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1
Department of Radiology, Samsung Medical Center, Sungkyunkwan University
School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Korea.
2
Department of Radiology, Osaka University Graduate School of Medicine, Osaka
565-0871, Japan.
3
Department of Diagnostic Pathology, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul 135-710, Korea.
4
Department of Radiology, Kurume University School of Medicine, Kurume,
Fukuoka, 830-0011, Japan.
5
Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul 135-710, Korea.
Received February 26, 2001;
accepted after revision June 20, 2001.
Partially supported by a Cancer Center research grant from the Samsung
Medical Center.
Abstract
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MATERIALS AND METHODS. The high-resolution CT findings of small peripheral adenocarcinoma of the lung in 224 patients were analyzed by two independent observers for location, size, marginal characteristics, and extent of ground-glass opacity and necrosis. The pathologic specimens were reviewed by an experienced lung pathologist.
RESULTS. One hundred and thirty-two patients had bronchioloalveolar carcinoma and 92 had adenocarcinoma. The extent of ground-glass opacity was greater in bronchioloalveolar carcinomas (mean ± SD, 29% ± 31.6%) than in other adenocarcinomas (8% ± 13.3%) (p < 0.001). The extent of ground-glass opacity was significantly greater in patients without recurrence (p = 0.020) and those without nodal (p = 0.017) or distant (p = 0.007) metastases than in patients with nodal or distant metastases or in whom the carcinoma had recurred.
CONCLUSION. The extent of ground-glass opacity in a nodule is greater in bronchioloalveolar carcinomas than in other adenocarcinomas. Greater extent of ground-glass opacity also correlates with improved prognosis.
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Localized bronchioloalveolar carcinoma may appear as an area of ground-glass opacity, as a mixed area of ground-glass opacity and more dense consolidation, or as a nodule [7, 8]. Kuriyama et al. [9] suggested that the percentage of ground-glass opacity in a localized bronchioloalveolar carcinoma is larger than that in other adenocarcinomas. Aoki et al. [10] asserted that adenocarcinoma appearing as a localized ground-glass opacity shows slow growth. In addition, Jung et al. [11] suggested that the prevalence of extrathoracic metastasis is significantly lower in a small peripheral lung cancer with ground-glass opacity than without it. The purpose of our study was to correlate the high-resolution CT findings of peripheral small adenocarcinoma of the lung with histopathologic subtypes and to evaluate whether any CT findings can help to predict the prognosis of such tumors.
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3 cm
in the longest diameter) peripheral adenocarcinoma of the lung. All surgical
patients who underwent preoperative contrast-enhanced CT during the same
period were included. None of the patients had an occult adenocarcinoma of
primary unknown site with a single pulmonary metastatic nodule of
adenocarcinoma. In all patients, any possibility of an extrathoracic primary
site of adenocarcinoma in the breast or gastrointestinal tract was excluded,
at either the initial or follow-up examinations, by physical examination or
imaging studies. Of the 224 patients, 131 were women and 93 were men; their ages ranged from 30 to 84 years (mean, 60 years). In all patients, the pulmonary nodule was 3 cm or less in the longest diameter on CT, was completely surrounded by the lung or visceral pleura on surgery, and showed no evidence of invasion more proximal than the lobar bronchus on bronchoscopy. Mediastinal lymph nodes were sampled at all nodal stations and the presence or absence of metastasis was histopathologically confirmed in all patients.
Chest CT scans were available for all patients. The scans were performed with a HiSpeed Advantage Scanner (General Electric Medical Systems, Milwaukee, WI) or an X-Vigor Scanner (Toshiba Medical, Tokyo, Japan). Helical CT scans were obtained from the lung apices to the middle portion of both kidneys with 7-mm collimation and a pitch of 1. This protocol enabled us to assess the entire liver and both adrenal glands. The scans were obtained after IV injection of contrast medium (a total of 100 mL of iopamidol [Iopamiron 300; Bracco, Milan, Italy]) at a rate of 2 mL/sec using a power injector (MCT Plus; Medrad, Pittsburgh, PA). Scanning parameters were 120 kVp, 250 mA, and 1-sec scanning time. Before helical CT, high-resolution CT scans were also obtained through the nodule with a 1-mm collimation and at intervals from 1 to 5 mm. All imaging data were reconstructed with a bone algorithm. The scans were obtained using lung window settings (width, 1500 H; level, 700 H) and mediastinal window settings (width, 400 H; level, 20 H).
The CT scans were analyzed retrospectively by two independent experienced chest radiologists who were unaware of the histopathologic findings. The observers assessed the location, size, marginal characteristics, and presence or absence of ground-glass opacity, calcification, and necrosis in the nodule. The location of the nodule was classified as being in the right upper lobe, right middle lobe, right lower lobe, left upper division, lingular segment, or left lower lobe. The margin of the nodule was classified as being smooth, lobulated, spiculated, or lobulated and spiculated. The size (the longest diameter) of the tumor was measured on the lung window of the axial image on high-resolution CT scans on which the tumor appeared largest among the contiguous scans. Ground-glass opacity in a nodule was presumed to be present when an area of hazy increased attenuation with preservation of bronchial and vascular markings was seen. Tumor necrosis was presumed to be present on mediastinal window images when a focal area of lower attenuation than the remaining large portion of enhancing tumor was seen on enhanced scans. The observers quantified subjectively and visually the percentage of ground-glass opacity and tumor necrosis in a tumor just on the equatorial image. The percentage was measured to the nearest 10% on both the ground-glass opacity and the tumor necrosis. Presence of mediastinal lymph node enlargement (defined as having a short axis > 10 mm in diameter) was also evaluated. A new mediastinal nodal mapping system was used for nodal grouping [12]. Thereafter, final decisions on the findings were reached by averaging the observation or quantification of two independent observers.
All pathologic specimens were reviewed by an experienced lung pathologist. The adenocarcinomas were classified into six histopathologic subtypes based on the classification by Noguchi et al. [4]. The Noguchi classification includes three subtypes of bronchioloalveolar carcinoma and three subtypes of other adenocarcinomas. Noguchi type A corresponds to localized bronchioloalveolar carcinoma; type B, localized bronchioloalveolar carcinoma with foci of collapse of alveolar structures; type C, localized bronchioloalveolar carcinoma with foci of active fibroblast proliferation; type D, poorly differentiated adenocarcinoma; type E, tubular adenocarcinoma; and type F, papillary adenocarcinoma with compressive and destructive growth.
The patients underwent serial evaluation during the follow-up period (range, 6-63 months; mean, 25.4 months) after surgical resection. Chest CT and abdominal sonography were performed at 3, 6, 9, 12, 18, and 24 months after surgery; further follow-up studies were performed annually. Regardless of which therapeutic regimens were given to the patients, CT and sonographic examinations were performed as a prospective follow-up evaluation. Bone scans were performed when the patients complained of bone pain and or tenderness (spontaneous, with palpation or motion), when alkaline phosphatase value was greater than 108 IU/dL, or when hypercalcemia was seen in peripheral blood. MR imaging of the brain was performed when patients complained of headache or any new neurologic symptoms or signs. During the follow-up period, all imaging, clinical, and histopathologic findings of tumor recurrence or lung, brain, bone, liver, adrenal, or lymph node metastasis were recorded. We defined "tumor recurrence" as a condition in which a tumor recurred at the operation site of the ipsilateral lung or pleura. We defined "metastasis" as a condition in which a tumor of the same histopathology as the primary lung lesion appeared in the contralateral lung or in the extrathoracic organs.
Interobserver agreement on CT findings for the size and extent of ground-glass opacity and necrosis was tested with linear regression analysis. Agreement on the presence of other findings was tested with kappa statistics. The CT findings of primary tumors were correlated with histopathologic subtypes (A—F of the classification of Noguchi et al. [4]) and correlated with the frequency of tumor recurrence and mediastinal nodal or extrathoracic metastases. The marginal characteristics and presence of calcification and mediastinal lymph node enlargement on CT were correlated with histopathologic subtypes using the chi-square test or Fisher's exact test including multiple logistic regression. Tumor size and the extent of ground-glass opacity and necrosis were correlated with histopathologic findings by using a parametric analysis of variance test or the Kruskal-Wallis test. Difference in the extent of ground-glass opacity between bronchioloalveolar carcinomas and other adenocarcinomas was tested with an independent samples t test. Tumor size and the extent of ground-glass opacity and necrosis were correlated with tumor recurrence and mediastinal nodal, pulmonary, and extrathoracic metastasis using Student's t test and the Mann-Whitney test. SPSS software was used for statistical analysis [13]. Statistical significance was given when the p value was less than 0.05.
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Tumor size ranged from 8 to 30 mm (mean ± standard deviation, 21.1 ± 5.6 mm). The extent of ground-glass opacity ranged from 0% to 100% (21% ± 28%). The extent of ground-glass opacity was greater in bronchioloalveolar carcinomas (29% ± 31.6%) than in other adenocarcinomas (8% ± 13.3%) (p <0.001). The mean extent (percentage) of ground-glass opacity in types A, B, and C (49% ± 46.3%, 44% ± 33.9%, and 23% ± 26.9%, respectively) was greater than in types D, E, and F (8% ± 14.7%, 8% ± 11.6%, and 14% ± 8.3%) (p < 0.001) (Figs. 1A,1B,2A,2B,3A,3B,4A,4B). The extent of necrosis, which was not significantly different among tumor subtypes, ranged from 0% to 75% (2.3% ± 8.57%) (p = 0.658). Other CT findings, including tumor size (p = 0.071), marginal characteristics (p = 0.079), calcification (p = 0.289), and extent of necrosis (p = 0.658), were not significant in distinguishing the six histologic subtypes (Table 1).
At presentation, mediastinal nodal enlargement was seen on CT in 46 (20%) of 224 patients and was different among histologic subtypes (p = 0.0035) (Table 1). Of these 46 patients, only 15 (five with type C, nine with type D, and one with type E) had true (histopathologically proven) nodal metastases. In 11 patients who had true mediastinal lymph node metastases (four with type C, five with type D, and two with type F), the nodal enlargement was not identified on CT. Therefore, histopathologically proven mediastinal nodal metastases were present in 26 (12%) of 224 patients.
Good agreement was seen between the two observers in estimating the extent of necrosis (p = 0.73), measuring the size of the lesion (p = 0.68), estimating the extent of ground-glass opacity (p = 0.67), classifying marginal characteristics (kappa score, 0.61), and assessing the presence of calcification (kappa score, 0.59) and mediastinal nodal enlargement (kappa score, 0.467) at the time of presentation.
Correlation Between High-Resolution CT Findings and Prognosis
At surgical lymph node dissection, 26 patients (none with types A and B,
nine with type C, 14 with type D, one with type E, and two with type F) had
histopathologically proven mediastinal nodal metastases. The frequency of
mediastinal nodal metastasis at the time of surgery was not significantly
different among the histologic subtypes (p = 0.438), except between
types B and D (p = 0.009). As the extent of ground-glass opacity
increased, mediastinal lymph nodes had negative nodal metastases (p =
0.001).
During the follow-up period, 77 metastases were found in 46 patients: four (15%) of 26 patients with type B tumor, 22 (49%) of 45 with type C tumor, 13 (23%) of 57 with type D tumor, and seven (23%) of 30 with type E tumor. The lung was the most common site of metastasis (n = 31), followed by bone (n = 21), brain (n = 16), liver (n = 4), pleura (n = 2), spleen (n = 1), skin (n = 1), and kidney (n = 1). During the follow-up period, evidence of tumor recurrence was observed in 35 patients: three (12%) of 26 patients with type B tumor, 18 (40%) of 45 with type C tumor, nine (16%) of 57 with type D tumor, and five (17%) of 30 with type E tumor. Evidence of new mediastinal nodal metastases other than those seen on surgery was revealed on follow-up studies in 11 patients: seven patients had type C and four had type D. None with type A or F tumors showed evidence of recurrence or of nodal or extrathoracic metastasis during the follow-up period. For the most part, no significant difference was found between initial CT findings in the patients with recurrence or metastasis and those without (Table 2). The extent of ground-glass opacity was significantly greater in patients without recurrence (p = 0.020) and those without new mediastinal nodal (p = 0.017) or distant (p = 0.007) metastasis than in patients with nodal or distant metastasis or in whom the carcinoma had recurred.
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Higashiyama et al. [5] classified small peripheral adenocarcinomas of the lung on the basis of the degree of bronchioloalveolar carcinoma involvement in surgical specimens. Tumors having a smaller bronchioloalveolar carcinoma component showed significantly more aggressive nodal involvement and more advanced stage than tumors having a less extensive bronchioloalveolar carcinoma component. Similarly, in our study, bronchioloalveolar carcinomas had a lower prevalence of mediastinal lymph node and distal metastases.
Adenocarcinomas of the lung have heterogeneous cellular origin and differentiation. In 1995, Noguchi et al. [4] classified 230 small peripheral adenocarcinomas into six subtypes (types A-F). Type C (n = 141, 61%) was the most common, followed by type D (n = 44, 19%), type A (n = 14, 6%), type B (n = 14, 6%), type E (n = 9, 4%), and type F (n = 8, 3%). In the Noguchi et al. study, types A and B showed no lymph node metastasis and the most favorable prognosis (100% 5-year survival rate). In our study (n = 224), 37 patients (17%) had type A or B, 95 patients (42%) had type C, and the remaining 92 patients (40%) had types D, E, or F. None with types A or B had mediastinal nodal metastasis at surgical mediastinal nodal dissection. However, the absence of mediastinal nodal metastasis in these types was not statistically significant among the six types, probably because other types also had low rates of mediastinal nodal metastasis. Only the 11 patients (5%) with type A tumors had neither mediastinal nodal nor distant metastasis at the time of diagnosis and at follow-up studies.
Aoki et al. [10] evaluated the evolution of peripheral adenocarcinoma of the lung related to tumor doubling time using CT findings and the histologic classification of Noguchi et al. [4]. Tumors of types A and B, in which ground-glass opacity was seen in five (83%) of six patients, had a tumor-doubling time of more than 1 year. Tumors of types D, E, and F, in which solid attenuation is the predominant finding, had a tumor-doubling time of less than 1 year in six (87%) of seven patients. Aoki et al. concluded that two main types of peripheral adenocarcinoma exist. One starts as a localized ground-glass opacity on CT and grows slowly; the other starts as a solid attenuation and exhibits rapid growth. The prevalence of extrathoracic metastasis in small peripheral lung cancer is significantly lower (p = 0.042) in tumors with ground-glass opacity on high-resolution CT [11]. In previous studies [4, 5, 9, 10] and in our study, it is clear that peripheral adenocarcinoma that shows a large proportion of ground-glass opacity in a tumor has a tendency to show a large component of bronchioloalveolar carcinoma (Noguchi types A or B) and to have a favorable prognosis. However, the usefulness of this information is somewhat limited because Noguchi type A and B tumors are a small proportion of all adenocarcinomas. Bronchioloalveolar carcinoma (type A or B) was seen in 28 (12%) of 230 patients in the Noguchi et al. study and in 37 (17%) of 224 patients in our study.
Researchers have different opinions on whether tumor size is a useful basis for predicting a prognosis [14,15,16]. In our study, tumor size was not an important factor in the prognosis. A recent study by Patz et al. [16] of 510 patients, 55% of whom had adenocarcinoma or bronchioloalveolar carcinoma, found no important relationship between tumor size and patient survival.
Our study has limitations. First, we used the Noguchi classification in subtyping the histopathology of adenocarcinomas, but because pathologists are unfamiliar with this classification, it might not be used in clinical practice in North America and Europe. Second, the study is obviously limited by a selection bias. Our study might not represent the true proportion of histopathologic subtypes of adenocarcinoma of the lung because we included surgically proven cases. Our population may have included more patients with tumors of bronchioloalveolar carcinoma because nonsurgical cases, which were excluded in this study, are more common in adenocarcinoma of Noguchi types D and E.
In conclusion, the extent of ground-glass opacity in a nodule is greater in bronchioloalveolar carcinomas than in other adenocarcinomas. Awareness of the extent of ground-glass opacity in peripheral adenocarcinomas helps to predict a prognosis because ground-glass opacity is greater in tumors of a good prognosis.
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