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J Thorac Cardiovasc Surg 2002;124:278-284
© 2002 The American Association for Thoracic Surgery
General Thoracic Surgery (GTS) |
From the Divisions of Thoracic Surgery,a Thoracic Diseases,b Pathology,c and Epidemiology,d Tochigi Cancer Center, Utsunomiya, Tochigi, Japan.
Received for publication July 5, 2001. Revisions requested Aug 14, 2001; revisions received Dec 4, 2001. Accepted for publication Dec 12, 2001. Address for reprints: Haruhisa Matsuguma, MD, Division of Thoracic Surgery, 4-9-13 Yohnan, Utsunomiya, Tochigi 320-0834, Japan (E-mail: hmatsugu{at}tcc.pref.tochigi.jp).
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Abstract |
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 Top Abstract IntroductionPatients and methodsResultsDiscussionReferences |
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2.0 cm) in group IV or V were histologically proved to be bronchioloalveolar carcinoma. Adjusted for smoking status and other characteristics, patients without ground-glass opacity on high-resolution computed tomography had a significantly increased risk of concurrent lymph node metastasis compared with those with ground-glass opacity. |
Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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There have been two concerns regarding operations for patients with clinical stage IA non-small cell lung cancer: one is to what extent the lymph node area should be dissected, and the other is the volume of the lung parenchyma that should be resected. Many surgeons advocate that systematic nodal dissection be routinely used for accurate intrathoracic staging of non-small cell lung cancer, even if a patient's disease is classified as clinical stage IA, because no clinical or pathologic subset of patients with a negligible incidence of N2 disease has been discriminated.
1-3 On the basis of the results of a prospective randomized trial comparing limited resection with lobectomy for the management of patients with T1 N0 disease, limited resection should not be recommended as the treatment of choice for these patients because of the high incidence of local recurrence. 4
Recently, the advent of high-resolution computed tomography (HRCT) has made it possible to investigate tumor shadows in more detail. Some cases of adenocarcinoma showed ground-glass opacity (GGO) at the tumor periphery that reflected the lepidic growth of the tumor cells seen in bronchioloalveolar carcinoma (BAC) microscopically. 5 Moreover, patients with peripheral adenocarcinoma accompanied by a high BAC component showed better prognosis. 6,7 Therefore, we reviewed HRCT scans of patients with cT1 N0 M0 peripheral adenocarcinoma to determine the value of the presence and extent of areas of GGO as a clinicopathologic indicator, especially for the extent of nodal involvement and the presence of intratumoral lymphatic and vascular invasion of tumor cells, which might reflect tumor aggressiveness. 8-10 We also investigated a correlation between the proportion of GGO on HRCT and histologic findings of the tumors and characteristics of patients with GGO.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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5 ng/mL), carbohydrate antigen 19-9 (37 U/mL), and sialyl Lewis(x) (38 U/mL), were analyzed preoperatively. Fifty-seven patients were women, and the mean age was 61.6 years (range, 40-80 years). For cigarette smoking, patients who never smoked and those who ever smoked numbered 53 and 43, respectively. Surgical treatment was performed as follows: pneumonectomy in 1 patient, lobectomy in 79 patients, segmentectomy in 11 patients, and partial resection in 5 patients. A patient with pleural disseminated disease underwent an extrapleural pneumonectomy. Systematic lymph node dissection was performed in 77 patients, whereas sampling or no resection of mediastinal lymph nodes was done in 19 patients in whom no node metastasis was clinically suspected. Of those 19 patients, 9 underwent intentionally limited operations without systematic nodal dissection because of the tumor's less aggressive appearance, and consequently, none of these tumors have recurred. The remaining 10 patients did not undergo complete nodal staging because of the impaired condition.
The tumors were classified into 3 histologic subtypes according to the classification of the World Health Organization (WHO), with some modification: BAC, BAC with small invasive foci (5 mm), and other subtypes, including acinar, papillary, solid carcinoma with mucin, and adenocarcinoma with mixed subtype. 11 BAC was defined as an adenocarcinoma with a pure bronchioloalveolar growth pattern and no evidence of stromal, vascular, or pleural invasion. Stromal invasion is suggested by tumor cells arranged in acinic, papillotubular structures or solid tumor cells in a fibroblastic stroma, often accompanied by collagenization. BACs with invasive foci 5 mm in diameter were classified as BAC with small invasive foci. If invasive foci were larger than 5 mm, the tumors were classified into other subtypes. Pathologic stage was classified according to the International System for Staging Lung Cancer criteria. 12
CT scanning was performed on a TCT 900S (Toshiba Medical Systems, Tokyo, Japan) or X-Vigor (Toshiba Medical Systems) scanner. HRCT scans were performed over a range of 50 mm, covering the entire lesion. The scanning parameters were a tube voltage of 120 kV, a tube current of 250 mA, 2-mm collimation, table speed of 2 mm/s, 1 rotation per second, pitch of 1, and a reconstruction interval of 2 mm by using a bone algorithm. The field of view was focused at about 20 cm in 60 patients. The images were photographed with a window level of -650 HU and a window width of 1800 HU. The analysis was made on hard-copy films. GGO was defined as a hazy increase in lung attenuation without obscuring the underlying vascular marking. In this study we defined GGO as reflection of a tumor cell lepidic growth pattern seen in BAC. Therefore, the area we thought to be secondary inflammation was not regarded as GGO. Three observers who were unaware of the pathologic staging and prognosis reviewed each HRCT scan of 96 peripheral adenocarcinomas and quantitated the percentage of lesions occupied by areas of GGO on all slices on which the tumor appeared visually. Then, according to the proportion of the GGO area, we classified the tumors into 5 groups: group I, 0%; group II, 1% to 25%; group III, 26% to 50% (Figure 1); group IV, 51% to 75%; and group V, 76% to 100% (Figure 2). Discrepancies in interpretation between observers were resolved by consensus. The reasons we estimated the proportion of GGO on all slices on which a tumor existed instead of on one level of the tumor equator were as follows. First, we thought that it was easier to classify each tumor into the 5 categories by considering more information than from one slice. Second, because the distribution of GGO was not uniform around the solid portion, all slices were superior to one slice for expressing the tumor characteristics.
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We investigated the association of the proportion of GGO area with maximal tumor size, lymph node metastasis, lymphatic invasion, vascular invasion, and the histologic subtype according to the new WHO classification. We also examined the characteristics of patients having a greater proportion of GGO area and the GGO classification in relation to the prediction of lymph node metastasis. The Mantel-Haenszel 
2 test was performed to examine correlations between the proportion of GGO and clinicopathologic factors. We also examined a relation of lymph node metastasis with selected characteristics. To further clarify the independent factors in association with lymph node metastasis, we performed multiple logistic regression analysis with the SAS software package (Statistical Analysis Systems, Inc, Cary, NC).
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Results |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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During the follow-up period, 23 patients had tumor recurrences. Of the 16 patients with locoregional relapse, 4 with pathologic N2 disease had lymph node recurrences beyond the dissected area of the mediastinum. No nodal recurrence was observed in patients with pathologic N0 disease.
Among the 96 tumors, 15 (15.6%) were classified as group V, 11 (11.5%) as group IV, 9 (9.3%) as group III, 22 (22.9%) as group II, and 39 (40.6%) as group I according to the proportion of GGO area. The distribution of pathologic N status and vessel invasion by proportion of GGO and maximal tumor diameter are shown in Table 1. The numbers of node-positive cases were 0 (0%) for groups V and IV, 2 (22.2%) for group III, 4 (18.2%) for group II, and 12 (30.8%) for group I, respectively. Among the patients with group V and IV tumors, no resected tumors showed lymphatic or vascular invasion, with the exception of one patient with a relatively large tumor (
2 cm) with vascular invasion. The patients in groups I, II, and III had several occurrences of lymph node metastasis and lymphatic and vascular invasion. According to the tumor size, only 5 (5.2%) tumors measuring 1 cm were accompanied with neither lymph node metastasis nor vessel invasion. On the other hand, lymph node metastasis was more often observed in patients with tumors larger than 1 cm in diameter. Except for the smallest tumors with a diameter 1 cm, the proportion of each GGO group was not different among the other 3 groups (P = .80).
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2 cm in diameter, all tumors in group IV and V patients were BACs. All patients classified as having BAC or BAC with minimal invasive foci are alive without recurrence.
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). A multiple logistic regression analysis revealed that absence of GGO area on CT was an independent risk factor for lymph node metastasis (odds ratio, 4.87; 95% confidence interval, 1.51-15.77; Table 3). In 77 patients with complete nodal staging, the analysis also showed basically the same results (odds ratio, 4.24; 95% confidence interval, 1.17-15.38).
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Including thoracoscopic surgery, limited surgical resection might have some advantages over a standard operation for selected patients. 13 However, patient selection was difficult because several studies revealed that mediastinal lymph node metastasis was common in patients with small peripheral adenocarcinomas. 1-2 Therefore, if the tumor is larger than 1 cm in diameter, lobectomy with systematic lymph node dissection is now recommended as the standard treatment, with the aim of accurate staging and possible improvement of prognosis. On the other hand, patients with a tumor 1 cm rarely have lymph node metastasis. 2 Yoshida and colleagues 3 found only 13 (1.2%) such cases among 1051 patients with lung cancer who underwent surgical resection. The proportion of these small tumors was only about 5% of clinical T1 N0 M0 cases and 0.8% of all surgically treated cases in our study. Therefore, a more reliable and useful indicator for predicting the possibility of lymph node metastasis in this clinical stage is desirable.
Shimosato and associates 14 noted a poorer prognosis in patients with an increased amount of collagenization or hyalinization in the central fibrotic focus in the tumor. As results of analyses of various prognostic factors in resected cases, it has been shown that the size of the central fibrotic area relates to outcome in patients with adenocarcinoma. 6,15 From a different point of view, Higashiyama and coworkers 7 suggested that the degree of BAC involvement might reflect clinicopathologic and prognostic characteristics. In 1996, Jang and colleagues 16 reported that GGO in BAC on thin-section CT was an early sign of BAC. In addition, the extent of GGO might be well correlated with that of bronchioloalveolar growth of lung adenocarcinoma. 5 Therefore, we classified the tumors according to the proportion of GGO in the tumor shadow on HRCT and confirmed that the patients with a higher proportion of GGO had a tendency for their tumors not to metastasize to the lymph nodes. There were 26 (27%) patients with a higher proportion of GGO (51%-100%), and they did not have lymph node metastasis or evidence of tumor recurrence. We believe that the proportion of GGO was a powerful indicator of lymph node metastasis and a powerful indicator for identifying patients suitable for limited resection.
The Lung Cancer Study Group reported the results of a prospective randomized trial comparing limited resection with lobectomy for the management of patients with T1 N0. 4 A total of 247 patients were eligible for analysis. The limited resection group had a significantly higher local recurrence rate than the lobectomy group. The Lung Cancer Study Group therefore concluded that limited resection should not be recommended as the resection of choice for patients with T1 N0 disease. Ichinose and associates 17 reported that 44% of tumors showed lymphatic invasion in patients with resected non-small cell lung cancers classified as pathologic stage I located on the periphery of the lung. They speculated that this was the main reason that the limited resection group had a higher local recurrence rate in the Lung Cancer Study Group trial. Others reported that lymphatic vessel invasion was correlated with poorer prognosis in patients with non-small cell lung cancer. 9 This suggested that intratumoral lymphatic invasion reflected tumor aggressiveness. Therefore, if we could select patients with tumors without lymphatic invasion, limited resection might be successfully performed without local recurrence. In our series tumors with a proportion of GGO greater than 50% did not show lymphatic invasion. According to the new WHO classification, BAC was defined as not showing invasive foci including vessel invasion. 11 In this study all the tumors that measured 2 cm in groups IV and V were histologically diagnosed as BAC. Tumors larger than 2 cm in diameter classified in group IV and V were found in 7 patients with BAC and 8 patients with BAC plus invasive foci. However, those 15 patients had neither lymphatic invasion nor nodal metastasis and are alive without recurrence. Therefore, we consider that patients with T1 tumors categorized to groups IV and V are candidates for limited resection. Meanwhile, it should be argued whether intraoperative pathologic examination would be useful to indicate a limited resection for a favorable BAC. Yamato and colleagues 18 proposed limited resection for BAC on the basis of the intraoperative pathologic examination. They converted wedge resection into lobectomy if active fibroblastic foci or invasive signs were presented on the frozen section. However, it is still unclear whether BACs with small invasive foci are not candidates for limited resection. Further studies will be necessary to clarify this issue.
Recently, positron emission tomography (PET) was introduced for mediastinal staging. It was shown to have a high percentage of negative predictive value in patients with stage I disease. 19 PET might provide more accurate lymph node staging than CT. However, it might not provide information on lower tumor invasiveness that could be obtained by GGO classification. Higashi and associates 20 reported that Fluorine-18-FDG PET imaging results were negative in 4 of 7 patients with BAC and 1 of 23 patients without BAC. 20 Although these results showed that PET could be used to diagnose some cases of BAC, we consider that PET is more expensive and not as accessible as CT. We believe that GGO classification on HRCT could be more useful than PET for planning limited operations.
In conclusion, by using this novel classification based on semiquantitative analysis of the GGO area in the tumor shadow on HRCT, we identified patients with less invasive tumors. Thus, it could be a useful tool for planning therapeutic strategies, particularly for limited surgical intervention.
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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