original magnification, x12; avidin-biotin complex method) obtained after immunostaining for VEGF shows weak cytoplasmic positive staining. (c) High-power photomicrograph (original magnification, x100; avidin-biotin complex method) obtained after immunostaining for microvessel density with CD 31 shows few stromal microvessels, a finding that suggests low vascularity. (d) On a dynamic enhancement study consisting of CT scans obtained with the same parameters as those in Figure 16d, the nodule had a peak enhancement of 84 HU, a net enhancement of 38 HU, and a time to peak enhancement of 80 seconds (moderate enhancement). Scale at left is in Hounsfield units. On an FDG PET scan (not shown), the nodule demonstrated less glucose uptake than other non-small cell lung cancers.
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Figure 17c. Adenocarcinoma with no mediastinal or hilar lymph node metastasis in a 66-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the right upper lobar bronchus shows a 14-mm nodule with a lobulated margin in the right upper lobe. (b) Low-power photomicrograph (original magnification, x12; avidin-biotin complex method) obtained after immunostaining for VEGF shows weak cytoplasmic positive staining. (c) High-power photomicrograph (original magnification, x100; avidin-biotin complex method) obtained after immunostaining for microvessel density with CD 31 shows few stromal microvessels, a finding that suggests low vascularity. (d) On a dynamic enhancement study consisting of CT scans obtained with the same parameters as those in Figure 16d, the nodule had a peak enhancement of 84 HU, a net enhancement of 38 HU, and a time to peak enhancement of 80 seconds (moderate enhancement). Scale at left is in Hounsfield units. On an FDG PET scan (not shown), the nodule demonstrated less glucose uptake than other non-small cell lung cancers.
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Figure 17d. Adenocarcinoma with no mediastinal or hilar lymph node metastasis in a 66-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the right upper lobar bronchus shows a 14-mm nodule with a lobulated margin in the right upper lobe. (b) Low-power photomicrograph (original magnification, x12; avidin-biotin complex method) obtained after immunostaining for VEGF shows weak cytoplasmic positive staining. (c) High-power photomicrograph (original magnification, x100; avidin-biotin complex method) obtained after immunostaining for microvessel density with CD 31 shows few stromal microvessels, a finding that suggests low vascularity. (d) On a dynamic enhancement study consisting of CT scans obtained with the same parameters as those in Figure 16d, the nodule had a peak enhancement of 84 HU, a net enhancement of 38 HU, and a time to peak enhancement of 80 seconds (moderate enhancement). Scale at left is in Hounsfield units. On an FDG PET scan (not shown), the nodule demonstrated less glucose uptake than other non-small cell lung cancers.
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Extrathoracic Metastasis of T1 Lung Cancer
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It has been suggested that, because the prevalence of extrathoracic metastasis is low, routine work-up for metastasis with bone scans, liver scans, or brain imaging is not justified in patients with T1 lung cancer, especially stage I cancer (ie, without nodal metastasis) (35,36). In addition, positive bone or liver scans frequently represent areas of nonmalignant change (eg, inflammation or old fractures) and may unnecessarily delay surgery and lead to invasive and costly work-up (37). Furthermore, the adrenal glands are a prominent site of nonmalignant lesions even in patients with lung cancer (38). Salbeck et al (39) reported that none of 26 patients with stage I lung cancer had extrathoracic metastasis. However, Sider and Horejs (40) found that 24 of 95 patients (25%) with a solitary pulmonary mass without evidence of mediastinal or hilar adenopathy, pleural effusion, or definite chest wall involvement at preoperative CT had extrathoracic metastases. In a study by Kormas et al (41), nine (6%) of 158 patients with non–small cell lung cancer, who were free of neurologic symptoms and were thought to be free of metastases on the basis of results of routine investigations, had brain metastases either at the time of diagnosis (n = 4 [3%]) or at 1-year follow-up (n = 5 [3%]). Ferrigno and Buccheri (42) reported that three (15%) of 20 patients with stage I lung cancer had brain metastases.
Jung et al (8) conducted a study to determine the prevalence of extrathoracic metastasis in T1 non–small cell lung cancer at the time of diagnosis and at 1-year follow-up and to compare the prevalence of metastases in terms of lung cancer cell type (squamous vs nonsquamous), size (
2 cm vs >2 cm), and CT findings in the tumor at the time of diagnosis. Twenty-two (24%) of 90 patients had extrathoracic metastases either at the time of diagnosis (n = 12 [13%]) or at 1-year follow-up (n = 10 [11%]). The most common sites of extrathoracic metastases at 1-year follow-up in decreasing order of frequency were the brain (n = 12 [13%]) (Fig 18), bone (n = 6 [7%]) (Fig 19), and liver (n = 5 [6%]), findings similar to those reported elsewhere (41–43). Tumors with ground-glass attenuation components at CT showed a significantly lower prevalence of metastases (P = .042). Ground-glass attenuation was seen in 23 patients: 11 of 13 patients (85%) with BAC and 12 of 53 patients (23%) with adenocarcinoma other than BAC (P < .001). There was no significant difference in the prevalence of metastases in squamous versus nonsquamous cell carcinoma, in tumors less than 2 cm in diameter (n = 17) versus those over 2 cm (n = 73), or in tumors with versus those without mediastinal nodal metastases (P > .05).
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Figure 18a. T1 adenocarcinoma of the lung with brain metastasis in a 52-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the left upper lobar bronchus shows a 19-mm nodule with a spiculated margin in the left upper lobe. (b) Transaxial gadolinium-enhanced T1-weighted MR image shows metastatic nodules in the right parietal and occipital lobes (arrows).
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Figure 18b. T1 adenocarcinoma of the lung with brain metastasis in a 52-year-old man. (a) Transaxial thin-section (1-mm collimation) CT scan (lung window) obtained at the level of the left upper lobar bronchus shows a 19-mm nodule with a spiculated margin in the left upper lobe. (b) Transaxial gadolinium-enhanced T1-weighted MR image shows metastatic nodules in the right parietal and occipital lobes (arrows).
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Abstract
LEARNING OBJECTIVES FOR TEST...
